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Abstract Self-amplifying RNAs (saRNAs) are versatile vaccine platforms that take advantage of a viral RNA-dependent RNA polymerase (RdRp) to amplify the messenger RNA (mRNA) of an antigen of interest encoded within the backbone of the viral genome once inside the target cell. In recent years, more saRNA vaccines have been clinically tested with the hope of reducing the vaccination dose compared to the conventional mRNA approach. The use of N1-methyl-pseudouridine (1mΨ), which enhances RNA stability and reduces the innate immune response triggered by RNAs, is among the improvements included in the current mRNA vaccines. In the present study, we evaluated the effects of this modified nucleoside on various saRNA platforms based on different viruses. The results showed that different stages of the replication process were affected depending on the backbone virus. For TNCL, an insect virus of the Alphanodavirus genus, replication was impaired by poor recognition of viral RNA by RdRp. In contrast, the translation step was severely abrogated in coxsackievirus B3 (CVB3), a member of the Picornaviridae family. Finally, the effects of 1mΨ on Semliki forest virus (SFV), were not detrimental in in vitro studies, but no advantages were observed when immunogenicity was tested in vivo.

Objective: With the remarkable advances in diagnostic ultrasound equipment, there is a growing need for ultrasound diagnosis of muscle and soft tissue injuries in sports injuries. Among these, hamstring strains are often difficult to treat and require early and accurate diagnosis. Injuries to the proximal part of the hamstring often take a long time to heal. For this reason, the diagnosis of proximal hamstring injuries is extremely important. The structure of the origin tendon is characteristic, and it is a complex in which the semitendinosus muscle (ST) of the medial hamstring and the long head of the biceps femoris muscle (BFLH) of the lateral hamstring share a conjoint tendon (CT). On the other hand, the semimembranosus muscle (SM) attaches to the ischial tuberosity independently. In this study, we created a classification of injury sites focusing on the origin tendon, and investigated the distribution of injury location, relationship to the player’s position, and the detection rate of ultrasound diagnosis. Material and Methods: We used ultrasound and MRI to diagnose 52 university men’s rugby players who had suffered a hamstring strain for the first time and investigated the distribution of the injured areas. We performed an ultrasound scan as the initial diagnosis and used MRI as a final diagnostic tool. A classification focusing on the origin of the muscle was created. First of all, it was divided into two types: the BFLH-ST complex type, which originates in the CT, and the SM type, which originates in the SM tendon. We also classified BFLH-ST complex damage, including CT damage, as Type I, a BFLH injury without CT injury as Type II, and a ST injury without CT injury as Type III. We then investigated the distribution of the injury location. The degree of ultrasound detection in each injury type was evaluated in three grades. The frequency of BFLH complex and SM injuries was investigated in players who played the forward (FW) and back (BK) positions. Results: The distribution was 40 limbs (77%) for BFLH-ST complex injury type and 12 limbs (23%) for SM injury type. In the BFLH complex type,19 limbs which met the Type I classification criteria for CT tear, 19 limbs met the Type II, and 2 limbs met the Type III. FWs had a higher incidence of SM injuries and BKs had a higher incidence of BFLH-ST complex injuries. With regard to the detection of muscle injuries via ultrasound, a high rate of detection was possible, except for a slight injury to the myofascial junction of the BFLH. Discussion: In terms of the distribution, the BFLH-ST complex, which shares the same origin tendon (i.e. CT), had a higher frequency of muscle tears than the SM. In addition, CT junction injuries occurred frequently in Type II as well as Type I (=CT injury). One possible cause is that the CT is subject to concentrated traction stress from both the medial and lateral hamstrings. With ultrasound, the detection rate of muscle damage around the BFLH-ST complex and SM originating tendon was high, suggesting that it is useful as an initial diagnosis. From this, it can be said that ultrasound is also useful for primary evaluation of “proximal hamstring injury”, which is prone to severe and should be given a final diagnosis using MRI. Conclusions: We created a classification system focusing on the originating tendons and clarified their incidence rates. In this study, ultrasound was found to be useful in the detection of originating tendon injuries. We also identified the characteristic sonographic findings of each type.

