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Background: Recent data suggest that myelin may be altered by physiological events occurring outside of the central nervous system, which may cause changes to cognition and behavior. Similarly, peripheral infection by non-neurotropic viruses is also known to evoke changes to cognition and behavior., Methods: Mice were inoculated with saline or influenza A virus. Bulk RNA-seq, lipidomics, RT-qPCR, flow cytometry, immunostaining, and western blots were used to determine the effect of infection on OL viability, protein expression and changes to the lipidome. To determine if microglia mediated infection-induced changes to OL homeostasis, mice were treated with GW2580, an inhibitor of microglia activation. Additionally, conditioned medium experiments using primary glial cell cultures were also used to test whether secreted factors from microglia could suppress OL gene expression., Results: Transcriptomic and RT-qPCR analyses revealed temporal downregulation of OL-specific transcripts with concurrent upregulation of markers characteristic of cellular stress. OLs isolated from infected mice had reduced cellular expression of myelin proteins compared with those from saline-inoculated controls. In contrast, the expression of these proteins within myelin was not different between groups. Similarly, histological and immunoblotting analysis performed on various brain regions indicated that infection did not alter OL viability, but increased expression of a cellular stress marker. Shot-gun lipidomic analysis revealed that infection altered the lipid profile within the prefrontal cortex as well as in purified brain myelin and that these changes persisted after recovery from infection. Treatment with GW2580 during infection suppressed the expression of genes associated with glial activation and partially restored OL-specific transcripts to baseline levels. Finally, conditioned medium from activated microglia reduced OL-gene expression in primary OLs without altering their viability., Conclusions: These findings show that peripheral respiratory viral infection with IAV is capable of altering OL homeostasis and indicate that microglia activation is likely involved in the process., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: In Japan, both the prevalence of the elderly and super-elderly and those of acute heart failure (AHF) have been increasing rapidly., Methods: This registry was a prospective multicenter cohort, which enrolled a total of 1253 patients with AHF. In this study, 1117 patients' follow-up data were available and were categorized into three groups according to age: <75 years old (nonelderly), 75-84 years old (elderly), and ≥ 85 years old (super-elderly). The endpoint was defined as all-cause death and each mode of death after discharge during the 3-years follow-up period., Results: Based on the Kaplan-Meier analysis, a gradually increased risk of all-cause death according to age was found. Among the three groups, the proportion of HF death was of similar trend; however, the proportion of infection death was higher in elderly and super-elderly patients. After adjusting for potentially confounding effects using the Cox and Fine-Gray model, the hazard ratio (HR) of all-cause death increased significantly in elderly and super-elderly patients (HR, 2.60; 95% confidence interval [CI], 1.93-3.54 and HR, 5.04; 95% CI, 3.72-6.92, respectively), when compared with nonelderly patients. The highest sub-distribution HR in detailed mode of death was infection death in elderly and super-elderly patients (HR, 4.25; 95% CI, 1.75-10.33 and HR, 10.10; 95% CI, 3.78-27.03, respectively)., Conclusions: In this population, the risk of all-cause death was found to increase in elderly and super-elderly. Elderly patients and especially super-elderly patients with AHF were at a higher risk for noncardiovascular death, especially infection death., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: This study investigated whether combination therapy (CT) with renin-angiotensin system inhibitors and β-blockers improved endpoints in acute heart failure (AHF). Methods and Results: AHF patients were recruited to this prospective multicenter cohort study between April 2015 and August 2017. Patients were divided into 3 categories based on ejection fraction (EF), namely heart failure (HF) with reduced EF (HFrEF), HF with midrange EF (HFmrEF), and HF with preserved EF (HFpEF), and a further into 2 groups according to physical status (those who could walk independently outdoors and those who could not). The composite endpoint included all-cause mortality and hospitalization for HF. Data at the 1-year follow-up were available for 1,018 patients. The incidence of the composite endpoint was significantly lower in the CT than non-CT group for HFrEF patients, but not among HFmrEF and HFpEF patients. For patients who could walk independently outdoors, a significantly lower rate of the composite endpoint was recorded only in the HFrEF group. The differences were maintained even after adjustment for comorbidities and prescriptions, with hazard ratios (95% confidence intervals) of 0.39 (0.20-0.76) and 0.48 (0.22-0.99), respectively. Conclusions: In this study, CT was associated with the prevention of adverse outcomes in patients with HFrEF. Moreover, CT prevented adverse events only among patients without a physical disorder, not among those with a physical disorder., Competing Interests: The authors have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021, THE JAPANESE CIRCULATION SOCIETY.)

