Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis.

Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons. Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels and negatively associated with the estimated glomerular filtration rate. No statistical significance was observed for other risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression analysis revealed that age (P<0.001), female sex (P<0.05), Lp(a) (P<0.01), and hemoglobin A1c (P<0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level is a potent risk factor of AVC in patients with high risk of atherosclerosis. J. Med. Invest. 70 : 450-456, August, 2023.

Association of Microluminal Structures Assessed by Optical Coherence Tomography With Local Inflammation in Adjacent Epicardial Adipose Tissue and Coronary Plaque Characteristics in Fresh Cadavers.

BACKGROUND: Coronary intraplaque microluminal structures (MS) are associated with plaque vulnerability, and the inward progression of vascular inflammation from the adventitia towards the media and intima has also been demonstrated. Therefore, in the present study we investigated the relationships among MS, local inflammation in adjacent epicardial adipose tissue (EAT), and coronary plaque characteristics.Methods and Results: Optical coherence tomography (OCT) revealed MS in the left anterior descending coronary artery in 10 fresh cadaveric hearts. We sampled 30 lesions and subdivided them based on the presence of MS: MS (+) group (n=19) and MS (-) group (n=11). We measured inflammatory molecule levels in the adjacent EAT and percentage lipid volume assessed by integrated backscatter intravascular ultrasound in each lesion. The expression levels of vascular endothelial growth factor B and C-C motif chemokine ligand 2 were significantly higher in the MS (+) group than in the MS (-) group (0.9±0.7 vs. 0.2±0.2 arbitrary units (AU), P=0.04 and 1.5±0.5 vs. 0.6±0.7 AU, P=0.02, respectively). Percentage lipid volume was significantly higher in the MS (+) group than in the MS (-) group (38.7±16.5 vs. 23.7±10.9%, P=0.03). CONCLUSIONS: Intraplaque MS observed on OCT were associated with lipid-rich plaques and local inflammation in the adjacent EAT. Collectively, these results suggest that local inflammation in the EAT is associated with coronary plaque vulnerability via MS.

Regression of left ventricular hypertrophy after tafamidis therapy in a patient with transthyretin amyloidosis variant.

Transthyretin amyloidosis (ATTR) variant is a life-threatening hereditary disease predominantly affecting the peripheral nervous system and heart. Tafamidis, which prevents the deposition of amyloid by stabilizing transthyretin, is available for the treatment of neuropathy and cardiomyopathy of ATTR. However, whether tafamidis could eliminate established amyloid deposits and improve cardiac function remains unknown. We reported a case of regression of left ventricular hypertrophy after tafamidis therapy in a patient with an ATTR variant. J. Med. Invest. 69 : 320-322, August, 2022.

Drug-coated balloon angioplasty for severe pulmonary vein stenosis resulting from cryoballoon ablation for atrial fibrillation.

We performed a drug-coated balloon (DCB) angioplasty for severe pulmonary vein (PV) stenosis resulting from cryoballoon ablation for atrial fibrillation. Three and fourteen months after the angioplasty, follow-up multidetector computed tomography did not show restenosis. Lesion regression was observed at 14-month follow-up. Two years after PV angioplasty with DCB, the patient was well without any symptoms. DCB angioplasty may become an alternative effective procedure for PV stenosis. Learning objective: The usefulness and safety of drug-coated balloon angioplasty for severe pulmonary vein stenosis resulting from cryoballoon ablation for atrial fibrillation was observed at 14-month follow-up.