Abstract We aimed to evaluate the blood lactate level in response to two bouts of exercise. First, we hypothesized that blood lactate elevation in response to moderate-intensity aerobic exercise (MIAE) would be lower at the end of the second bout of MIAE than the first bout of MIAE. In this context, we also hypothesized that lactate accumulation at the end of resistance exercise (RE) would be reduced if MIAE is performed before RE (i.e., concurrent exercise; CE). If so, we hypothesized that the order of the CE (i.e., RE + MIAE vs. MIAE + RE) influences blood lactate kinetics. To test the hypotheses, forty-three healthy men participated in three studies. In study 1, 20 men (age 21 ± 2 years) performed two bouts of a 20-min MIAE separated by a 20-min rest interval. In study 2, 11 men (age 22 ± 1 years) performed RE only and CE (MIAE + RE; ARCE) with a 20-min rest interval in a crossover design. In study 3, 12 men (age 21 ± 2 years) performed both CEs, which were ARCE and RE + MIAE (RACE), with a 20-min rest interval in a crossover design. We measured blood lactate before and at the end of each exercise session. In study 1, the blood lactate response to the second bout of MIAE was lower than that of the first bout (P

Abstract Background The present study aimed to describe the frequency and severity of tram‐track lesions in anterior ankle impingement in athletes and to evaluate the association between osteophyte morphology and severity of tram‐track lesions, the distinctive cartilage lesions associated with tibial osteophytes in anterior ankle impingement syndrome. Methods We evaluated 34 athletes who underwent arthroscopic osteophyte resection for anterior ankle impingement between January 2017 and March 2021. Results We found tram‐track lesions in 26 athletes (76.5%). Arthroscopic findings revealed the distribution of the International Cartilage Repair Society grades of tram‐track lesions (grade 0, eight; grade 1, seven; grade 2, ten; grade 3, nine; grade 4, zero). These findings indicate that athletes with anterior ankle impingement syndrome may have more severe cartilage lesions than non‐athletes. There was a positive correlation between the International Cartilage Repair Society grade and osteophyte size (r = 0.393, p = 0.021). We divided athletes into two groups according to the presence or absence of osteophyte protrusion into the joint space. Osteophyte protrusion was present in 14 athletes (41.2%). All athletes in the protrusion‐type group had tram‐track lesions; seven (50%) had International Cartilage Repair Society grade 3. The protrusion‐type group's International Cartilage Repair Society grade was significantly higher than that of the non‐protrusion‐type group (p = 0.008). The osteophyte sizes in the two groups were not significantly different (p = 0.341). Conclusions Based on these findings, osteophyte protrusion should be assessed when an indication of arthroscopic treatment for anterior ankle impingement syndrome is considered, particularly in athletes.

Fever due to Helicobacter cinaedi bacteremia under chemotherapy has not been widely recognized among clinicians. We experienced a 72-year-old man with diffuse large B-cell lymphoma, who was complicated with H. cinaedi bacteremia-induced fever under R-CHOP chemotherapy. We summarized 6 cases including ours, suggesting that fever without neutropenia developing around day 6 from starting chemotherapy is a possible symptom caused by H. cinaedi bacteremia. We should discriminate fever due to H. cinaedi bacteremia if fever emerged before myelosuppression in the course of chemotherapy.