Home treatment for heart failure (HF) is one of the most important problems in patients after discharge as a secondary preventive measure for rehospitalization for HF. However, there are no detailed studies on gender differences in sociopsychological factors such as living alone for HF rehospitalization among patients with acute HF (AHF).This prospective multicenter cohort study enrolled patients with AHF between April 2015 and August 2017. Patients of each gender with first AHF were divided into those living alone and those not living alone. The primary endpoint was defined as rehospitalization for HF after discharge. Cox proportional hazard analysis was performed to determine the association between living alone and the endpoint.Overall, 581 patients were included in this study during the 3-year follow-up. The proportion of rehospitalization for HF was significantly higher in patients living alone than in those not living alone among male patients. However, female patients showed no difference in endpoints between the two groups. The difference was independently maintained even after adjusting for differences in social backgrounds in male patients (adjusted hazard ratio (HR) 2.02; 95% confidence interval (CI), 1.07-3.70). In female patients, the HR for rehospitalization for HF showed no difference between the two groups (adjusted HR, 0.99; 95% CI, 0.56-1.69).In this study population, male patients living alone after first AHF discharge had a higher risk of rehospitalization for HF than those not living alone, but these differences were not observed in female patients.

Background: In Japan, the long-term care insurance (LTCI) system has an important role in helping elderly people, but there have been no clinical studies that have examined the relationship between the LTCI and prognosis for patients with acute heart failure (HF)., Methods and results: This registry was a prospective multicenter cohort, 1,253 patients were enrolled and 965 patients with acute HF aged ≥65 years were comprised the study group. The composite endpoint included all-cause death and hospitalization for HF after discharge. We divided the patients into 4 groups: (i) patients without LTCI, (ii) patients requiring support level 1 or 2, (iii) patients with care level 1 or 2, and (iv) patients with care levels 3-5. The Kaplan-Meier analysis identified a lower rate of the composite endpoint in group (i) than in the other groups. After adjusting for potentially confounding effects using a Cox proportional regression model, the hazard ratio (HR) of the composite endpoint increased significantly in groups (iii) and (iv) (adjusted HR, 1.62; 95% confidence interval [CI], 1.22-1.98 and adjusted HR, 1.62; 95% CI, 1.23-2.14, respectively) when compared with group (i). However, there was no significant difference between groups (i) and (ii)., Conclusions: The level of LTCI was associated with a higher risk of the composite endpoint after discharge in acute HF patients.

Background: Although activities of daily living (ADL) are recognized as being pertinent in averting relevant readmission of heart failure (HF) and mortality, little research has been conducted to assess a correlation between a decline in ADL and outcomes in HF patients., Methods: The Kitakawachi Clinical Background and Outcome of Heart Failure Registry is a prospective, multicenter, community-based cohort of HF patients. We categorized the patients into four types of ADL: independent outdoor walking, independent indoor walking, indoor walking with assistance, and abasia. We defined a decline in ADL (decline ADL) as downgrade of ADL and others (non-decline ADL) as preservation of ADL before discharge compared with admission., Results: Among 1253 registered patients, 923 were eligible, comprising 98 (10.6%) with decline ADL and 825 (89.4%) with non-decline ADL. Decline ADL exhibited a higher risk of hospitalization for HF and mortality compared with non-decline ADL. A multivariate analysis revealed that decline ADL emerged as an independent risk factor of hospitalization for HF [hazard ratio (HR), 1.42; 95% confidence interval (CI): 1.01-1.96; p=0.046] and mortality (HR, 1.95; 95% CI: 1.23-2.99; p<0.01). Although 66.3% of patients with decline ADL were registered for long-term care insurance, few received daycare services (32.7%) or home-visit medical services (8.2%)., Conclusions: Decline in ADL is a predictor of hospitalization for HF and mortality in HF patients., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Lysosomal associated membrane protein 2 (LAMP2) is physiologically implicated in autophagy. A genetic LAMP2 defect causes Danon disease, which consists of two major phenotypes of myopathy and cardiomyopathy. In addition, arteriopathy may manifest on rare occasions but the pathological basis remains unknown. We encountered two Danon families that developed small-vessel vasculopathy in the coronary or cerebral arteries. To investigate the underlying mechanisms, we characterized the biological features of LAMP-2-deficient mice and cultured cells. LAMP-2-deficient mice at 9-24 months of age showed medial thickening with luminal stenosis due to proliferation of vascular smooth muscle cells (VSMC) in muscular arteries. Ultrastructural analysis of VSMC revealed various autophagic vacuoles scattered throughout the cytoplasm, suggesting impaired autophagy of long-lived metabolites and degraded organelles (i.e., mitochondria). The VSMC in Lamp2 null mice expressed more vimentin but less α-smooth muscle actin (α-SMA), indicating a switch from contractile to synthetic phenotype. Silencing of LAMP2 in cultured human brain VSMC showed the same phenotypic transition with mitochondrial fragmentation, enhanced mitochondrial respiration, and overproduction of reactive oxygen species (ROS). These findings indicate that LAMP-2 deficiency leads to arterial medial hypertrophy with the phenotypic conversion of VSMC, resulting from age-dependent accumulation of cellular waste generated by aberrant autophagy.

