Heart failure with silent coronary artery spasm exhibiting microscopic focal myocardial necrosis and amyloid-deposition

We report a 67-year-old Japanese man who presented with worsening heart failure with asymptomatically transient ischemic ST-segment depression. Left ventriculography showed diffuse hypokinesis; asymptomatic coronary artery spasm was evoked by the acetylcholine provocation test. Endomyocardial biopsy exhibited hypertrophic cardiomyocytes and scattered microscopic focal myocardial necrosis with amyloid-deposition. Transient ST-segment depression improved after treatment with a calcium antagonist, but cardiac contraction was still impaired. We hypothesize that asymptomatic coronary spasm may cause irreversible cardiac damage and heart failure with amyloid-deposition; the presence or absence of coronary spasm in heart failure patients should be clarified in order to determine therapeutic strategy.     

Safety,tolerability, and feasibility of antifungal prophylaxis with micafungin at 2 mg/kg daily in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation

Introduction

Micafungin (MCFG) is used for the prophylaxis of invasive fungal disease (IFD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, the safety, efficacy, or optimal dosage/blood levels as prophylaxis is uncertain in pediatric HSCT-patients.

Methods

We prophylactically administered MCFG at 2 mg/kg once daily to 38 children and adolescents undergoing allogeneic HSCT.

Results

During MCFG prophylaxis, infusion reactions or adverse events (grades 2–5) related to MCFG use were not found in all the patients. Thus, MCFG prophylaxis was not discontinued and other antifungal agents were not added except for 2 patients in whom probable or possible IFDs developed (completion rate, 94.7 %). To elucidate the influence of HSCT-related complications/drugs on blood concentration of MCFG, we determined the plasma trough and peak levels in 13 and 10 among 38 patients, respectively. The mean trough and peak levels were 3.04 ± 1.21 μg/mL (569 samples) and 9.63 ± 3.62 μg/mL (44 samples), respectively. The peak levels were moderately correlated to the trough levels (R ² = 0.466). In a patient, the trough level of MCFG transiently increased up to 10.21 μg/mL during hepatic dysfunction due to acute graft-versus-host disease. The MCFG trough levels strongly correlated with T-Bil value (R ² = 0.894). There was no relationship between the trough levels of MCFG and the circulating concentrations of tacrolimus (R ² = 0.040). Additionally, MCFG levels were not influenced by treatment with cyclophosphamide or corticosteroids.

Conclusions

Prophylaxis with MCFG at 2 mg/kg once daily may be safe, tolerable, and feasible in pediatric HSCT-patients.     

Risk factors for diabetes mellitus and impaired glucose tolerance following allogeneic hematopoietic stem cell transplantation in pediatric patients with hematological malignancies

Long-term surviving recipients of allogeneic hematopoietic stem cell transplantation (HSCT) often suffer from diabetes mellitus (DM). We sought to identify risk factors for the development of post-transplant DM and impaired glucose tolerance (IGT) in pediatric HSCT patients. Glucose tolerance statuses were evaluated in 22 patients aged 6.3–21.8 years who had received allogeneic HSCT between the ages of 0.8–13.5 years. Five patients were diagnosed as having type 2 DM, and treated with insulin or oral hypoglycemic agents. Five patients were included in the IGT group, and the remaining 12 children were in the normal glucose tolerance (NGT) group. The cumulative incidence of DM plus IGT was 11.6 % at 5 years and 69.3 % at 10 years. None of the patients were obese/overweight and none had a family history of DM. There were no significant differences in serum levels of leptin and adiponectin between the DM + IGT and the NGT groups. An average preprandial glucose levels in the DM + IGT group were significantly higher than those in the NGT group from preparative conditioning to 60 days after HSCT. In multivariate analysis, an age of ≥6 years at the time of HSCT was significantly associated with the development of DM + IGT. Additionally, careful follow-up is necessary, even for NGT patients.     

Dynamics of genomic 5‐hydroxymethylcytosine during mouse oocyte growth

Recent studies of the demethylation process in murine zygotes have shown that 5‐methylcytosine (5mC) is first converted into 5‐hydroxymethylcytosine (5hmC) or further‐oxidized cytosines in the paternal genome by the maternal ten–eleven translocation 3 (TET3) enzyme. This process is crucial for normal embryogenesis, and our aim was to elucidate the effect of Tet3 on the maternal genome during female germ‐line development. Immunofluorescence analysis showed that 5hmC was clearly present in fully grown oocytes but not in nongrowing and early growth‐stage oocytes. The 5hmC in the maternal genome was clearly detectable in DNA methyltransferase 3‐like enzyme (Dnmt3L)‐null oocytes and their fertilized zygotes, although Dnmt3L is essential for DNA methylation in oocytes. An analysis using an enzyme digestion‐based method showed that 5hmC was present in LTR retrotransposons from the late growth period of oocytes. Quantitative RT‐PCR analysis showed that Tet3 expression was enhanced during oocyte growth and exhibited an approximately 40‐fold increase between nongrowing and fully grown oocytes. Our results show that 5hmC is generated since the oocyte growth stage, accompanied by up‐regulation of Tet3; 5hmC is located mainly in LTR retrotransposons, indicating that 5hmC generated in growth‐stage oocytes is responsible for genomewide demethylation after fertilization.     

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.     

Novel non‐alcoholic steatohepatitis model with histopathological and insulin‐resistant features

Although several non‐alcoholic steatohepatitis (NASH) models have been reported to date, few of these models fully reflect the histopathology and pathophysiology of human NASH. The aim of this study was to establish a novel NASH model by feeding a high‐fat (HF) diet and administering both carbon tetrachloride (CCl₄) and the Liver X receptor agonist T0901317. Male C57BL/6J mice were divided into four groups (each n = 5): HF, HF + CCl₄, HF + T0901317, and the novel NASH model (HF + CCl₄ + T0901317). CCl₄ (0.1 mL/kg) and T0901317 (2.5 mg/kg) were intraperitoneally administered four times and five times, respectively. The livers of the novel NASH model group presented a whitish colour. The serum levels of TNF‐α and IL‐6 were significantly increased in the novel NASH model group, and mice in this group exhibited histopathological features and insulin resistance reflective of NASH, i.e., macrovesicular hepatic steatosis, ballooning hepatocytes, Mallory‐Denk bodies, lobular inflammation and fibrosis. The novel NASH model group presented significantly upregulated expression levels of mRNAs related to lipogenesis, oxidative stress, fibrosis and steatosis and significantly downregulated expression levels of mRNAs related to triglyceride export. We successfully established a novel experimental NASH model that exhibits similar histopathology and pathophysiology to human NASH.     

Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression

Background  

Cimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, however the mechanism of action underlying this effect is unknown. Adenoid cystic carcinoma is well known as a malignant salivary gland tumor which preferentially invades neural tissues. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express neural cell adhesion molecule (NCAM), that HSG cell proliferation may be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. We further demonstrated that cimetidine inhibited NCAM expression and induced apoptosis in HSG cells. Here, we investigated the effects of cimetidine on growth and perineural/neural invasion of salivary gland tumor cells.