Clinical clerkship students' preferences and satisfaction regarding online lectures during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has caused an unprecedented disruption in medical education. Students and lecturers had to adapt to online education. The current study aimed to investigate the level of satisfaction and future preference for online lectures among clinical clerkship students and elucidated the factors that affect these outcomes. METHODS: We selected a sample of 114 medical students undergoing clinical clerkship during the COVID-19 pandemic. We conducted onsite lectures before the pandemic and online lectures after the outbreak. A survey was conducted, and the sample included students and 17 lecturers. The average scores of total satisfaction and future preference related to online lectures were computed. RESULTS: Students' scores on total satisfaction with online lectures and their future preference were higher than those for onsite lectures. Scores on the ease of debating dimension were low and those on accessibility of lectures in online lectures were higher than those in onsite lectures. There was no difference between the two groups in the scores on the comprehensibility and ease of asking questions dimensions. Results of the multiple regression analysis revealed that accessibility determined total satisfaction, and future preference was determined by comprehensibility as well as accessibility. Contrary to students' future preferences, lecturers favored onsite lectures to online ones. CONCLUSION: Online lectures are an acceptable mode of teaching during the COVID-19 pandemic for students undergoing clinical clerkship. Online lectures are expected to become more pervasive to avoid the spread of COVID-19.

STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.

AIMS: Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-ß) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. CONCLUSION: Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

Infective Endocarditis from Furuncle with Meningitis Complication Caused by Methicillin-resistant Staphylococcus aureus.

Infective endocarditis (IE) may be acquired in the community as community-acquired (CA) IE or in the healthcare setting. In Japan, cases of CA-methicillin-resistant Staphylococcus aureus (MRSA) infection as skin infection have been increasing. CA-MRSA strains, including the USA300 clone, have higher pathogenicity and are more destructive to tissue than healthcare-associated MRSA strains because of the toxins they produce, including arginine-catabolic mobile element (ACME) and Panton-Valentine leukocidin (PVL). However, only a few IE cases induced by USA300 have been reported. We herein report a 64-year-old man who developed CA-IE from a furuncle caused by USA300 MRSA producing PVL and ACME, which resulted in complications of meningitis.

Atherosclerotic Coronary Plaque Is Associated With Adventitial Vasa Vasorum and Local Inflammation in Adjacent Epicardial Adipose Tissue in Fresh Cadavers.

BACKGROUND: The coronary adventitia has recently attracted attention as a source of inflammation because it harbors nutrient blood vessels, termed the vasa vasorum (VV). This study assessed the link between local inflammation in adjacent epicardial adipose tissue (EAT) and coronary arterial atherosclerosis in fresh cadavers.Methods and Results:Lesion characteristics in the left anterior descending coronary artery of 10 fresh cadaveric hearts were evaluated using integrated backscatter intravascular ultrasound (IB-IVUS), and the density of the VV and levels of inflammatory molecules from the adjacent EAT were measured for each of the assessed lesions. The lesions were divided into lipid-rich, lipid-moderate, and lipid-poor groups according to percentage lipid volume assessed by IB-IVUS. Higher expression of inflammatory molecules (i.e., vascular endothelial growth factor A [VEGFA] andVEGFB) was observed in adjacent EAT of lipid-rich (n=11) than in lipid-poor (n=11) lesions (7.99±3.37 vs. 0.45±0.85 arbitrary units [AU], respectively, forVEGFA; 0.27±0.15 vs. 0.11±0.07 AU, respectively, forVEGFB; P<0.05). The density of adventitial VV was greater in lipid-rich than lipid-poor lesions (1.50±0.58% vs. 0.88±0.23%; P<0.05). CONCLUSIONS: Lipid-rich coronary plaques are associated with adventitial VV and local inflammation in adjacent EAT in fresh cadavers. This study suggests that local inflammation of EAT is associated with coronary plaque progression via the VV.

Effects of L-/N-Type Calcium Channel Blockers on Angiotensin II-Renin Feedback in Hypertensive Patients.