Reactive microglia and astrocytes are present in lesions of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, it is not clear whether they are actively involved in the pathogenesis of these disorders. Previous studies demonstrated that microglia, but not astrocytes, are required for lipopolysaccharide (LPS)-induced selective killing of developing oligodendrocytes (preOLs) and that the toxicity is mediated by microglia-derived peroxynitrite. Here we report that, when astrocytes are present, the LPS-induced, microglia-dependent toxicity to preOLs is no longer mediated by peroxynitrite but instead by a mechanism dependent on tumor necrosis factor-alpha (TNFalpha) signaling. Blocking peroxynitrite formation with nitric oxide synthase (NOS) inhibitors or a decomposition catalyst did not prevent LPS-induced loss of preOLs in mixed glial cultures. PreOLs were highly vulnerable to peroxynitrite; however, the presence of astrocytes prevented the toxicity. Whereas LPS failed to kill preOLs in cocultures of microglia and preOLs deficient in inducible NOS (iNOS) or gp91(phox), the catalytic subunit of the superoxide-generating NADPH oxidase, LPS caused a similar degree of preOL death in mixed glial cultures of wild-type, iNOS-/-, and gp91(phox-/-) mice. TNFalpha neutralizing antibody inhibited LPS toxicity, and addition of TNFalpha induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNFalpha or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNFalpha signaling, rather than peroxynitrite, is essential in LPS-triggered preOL death in an environment containing all major glial cell types and underscore the importance of intercellular communication in determining the mechanism underlying inflammatory preOL death.

Deletions in the DAP12 gene in humans result in Nasu-Hakola disease, characterized by a combination of bone fractures and psychotic symptoms similar to schizophrenia, rapidly progressing to presenile dementia. However, it is not known why these disorders develop upon deficiency in DAP12, an immunoreceptor signal activator protein initially identified in the immune system. Here we show that DAP12-deficient (DAP12(-/-)) mice develop an increased bone mass (osteopetrosis) and a reduction of myelin (hypomyelinosis) accentuated in the thalamus. In vitro osteoclast induction from DAP12(-/-) bone marrow cells yielded immature cells with attenuated bone resorption activity. Moreover, immature oligodendrocytes were arrested in the vicinity of the thalamus, suggesting that the primary defects in DAP12(-/-) mice are the developmental arrest of osteoclasts and oligodendrocytes. In addition, the mutant mice also showed synaptic degeneration, impaired prepulse inhibition, which is commonly observed in several neuropsychiatric diseases in humans including schizophrenia, and aberrant electrophysiological profiles in the thalami. These results provide a molecular basis for a unique combination of skeletal and psychotic characteristics of Nasu-Hakola disease as well as for schizophrenia and presenile dementia.

