Non-suppressive regulatory T cell subset expansion in pulmonary arterial hypertension

Regulatory T cells (Tregs) have been reported to play a pivotal role in the vascular remodeling of pulmonary arterial hypertension (PAH). Recent studies have revealed that Tregs are heterogeneous and can be characterized by three phenotypically and functionally different subsets. In this study, we investigated the roles of Treg subsets in the pathogenesis of PAH in eight patients with PAH and 14 healthy controls. Tregs and their subsets in peripheral blood samples were analyzed by flow cytometry. Treg subsets were defined as CD4⁺CD45RA⁺FoxP3^low resting Tregs (rTregs), CD4⁺CD45RA^?FoxP3^high activated Tregs (aTregs), and CD4⁺CD45RA^?FoxP3^low non-suppressive Tregs (non-Tregs). The proportion of Tregs among CD4⁺ T cells was significantly higher in PAH patients than in controls (6.54 ± 1.10 vs. 3.81 ± 0.28 %, p < 0.05). Of the three subsets, the proportion of non-Tregs was significantly elevated in PAH patients compared with controls (4.06 ± 0.40 vs. 2.79 ± 0.14 %, p < 0.01), whereas those of rTregs and aTregs were not different between the two groups. Moreover, the expression levels of cytotoxic T lymphocyte antigen 4, a functional cell surface molecule, in aTregs (p < 0.05) and non-Tregs (p < 0.05) were significantly higher in PAH patients compared with controls. These results suggested the non-Treg subset was expanded and functionally activated in peripheral lymphocytes obtained from IPAH patients. We hypothesize that immunoreactions involving the specific activation of the non-Treg subset might play a role in the vascular remodeling of PAH.     

A case of pulmonary hypertrophic osteoarthropathy associated with primary lung cancer in a young adult successfully treated with gefitinib]

The patient was a 39-year-old woman admitted with complaints of fever, clubbed fingers and arthralgia. A chest roentgenogram and chest computed tomographic scan revealed a mass in the left lower lobe. Transbronchial lung biopsy was performed, and a diagnosis of moderately differentiated adenocarcinoma was made. Physical examination confirmed finger clubbing in both hands. Bone scintigram showed marked accumulation of 99mTc-MDP in the long bones, bones of the elbows, and patellae. These findings yielded a diagnosis of pulmonary hypertrophic osteoarthropathy associated with primary lung cancer in young adult. The patient had fever and disturbance of gait of arthralgia on admission, and was treated with an oral non-steroidal anti-inflammation drug (NSAID). Advanced non small cell lung cancer (clinical stage T2 N3 M1, Stage IV) was then diagnosed. Gefitinib was administered after EGFR mutation was found in the tumor specimen. NSAID therapy alleviated the fever and arthralgia. After starting gefitinib and discontinuing the NSAID, She had kept a remission of rational symptom with cytoreductive effect. The abnormal findings of bone scintigrams subsequently disappeared and the patient's serum ICTP dropped.     

Early Detection of High-grade Biliary Intraepithelial Neoplasia (BilIN-3) in the Cystic Duct Visualized by SpyGlass DS Cholangioscopy

An 84-year-old man was admitted with epigastralgia. Computed tomography showed contrast-enhanced wall thickness in the cystic duct. An endoscopic examination revealed short irregular stricture in the cystic duct, and per-oral cholangioscopy revealed a reddish papillary tumor at the stricture site. Surgical resection revealed high-grade biliary intraepithelial neoplasia (BilIN) at the stricture site of the cystic duct. To our knowledge, this is the first case of a solitary high-grade BilIN epithelium in the cystic duct detected by per-oral cholangioscopy.     

Clinical effects of long-term administration of pimobendan in patients with moderate congestive heart failure

Summary The long-term efficacy of the positive inotropic and vasodilator drug, pimobendan, was assessed in 21 patients suffering from symptomatic heart failure. Patients were randomized to 16 weeks of double-blind therapy with either 2.5 or 5.0mg/day of pimobendan (n = 10), or a matching placebo (n = 11). Patients were blinded on the study drug if their clinical status had not substantially worsened during the study. Of the placebo-treated patients, 5 patients were withdrawn from the study because of a deterioration of their heart failure, while none of the active treated group was withdrawn because of increased symptoms. Quality of life, assessed by the specific activity scale derived from the metabolic costs of individual physical activity, was 3.45 ± 0.90 (SD) mets in the baseline state and increased significantly after week 16, averaging 5.07 ± 1.40 and 4.67 ± 1.47 mets at weeks 16 and 24, respectively. In the placebo-treated group, the specific activity scale was 3.27 ± 1.21 mets at the baseline and remained unchanged throughout the study period. Patients treated with pimobendan were able to significantly increase their exercise duration. The accompanying increase in peak oxygen uptake was statistically insignificant, due to the limited number of patients enrolled in the study. These results suggest that in contrast to the recent pessimistic view of the long-term efficacy of cardiotonic drugs, pimobendan is beneficial in treating patients with congestive heart failure and may favorably modify their prognosis. Further largescale evaluation of this agent is warranted.     

Relationship between interleukin-1β gene expression in epicardial adipose tissue and coronary atherosclerosis based on computed tomographic analysis

BackgroundAnti-inflammatory therapy targeting interleukin (IL)-1β reduced cardiovascular events in a randomized trial. We evaluated the relationship between IL-1β mRNA expression in epicardial adipose tissue (EAT) and clinically-assessed coronary atherosclerosis on computed tomography (CT).MethodsWe studied 45 patients before cardiac surgery (coronary artery bypass grafting [CABG], n ?= ?18; non-CABG, n ?= ?27). EAT volume, the coronary calcium score (CCS), and the presence of non- and/or partially-calcified coronary plaques (NCPs) and high-risk coronary plaques (HRPs; minimum CT density <30 Hounsfield units and vascular remodeling index >1.1) on CT angiography were assessed. EAT samples were obtained during cardiac surgery. IL-1β mRNA expression in EAT was measured using quantitative real-time PCR and normalized to that of β-actin in each patient.ResultsThere was no difference in IL-1β mRNA levels between patients who were scheduled for CABG and non-CABG surgery or among subgroups based on the CCS. However, patients with NCPs (median [interquartile range], 4.1[2.0-11.6]E-4 versus 1.8[0.6-4.5]E-4, p ?= ?0.024) and HRP (7.6[3.0-20.4]E-4 versus 1.9[0.7-4.3]E-4, p ?= ?0.0023) had higher IL-1β mRNA levels than those without these plaques. On multivariate analysis adjusted for age, sex, coronary risk factors, statin therapy, CCS, and EAT volume, the presence of HRPs was significantly correlated with elevated IL-1β mRNA levels in EAT (β ?= ?0.39, p ?= ?0.047).ConclusionOur data suggest a contribution of EAT to coronary atherosclerosis through molecular behavior, such as IL-1β gene expression, which may be a new therapeutic target.