Aim: Maternal high-fat diet (HFD) is associated with the development of cardiovascular disease (CVD) in adult offspring. Atherosclerotic vascular calcification is well documented in patients with CVD. We examined the effect of maternal HFD on calcified plaque formation. Methods and results: Seven-week-old female apo-E−/− mice (C57BL6/J) were nourished either an HFD or a normal diet (ND) a week before mating, and during gestation and lactation. Offspring of both the groups were fed a high-cholesterol diet (HCD) from 8 weeks of age. Osteogenic activity of the thoracic aorta, assessed using an ex vivo imaging system, was significantly increased after 3 months of HCD in male offspring of HFD-fed dams (O-HFD) as compared with those of ND-fed dams (O-ND). Alizarin-red-positive area in the aortic root was significantly increased after 6 months of HCD in male O-HFD as compared to that of O-ND. Plaque size and Oil Red O-positive staining were comparable between the two groups. Primary cultured vascular smooth muscle cells (VSMCs) of the thoracic aorta were treated with phosphate and interleukinL-1β (IL-1β) to transform them into an osteochondrocytic-like phenotype. Intracellular calcium content and alkaline phosphatase activity were markedly higher in the VSMCs of O-HFD than in O-ND. IL-1β concentration in the supernatant of bone marrow-derived macrophages was markedly higher in O-HFD than in O-ND. Conclusion: Our findings indicate that maternal HFD accelerates the expansion of atherogenic calcification independent of plaque progression. In vitro phosphate- and IL-1β-induced osteochondrocytic transformation of VSMCs was augmented in O-HFD. Inhibition of VSMCs, skewing toward osteochondrocytic-like cells, might be a potential therapeutic strategy for preventing maternal HFD-associated CVD development.

This is a case report of a 60-year-old male patient with essential thrombocythemia (ET) that progressed to acute myeloid leukemia (AML) in approximately 9 years. His platelet count decreased approximately 8 years after ET treatment with hydroxyurea (HU) and aspirin. The dose of HU was reduced because of suspected myelosuppression due to HU; however, myelosuppression did not improve. Bone marrow examination revealed myelofibrosis; therefore, ruxolitinib was administered. Approximately 1 year later, his leukocyte and blast counts in the peripheral blood increased; thus, ET was judged to have progressed to AML-myelodysplasia-related change. Induction chemotherapy and consolidation therapy were initiated; however, the patient unfortunately failed to achieve complete remission. We then continued to administer salvage chemotherapy; however, his general condition worsened, and he died from cerebral hemorrhage. The karyotype at the onset of ET was 46,XY, which changed to 47,XY,del(7q),+8 at the time of AML diagnosis. In addition, genetic testing revealed FLT-3 ITD mutation. His histopathological analysis showed subarachnoid and intraparenchymal hemorrhages and tumor cell infiltration into the cerebrum, brainstem, and cerebellum. In this case, deletion of the long arm of chromosome 7, additional abnormalities in chromosome 8, and FLT3-ITD mutation were confirmed as risk factors for having developed secondary AML for approximately 9 years and death from cerebral hemorrhage 1 year later.

Abstract Successful treatment of the acute phase of bradycardia in patients with cardiac lymphoma via medical therapy alone has not been reported. This case report describes the successful treatment of sick sinus syndrome in an 84‐year‐old man with cardiac lymphoma via chemotherapy without pacemaker implantation.

Background: Co-administration of Piperacillin/Tazobactam (PIPC/TAZ) and Vancomycin (VCM) as an antibiotic therapy for severe infectious diseases increases the risk of nephrotoxicity. We retrospectively investigated the utility of monitoring VCM trough concentration in early stage of developing acute kidney injury (AKI) on this combination therapy. Methods: We enrolled all infectious disease patients who were managed with concurrent PIPC/TAZ and VCM. The record of dosage and the administration interval of each antibiotic and its clinical parameters, as well as the VCM trough concentrations, blood culture for bacteria, and serum creatinine values, were collected. VCM trough concentration was measured during the initial 48–72 h of VCM administration. Nephrotoxicity was evaluated as the degree of AKI. Results: A total of 47 patients fulfilling the criteria were registered, and AKI developed in 10 patients. There was no statistical difference between the AKI and non-AKI groups with regard to age, height, weight, basal creatinine level, body surface area, body mass index, PIPC/TAZ dose, VCM dose, gender, artificial management, and death within around 30 days. The VCM trough level was increased significantly in the AKI group (mean [standard deviation {SD}]: 25.9 [7.8] μg/mL) compared to that in the non-AKI group (mean [SD]: 15.7 [6.9] μg/mL) (p = 0.003). During the clinical course, renal function returned to normal levels in three out of four AKI stage 2 patients, whereas only partial recovery was achieved in all AKI stage 3 patients. Conclusions: A high VCM trough concentration may have an influence on the occurrence of AKI during combination therapy of PIPC/TAZ and VCM. Careful monitoring of VCM trough concentration will be required to prevent AKI progression.