OBJECTIVES: Cilnidipine, an L-/N-type calcium channel blocker (CCB), has unique organ-protective properties due to suppression of hyperactivity in the sympathetic nervous system and renin-angiotensin system (RAS). In this study, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing the RAS. METHODS: A total of 25 hypertensive patients receiving a RAS inhibitor were randomly assigned to a cilnidipine (n = 12) or amlodipine (n = 13) group. The effects of cilnidipine on proteinuria and angiotensin II-renin feedback were assessed. RESULTS: After 6 months of treatment, both systolic and diastolic blood pressures were significantly reduced to a similar extent in both groups. The urine albumin-to-creatinine ratio was significantly lower in the cilnidipine group (p < 0.05) than in the amlodipine group. Amlodipine increased plasma angiotensin I and angiotensin II levels (p < 0.05), whereas cilnidipine did not. Interestingly, the cilnidipine group had a higher ratio of angiotensin-(1-7) (Ang-(1-7)) to angiotensin II in plasma than the amlodipine group (p < 0.05). CONCLUSIONS: The L-/N-type CCB cilnidipine, but not amlodipine, decreased urinary albumin excretion in hypertensive patients. Cilnidipine also increased the ratio of Ang-(1-7) to angiotensin II in plasma, which might be one factor underlying its beneficial effects.

Osteolytic primary bone lymphoma in the multiple bones.

Primary non-Hodgkin bone lymphoma (PBL) can involve solitary or multiple destructive bone lesions such as those of the femur or pelvis humerus, and some cases have osteolytic lesions. PBL is a rare disease in adults. Thus, PBL is rarely considered a differential diagnosis of the osteolytic tumor. In addition, PBL can be underdiagnosed because patients do not experience symptoms or show objective abnormalities in the early stage. Here, we reported an elderly patient with PBL in multiple bones, including the cranial and femoral bones that were fractured due to falling. J. Med. Invest. 66 : 347-350, August, 2019.

Association of Decreased Docosahexaenoic Acid Level After Statin Therapy and Low Eicosapentaenoic Acid Level with In-Stent Restenosis in Patients with Acute Coronary Syndrome.

AIM: It is speculated that statin therapy modulates the synthesis of polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, the data available on the effects of statin therapy on the serum levels of PUFA and the subsequent impact on in-stent restenosis (ISR) in patients with acute coronary syndrome (ACS) are limited. METHODS: A total of 120 ACS patients who received emergent coronary stent implantation, follow-up coronary angiography to evaluate ISR, and new statin therapy were enrolled. We measured the serum levels of the PUFA and lipids at the onset of ACS and at the follow-up coronary angiography. RESULTS: The follow-up coronary angiography revealed 38 ISR cases. New statin therapy significantly reduced the serum levels of DHA and low-density lipoprotein cholesterol (LDL-C), while it did not affect EPA level. Single regression analysis revealed that a decreased serum level of LDL-C was associated with decreased DHA level. The multiple logistic regression analysis revealed that the decreased DHA level after statin therapy and low serum level of EPA on admission were determinants of prevalence of ISR. CONCLUSION: Statin therapy decreased the serum level of DHA with a parallel reduction in LDL-C level in patients with ACS. Decreased DHA level after statin therapy and low EPA level on admission are risk factors for ISR, indicating that in patients with ACS, decreased serum levels of DHA may be a residual target for the prevention of ISR.

Septic True Aneurysm of the Posterior Tibial Artery Diagnosed after Anterior Arthroscopic Debridement of a Septic Ankle following Infective Endocarditis: A Case Report.

INTRODUCTION: There have been reports of true aneurysm of the posterior tibial artery, but only three reports have described true aneurysm of the posterior tibial artery at the ankle, and there has been only one report of tarsal tunnel syndrome caused by true aneurysm of this artery. In this case report, we describe a rare case of true septic aneurysm of the posterior tibial artery presenting as tarsal tunnel syndrome which was found after anterior arthroscopic debridement of a septic ankle in a 55-year-old man. CASE REPORT: 13 years earlier, this patient had undergone aortic valve replacement for severe aortic regurgitation caused by infective endocarditis with aortic valve vegetations. Since then, the patient had been treated with the oral anticoagulant warfarin. The aneurysm was successfully treated by a saphenous vein graft and administration of antibiotics. The patient likely developed septic ankle and aneurysm as a consequence of infective endocarditis. CONCLUSIONS: Magnetic resonance imaging should be performed before arthroscopic surgery to rule outaneurysm, especially in a patient with a septic ankle and/ora history of infective endocarditis.