A 56-year-old man presented with an inferior myocardial infarction and a huge pseudoaneurysm below the inferior surface of the left ventricle, which had progressed from a small subepicardial aneurysm over a 6-month period. Transthoracic echocardiography, Doppler color flow images, radionuclide angiocardiography, magnetic resonance imaging and contrast ventriculography all revealed an abrupt disruption of the myocardium at the neck of the pseudoaneurysm, where the diameter of the orifice was smaller than the aneurysm itself, and abnormal blood flows from the left ventricle to the cavity through the orifice with an expansion of the cavity in systole and from the cavity to the left ventricle with the deflation of the cavity in diastole. Coronary angiography revealed 99% stenosis at the atrioventricular nodal branch of the right coronary artery. At surgery the pericardium was adherent to the aneurysmal wall and a 1.5-cm orifice between the aneurysm and the left ventricle was seen. Pathological examination revealed no myocardial elements in the aneurysmal wall. The orifice was closed and the postoperative course was uneventful. Over-intense physical activity as a construction worker was considered to be the cause of the large pseudoaneurysm developing from the subepicardial aneurysm. These findings indicate that a subepicardial aneurysm may progress to a larger pseudoaneurysm, which has a propensity to rupture, however, it can be surgically repaired.

A report is presented of a liquefaction necrosis of mitral annular calcification in a patient with chronic renal failure and secondary hyperparathyroidism who had been managed by hemodialysis for 11 years. The mass was echogenic with an echo-lucent area inside, high density on computed tomography and low intensity on magnetic resonance imaging. The uptake of gallium-67 (67Ga)-citrate and the bone agent technetium-99m-methylene diphosphate (99mTc-MDP) was seen in the mass. These findings were compatible with liquefaction necrosis of the mitral annular calcification. After treatment with low calcium concentration hemodialysis, the size of the mass reduced with disappearance of the echo-lucent area on the echocardiography and there was no uptake of 67Ga-citrate or 99mTc-MDP. Liquefaction necrosis might be the early and reversible form of mitral annular calcification. When a tumorlike echogenic mass at the base of mitral leaflets is seen in patients with predisposing factors for mitral annular calcification, consider the possibility of this specific form of mitral annular calcification in order to avoid any unnecessary surgical intervention.

The mediastinal and cardiovascular anatomy is complex. We have developed a three-dimensional (3D) reconstruction system for the major mediastinal structures using magnetic resonance imaging data on a NeXT workstation. The program uses a combination of automatic and manual procedures to determine the contours of the cardiac structures. The geometric centers of the contours are connected by a 3D space curve, and the central axis of each cardiac structures is determined. The contours are projected on the perpendicular plane to the central axis and semiautomatically processed until the contours of one pixel are obtained. Then the surface rendering with transparency is performed. Compositing combines two images so that both appear in the composite, superimposed on each other. Demonstration of the various mediastinal lines and cardiovascular diseases by the composits of the partly transparent 3D images has promoted a better understanding of the complex mediastinal and cardiovascular anatomy and diseases.

In vitro immune responses to Legionella pneumophila were investigated. When human peripheral blood lymphocytes (PBL) from healthy volunteers were stimulated with formalin-killed L. pneumophila for 7 days in vitro, strong proliferative responses were observed. The responding cells were shown to be a CD4 T cell subset. It was also found that the CD4 T cells secreted significant amounts of IFN-gamma into the PBL culture supernatant. The production of IFN-gamma and IL-4 by PBL was measured semiquantitatively by reverse transcriptase-assisted polymerase chain reaction (RT-PCR) methods. Formalin-killed or live L. pneumophila-stimulated PBL expressed the mRNA for IFN-gamma but not the mRNA for IL-4. The results suggest that the whole bacterium, as opposed to the supernatant, predominantly stimulates Th1 type helper T cells. The cloned T cells specific for L. pneumophila expressed the mRNA for IFN-gamma but not for IL-4. In contrast to formalin-killed or live L. pneumophila stimulation, when PBL were stimulated with the bacterial culture supernatant, the proliferating T cells produced the mRNA for IL-4 as well as for IFN-gamma. A significant correlation between the proliferative response to formalin-killed L. pneumophila and IFN-gamma release in culture was observed (r = 0.6932, P < 0.001) in PBL from 30 healthy volunteers. From these in vitro studies, it is suggested that the whole L. pneumophila bacterium and their soluble antigens stimulate T cells in a manner which results in a different pattern of cytokine production.