Background. Bone marrow infiltration of lymphoma cells is a candidate risk factor for infusion-related reactions (IRRs) in patients with CD20-positive B-cell non-Hodgkin lymphoma (B-NHL). However, despite with the lack of sufficient data, the effect of bone marrow infiltration of B-NHL cells on the incidence rate of grade 2 or higher IRRs with the administration of rituximab has been retrospectively studied in this paper. Methods. Patients with CD20-positive B-NHL who received the rituximab induction therapy for the first time were enrolled in this study. To evaluate the bone marrow infiltration of B-NHL cells, May–Giemsa stain of bone marrow films and flow cytometry examination of bone marrow aspiration samples were performed. IRR grade was determined using the IRR criteria in the Common Terminology Criteria for Adverse Events version 4.0. Results. A total of 127 patients were eligible for this study. Grade 2 or higher IRRs were observed in 43 (34%) patients. In univariate analysis, use of glucocorticoid before rituximab infusion was a strong risk-avoiding factor for grade 2 or higher IRRs. Advanced stage of disease (Ann Arbor: stages III and IV) or bone marrow infiltration of B-NHL cells revealed the risk factors, regardless of glucocorticoid premedication. Using multivariate analysis, bone marrow infiltration was found to be an independent risk factor for patients without prior glucocorticoid use. Conclusion. Bone marrow infiltration of B-NHL cells is a risk factor for grade 2 or higher IRRs at the first rituximab induction therapy without glucocorticoid premedication.

Abstract Resistance exercise (RE) with blood flow restriction (BFR) is recognized as a beneficial strategy in increasing skeletal muscle mass and strength. However, the effects of BFR on changes in perceptual parameters, particularly those related to exercise adherence, induced by RE are not completely understood. In this study, we examined the exercise adherence‐related perceptual responses to low‐load BFR‐RE. Sixteen young males performed both BFR and non‐BFR (NBFR) sessions in a crossover design. The bilateral knee extensor low‐load RE was performed with a standard BFR‐RE protocol, consisting of four sets (total 75 repetitions), using 20% of one‐repetition maximum. BFR‐RE was performed with 200 mmHg pressure cuffs placed around the proximal region of the thighs. NBFR‐RE was performed without pressure cuffs. The ratings of perceived exertion and leg discomfort measured using the Borg's Scales were higher for BFR‐RE session than for NBFR‐RE session (both p < 0.001 for interaction effect). The Feeling Scale‐measured affect and Task Motivation Scale‐measured task motivation were lower for BFR‐RE session than for NBFR‐RE session (both p < 0.05 for interaction effect); by contrast, the Numerical Rating Scale‐measured perceived pain was higher for BFR‐RE session than for NBFR‐RE session (p < 0.001 for interaction effect). The Physical Activity Enjoyment Scale‐measured enjoyment immediately after RE was lower with BFR than with NBFR (p < 0.001). These findings suggest that BFR exacerbates the exercise adherence‐related perceptual responses to low‐load RE in young males. Therefore, further studies are needed to develop effective strategies that minimize the BFR‐RE‐induced negative effects on perceptual responses.

