Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest

ObjectiveRemote ischemic preconditioning is known to elicit production of a blood-borne cardioprotective factor that is infarct sparing in models of ischemia–reperfusion injury and myocardial damage reducing after cardiopulmonary bypass in human subjects. The mechanism of protection remains incompletely understood. In this study, we examined effects on mitochondrial structure and function in a noninfarct model of cardioplegic arrest.MethodsExplanted neonatal rabbit hearts were mounted in a Langendorff preparation and perfused with dialysate of blood taken from sham-treated or remotely preconditioned rabbits. Each heart was subsequently subjected to 1-hour cardioplegic arrest and 30-minute reperfusion periods, during which hemodynamic responses were measured. Mitochondria were isolated for structural and functional measurements.ResultsRelative to hearts with sham-treated dialysate, myocardial performance (systolic pressure, maximum positive and negative first derivatives of left ventricular pressure, and left ventricular end-diastolic pressure) was better preserved with dialysate from preconditioned rabbits. Similarly, mitochondria isolated from hearts with dialysate from preconditioned rabbits showed preserved respiration at complex I and IV in the electron transport chain (P < .01 and P < .05, respectively). Mitochondrial outer membrane integrity was also preserved, with diminished sensitivity of mitochondrial respiration to exogenous cytochrome c (P < .01) and less cytosolic diffusion of cytochrome c (P < .01). Mitochondrial resistance to calcium-mediated mitochondrial permeability transition pore opening was not affected.ConclusionThe cardioprotective factor in plasma dialysate after remote preconditioning preserves mitochondrial structure and function in a noninfarct cardioplegic arrest model. This protection is associated with preservation of global myocardial performance

Association Between Visceral Adipose Tissue Area and Coronary Plaque Morphology Assessed by CT Angiography

ObjectivesWe sought to investigate the association between visceral adipose tissue (VAT) with the presence, extent, and characteristics of noncalcified coronary plaques (NCPs) using 64-slice computed tomography angiography (CTA).BackgroundAlthough visceral adiposity is associated with cardiovascular events, its association with NCP burden and vulnerability is not well known.MethodsThe study population consisted of 427 patients (age 67 ± 11 years; 63% men) with proven or suspected coronary artery disease who underwent 64-slice CTA. We assessed the presence and number of NCPs for each patient. The extent of NCP was tested for the difference between high (≥2) and low (≤1) counts. We further evaluated the vulnerable characteristics of NCPs with positive remodeling (remodeling index >1.05), low CT density (≤38 HU), and the presence of adjacent spotty calcium. Plain abdominal scans were also performed to measure the VAT and subcutaneous adipose tissue area.ResultsA total of 260 (61%) patients had identifiable NCPs. Multivariate analyses revealed that increased VAT area (per 1 standard deviation, 58 cm2) was significantly associated with both the presence (odds ratio [OR]: 1.68; 95% confidence interval [CI]: 1.28 to 2.22) and extent (OR: 1.31; 95% CI: 1.03 to 1.68) of NCP. Other body composition measures, including subcutaneous adipose tissue area, body mass index, and waist circumference were not significantly associated with either presence or extent of NCP. Increased VAT area was also independently associated with the presence of NCP with positive remodeling (OR: 1.71; 95% CI: 1.18 to 2.53), low CT density (OR: 1.69; 95% CI: 1.17 to 2.47), and adjacent spotty calcium (OR: 1.52; 95% CI: 1.03 to 2.27).ConclusionsIncreased VAT area was significantly associated with NCP burden and vulnerable characteristics identified by CTA. Our findings may explain the excessive cardiovascular risk in patients with visceral adiposity, and support the potential role of CTA to improve risk stratification in such patients

Outbreaks of Pneumocystis Pneumonia in 2 Renal Transplant Centers Linked to a Single Strain of Pneumocystis: Implications for Transmission and Virulence

By restriction fragment length polymorphism analysis, 2 outbreaks of Pneumocystis pneumonia in renal transplant patients in Europe were shown to be caused by the same strain of Pneumocystis; another outbreak in Japan was caused by a different strai

Common Variants in the COL4A4 Gene Confer Susceptibility to Lattice Degeneration of the Retina

Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. The etiology of this degeneration is still uncertain, but it is likely that both genetic and environmental factors play important roles in its development. To identify genetic susceptibility regions for lattice degeneration of the retina, we performed a genome-wide association study (GWAS) using a dense panel of 23,465 microsatellite markers covering the entire human genome. This GWAS in a Japanese cohort (294 patients with lattice degeneration and 294 controls) led to the identification of one microsatellite locus, D2S0276i, in the collagen type IV alpha 4 (COL4A4) gene on chromosome 2q36.3. To validate the significance of this observation, we evaluated the D2S0276i region in the GWAS cohort and in an independent Japanese cohort (280 patients and 314 controls) using D2S0276i and 47 single nucleotide polymorphisms covering the region. The strong associations were observed in D2S0276i and rs7558081 in the COL4A4 gene (Pc = 5.8×10−6, OR = 0.63 and Pc = 1.0×10−5, OR = 0.69 in a total of 574 patients and 608 controls, respectively). Our findings suggest that variants in the COL4A4 gene may contribute to the development of lattice degeneration of the retina

Exogenous Cytokine-Free Differentiation of Human Pluripotent Stem Cells into Classical Brown Adipocytes