Response Prediction and Influence of Tolvaptan in Chronic Heart Failure Patients Considering the Interaction of the Renin-Angiotensin-Aldosterone System and Arginine Vasopressin.

The renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP) regulate body fluids. Although conventional diuretics have been used for treating heart failure, they activate RAAS and exacerbate renal function. Tolvaptan, a newly developed vasopressin-2 receptor antagonist, elicits aquaresis and improves volume overload in heart failure patients, however, the predictors of tolvaptan effectiveness and the influence on the RAAS and renal function according to tolvaptan therapy are not established. We evaluated 26 chronic heart failure patients receiving therapy with 15 mg/day tolvaptan and examined their laboratory and urinary data before and after tolvaptan therapy. A response to tolvaptan was defined as a body weight decrease by more than 2 kg in a week and a urine volume increase by 500 mL/ day compared with that before tolvaptan administration. Body weight, urine volume, and brain natriuretic peptide levels significantly improved (P < 0.05), without any worsening of renal function represented by serum creatinine, sodium, and potassium. Moreover, no significant changes were observed in the plasma renin activity and plasma aldosterone concentration (PAC). In the responder group, urine osmolality before tolvaptan administration was significantly higher (P < 0.05) but declined significantly after tolvaptan administration (P < 0.05). The AVP/PAC ratio before administration was positively correlated with the efficacy of tolvaptan. Tolvaptan treatment could prevent RAAS activation in chronic heart failure patients. Moreover, monitoring the AVP/PAC ratio may be useful in predicting the tolvaptan response.

Significance of Ser-188 in human mitochondrial NAD kinase as determined by phosphomimetic and phosphoresistant amino-acid substitutions.

Human mitochondrial NAD kinase is a crucial enzyme responsible for the synthesis of mitochondrial NADP(+). Despite its significance, little is known about the regulation of this enzyme in the mitochondria. Several putative and known phosphorylation sites within the protein have been found using phosphoproteomics, and here, we examined the effect of phosphomimetic mutations at six of these sites. The enzymatic activity was downregulated by a substitution of an Asp residue at Ser-289 and Ser-376, but not a substitution of Ala, suggesting that the phosphorylation of these residues downregulates the enzyme. Moreover, the activity was completely inhibited by substituting Ser-188 with an Asp, Glu, or in particular Ala, which highlights two possibilities: first, that Ser-188 is critical for catalytic activity, and second, that phosphorylation of Ser-188 inhibits the activity. Ser-188, Ser-289, and Ser-376 were found to be highly conserved in the primary structures of mitochondrial NAD kinase homologs in higher animals. Moreover, Ser-188 has been frequently detected in human and mouse phosphorylation site studies, whereas Ser-289 and Ser-376 have not. Taken together, this indicates that Ser-188 (and perhaps the other residues) is an important phosphorylation site that can downregulate the NAD kinase activity of this critical enzyme.

Quantitative analysis of the effect of triglyceride alkyl-chain length on the partitioning of highly lipophilic compounds to the mesenteric lymph in intestinal cells.

The purpose of this study was to quantitatively clarify the effect of alky-chain length of a triglyceride in an emulsion on the partitioning of highly lipophilic compounds into the lymph fluid after their oral administration. Highly lipophilic anthraquinone derivatives were orally administered in emulsions to rats. Emulsions composed of long-, medium-, and short-chain triglycerides (LCT, MCT, and SCT emulsions, respectively) were used. The concentrations of the compounds in plasma and lymph fluid were periodically determined and their partitioning to the lymph was calculated using a mathematical model. Intestinal absorption of all compounds was enhanced and the plasma concentrations of the compounds were found to be in the following order: LCT emulsion > MCT emulsion > SCT emulsion. The amounts of each compound recovered in the lymph were not in agreement with their lipophilicity. Quantitative analysis revealed that the partitioning of the compounds to the lymph may be determined by the solubility of the compound in the triglyceride in the form of an emulsion and the amount of triglyceride transferred to the lymph fluid. These results suggest a possibility that the amount of a compound absorbed via the lymph route after oral administration can be quantitatively controlled by the formulations.