The length of rest interval between sets (i.e., inter-set rest interval) is an important variable for resistance exercise program. However, the impact of the inter-set rest interval on improvements in cognitive function following resistance exercise remains unknown. In this study, we compared the effect of short rest interval (SRI) vs. long rest interval (LRI) protocols on post-exercise cognitive inhibitory control (IC) improvements induced by low-intensity resistance exercise. Twenty healthy, young males completed both SRI and LRI sessions in a crossover design. The bilateral knee extensor low-intensity resistance exercise was programed for six sets with 10 repetitions per set using 40% of one-repetition maximum. The inter-set rest interval lengths for SRI and LRI protocols were set for 1 and 3min, respectively. The color-word Stroop task (CWST) was administrated at six time points: baseline, pre-exercise, immediate post-exercise, and every 10min during the 30-min post-exercise recovery period. The levels of blood lactate, which may be an important determinant for improving IC, throughout the 30-min post-exercise recovery period were significantly higher following SRI protocol than following LRI protocol (p=0.002 for interaction effect). In line with this result, large-sized decreases in the reverse-Stroop interference score, which represent improved IC, were observed immediately after SRI protocol (d=0.94 and 0.82, respectively, vs. baseline and pre-exercise) as opposed to the moderate-sized decreases immediately after LRI protocol (d=0.62 and 0.66, respectively, vs. baseline and pre-exercise). Moreover, significant decreases in the reverse-Stroop interference score were observed from 10 to 30min after SRI protocol (all ps

Abstract Background Vascular closure devices have been widely used to achieve rapid hemostasis after percutaneous catheterization procedures via the common femoral artery. The EXOSEAL vascular closure device is a device that can deliver a bioabsorbable polyglycolic acid plug to fill the subcutaneous puncture route at the groin for rapid hemostasis, and this device has a lower risk of arterial occlusion than other vascular closure devices. Case presentation An 83-year-old Japanese man underwent percutaneous coronary intervention for a proximal stenosis in his left circumflex artery through a 7-Fr sheath from his right common femoral artery. We encountered acute popliteal artery occlusion associated with EXOSEAL vascular closure device. We detected the plug material of this device at the occluded lesion by intravascular ultrasound, and performed successful bailout stenting after pulling the embolus with an inflated balloon catheter up to the superficial femoral artery from the popliteal artery. Conclusion Acute limb ischemia caused by an EXOSEAL vascular closure device is a very rare complication. Balloon angioplasty and stenting are considered to be effective options to deal with the plug dislodgement of an EXOSEAL vascular closure device. We must be prepared for every rare complication during endovascular treatment.

Background: The extremely low loads (e.g., 32 and 25%, respectively, vs. baseline and/or pre-exercise for both protocols; all Ps < 0.05). The improved IC following ST-VLRE, but not following VLRE, remained significant until the 20-min post-exercise recovery period (decreasing rate >48% vs. baseline and pre-exercise; both Ps < 0.001). The degree of post-exercise IC improvements was significantly higher for ST-VLRE than for VLRE (P = 0.010 for condition × time interaction effect). Conclusions: These findings suggest that ST-VLRE can improve post-exercise IC effectively. Therefore, ST-VLRE may be an effective resistance exercise protocol for improving cognitive function.

Abstract Purpose To evaluate the usefulness of the false‐pouch closure technique with an intact superior peroneal retinaculum (SPR). Methods From 2016 to 2020, 30 patients with recurrent dislocation of the peroneal tendon were treated with the current procedure. Clinical outcomes, including the time to resume running, the rate and time to return to sports, and the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle‐Hind Foot score, were evaluated preoperatively and at the last follow‐up. Results The rate of return to the pre‐injury level of sports activity was 93.3%, and the mean duration to return to running and sports was 8.0 ± 2.8 weeks (range: 3–12 weeks) and 14.4 ± 3.2 weeks (range: 10–24 weeks), respectively. The mean preoperative AOFAS score was 79.7 ± 9.6 points (range: 41–90), which improved significantly to 98.9 ± 3.2 (87–100) postoperatively (p

Abstract We previously determined that improvement in cognitive inhibitory control (IC) immediately after localized resistance exercise was greater for high‐intensity resistance exercise (HRE) than for low‐intensity resistance exercise (LRE). However, our previous study used the same total repetitions (i.e., same repetitions per set) between HRE and LRE; therefore, the difference in postexercise IC improvement might be due to a difference in work volume (i.e., intensity × total repetitions). In this study, we compared the effect of high‐volume (HV)‐LRE to that of volume‐matched HRE on postexercise IC improvements. Twenty‐two healthy, young males performed both HV‐LRE and HRE in a crossover design. Exercise loads for HV‐LRE and HRE were set at 35% and 70% of one‐repetition maximum, respectively. The bilateral knee extension exercises for HV‐LRE and HRE were programmed for six sets with 20 and 10 repetitions, respectively, per set. IC was measured using the color‐word Stroop task (CWST) at six time points; baseline, pre‐exercise, immediate postexercise, and every 10 min during the 30‐min postexercise recovery period. The reverse‐Stroop interference score decreased significantly immediately after HV‐LRE and HRE compared with that before each exercise (decreasing rate >34 and >38%, respectively, vs. baseline and pre‐exercise; all ps 40 and >38%, respectively, vs. baseline and pre‐exercise; all ps