We previously established a method for a directed differentiation of human pluripotent stem cells into classical brown adipocytes (BA) by forming aggregates via massive floating culture in the presence of a specific cytokine cocktail. However, use of recombinant cytokines requires significant cost. Moreover, an enforced differentiation by exogenously added cytokines may amend skewed differentiation propensity of patient&#8217;s pluripotent stem cells, providing unsatisfactory disease models. Therefore, an exogenous cytokine-free method, where cytokines required for differentiation are provided in an auto/paracrine manner mimicking natural developmental process, is beneficial. Here we show that, if human pluripotent stem cells are cultured as size-controlled spheroids (100&#8211;120 &#181;m radius, 2000&#8211;2500 cells/spheroid) in a mutually segregated manner with half-change of the medium every other day, they differentiate into classical BA via an authentic MYF5-positive myoblast route in the absence of exogenous cytokines. Differentiated BA exerted thermogenic activity in transplanted mice in response to beta-adrenergic receptor agonist stimuli. The cytokine-free differentiation method has further advantages in exploring BATokines, BA-derived physiologically active substances. Indeed, we have found that BA produces an unknown small (&lt;1000 Da), highly hydrophilic molecule that augments insulin secretion from pancreatic beta cells. Our upgraded technique will contribute to an advancement of stem cell study for diverse purposes

Coronary Calcium Score as a Predictor for Coronary Artery Disease and Cardiac Events in Japanese High-Risk Patients

Background: Although the coronary artery calcium (CAC) score as measured with computed tomography (CT) is associated with cardiovascular mortality and morbidity in Western countries, little is known in Asian populations. Methods and Results: Three hundred and seventeen Japanese patients (205 men and 112 women) were followed in the study and they underwent both coronary angiography and CT for CAC measurements. The frequencies of angiographic coronary artery disease (CAD) were 5%, 36%, 76%, 80%, and 94% (P1,000 (n=49), respectively. In the average of 6.0 (range, 1-10) years follow-up period, 34 patients died including 13 from reasons of cardiac disease. In a Cox proportional hazard model after adjustment for age and sex, traditional coronary risk factors, previous myocardial infarction, and the need for revascularization, the hazard ratio for cardiac mortality in patients with a CAC score >1,000 was 2.98 (95% confidence interval: 1.15-9.40) compared with those with a CAC score=0-100. Conclusions: The CAC score has a predictive value for angiographical CAD and long-term mortality from cardiac disease in Japanese high-risk patients who undergo coronary angiography. (Circ J 2011; 75: 2424-2431

Clinical trial of photodynamic therapy for peripheral-type lung cancers using a new laser device in a pilot study

Introduction/AimPhotodynamic therapy (PDT) involves the use of a tumor-specific photosensitizer and laser irradiation, and is one of the treatment options recommended for early centrally located lung cancers, but not yet for peripheral-type lung cancers. We developed a new laser probe, the composite-type optical fiberscope (COF), which allows accurate laser irradiation of a cancer lesion with simultaneous visualization of the lesion. In this study, we attempted a new endobronchial PDT technique using the new laser probe, and evaluated the effectiveness and feasibility of this novel PDT technique for peripheral lung cancers.MethodsThis phase I study was conducted in 7 patients with peripheral lung cancers (primary tumor ≤20 mm in diameter). We performed endobronchial PDT for these patients using the new laser probe and talaporfin sodium as the photosensitizer.ResultsWe performed PDT for 3 patients with peripheral lung cancer using a laser dose of 50 J/cm2 at 120 mW, and confirmed the feasibility of using this dose. Then, we escalated the laser dose to 100 J/cm2 in 4 additional patients. A total of 7 patients met our inclusion criteria. Evaluation at 2 weeks and 3 months after the PDT revealed no complication such as pneumonia or pneumothorax. At the evaluation conducted 6 months later, we found CR in 3 cases and SD in the remaining 4 cases.ConclusionPDT was found to be a feasible and non-invasive treatment modality for early peripheral-type lung cancer. In the future, PDT could become a standard treatment option for peripheral-type lung cancer

Association Between Plasma High-Molecular-Weight Adiponectin and Coronary Plaque Characteristics Assessed by Computed Tomography Angiography in Conditions of Visceral Adipose Accumulation

Background: Our group has previously reported that visceral adipose tissue (VAT) accumulation was associated with the extent and vulnerable characteristics of coronary plaques using coronary computed tomography angiography (CTA). An investigation of the associations between these coronary lesions with plasma adiponectin and leptin was performed. Methods and Results: A total of 394 patients (220 men and 174 women) in the study were referred for CTA. Plain abdominal scanning was simultaneously performed to evaluate VAT areas. The median level of plasma high-molecular-weight (HMW) adiponectin in patients with CTA-based obstructive coronary artery disease was significantly lower than that in patients without (men: 1.45 vs. 1.88μg/ml, P=0.002; women: 2.49 vs. 3.44μg/ml, P<0.001). Multivariate analyses revealed that a lower HMW adiponectin concentration was significantly associated with the presence (men: P=0.019; women: P=0.018) and involved segment numbers (men: P=0.001; women: P=0.003) of coronary plaques. Furthermore, it was significantly related to coronary plaque with all 3 vulnerable characteristics of positive remodeling, low CT density (≤38 Hounsfield units), and adjacent spotty calcium (men: P=0.019; women: P=0.016). These associations were also observed with VAT areas, but not with plasma leptin concentrations, in both genders. Conclusions: Lower plasma HMW adiponectin is associated with the presence, extent, and vulnerable characteristics of coronary plaques assessed by CTA in both genders.  (Circ J 2012; 76: 1687–1696