Abstract We previously demonstrated that duration of aerobic exercise plays an important role in improving cognitive inhibitory control (IC). Repeated bouts of aerobic exercise (R‐EX), which are performed with a rest interval, is a useful strategy in improving physical health parameters in similar manners to a single bout of aerobic exercise (S‐EX). However, whether R‐EX would be effective in improving IC remains unknown. This study compared the effect of R‐EX versus S‐EX of moderate‐intensity exercise on postexercise IC. Twenty healthy, young males performed both R‐EX and S‐EX in a crossover design. R‐EX consisted of two 20‐min moderate‐intensity bouts (60% of peak oxygen consumption) for 20 min, which were separated by a 20‐min rest interval. S‐EX consisted of a once‐off 40‐min moderate‐intensity bout without rest interval. To evaluate IC, the color‐word Stroop task was administered before exercise, immediately after exercise, and every 10 min during the 30‐min postexercise recovery period. The reverse‐Stroop interference score, which is a parameter of IC, significantly decreased immediately after both R‐EX and S‐EX compared with that before each exercise (both Ps

Background: Blood flow restriction (BFR) exercise is recognized as a beneficial strategy in increasing skeletal muscle mass and strength. These positive effects can also be obtained by a mild exercise mode such as walking. However, BFR exacerbates some perceptual responses, such as perceived exertion response, induced by exercise. Despite this knowledge, the negative effects of BFR exercise on major perceptual parameters related to exercise adherence remain unknown. Furthermore, compared with other exercise modes (e.g., resistance exercise), little is known regarding the effects of BFR on perceptual responses to walking. To clarify these issues, we examined the effects of BFR walking on perceptual parameters, including exercise adherence-related parameters. Methods: Eighteen healthy, young males performed both BFR and non-BFR (NBFR) walking on a treadmill in a crossover design. Exercise was performed as five sets of 2-min walking with 1-min rest intervals. BFR walking was performed with 200 mmHg pressure cuffs placed around the proximal region of the thighs. NBFR walking was performed without pressure cuffs. Results: Ratings of perceived exertion and leg discomfort were significantly higher during BFR walking than during NBFR walking. Affect and task motivation were significantly lower during BFR walking than during NBFR walking; by contrast, perceived pain was significantly higher during BFR walking than during NBFR walking. Enjoyment immediately after walking was significantly lower with BFR than with NBFR. Conclusions: These findings suggest that BFR walking induces greater responses of perceptual parameters, including exercise adherence-related parameters, than does NBFR walking. Therefore, BFR walking may decrease adherence to this exercise. To further popularize BFR exercise, further studies are needed to develop effective strategies to minimize the BFR-induced negative effects on perceptual responses.

Objective: Maternal high-fat diet (HFD) has been shown to promote the development of insulin resistance (IR) in adult offspring; however, the underlying mechanisms remain unclear. Methods: Eight-week-old female wild-type mice (C57BL/6) were fed either an HFD or a normal diet (ND), one week prior to mating, and the diet was continued throughout gestation and lactation. Eight-week-old male offspring of both groups were fed an HFD for 8 weeks. Results: Offspring of HFD-fed dams (O-HFD) exhibited significantly impaired insulin sensitivity compared with the offspring of ND-fed dams (O-ND). The adipocyte size of the eWAT increased significantly in O-HFD and was accompanied by abundant crown-like structures (CLSs), as well as a higher concentration of interleukin 1β (IL-1β) in the eWAT. Treatment with an inflammasome inhibitor, MCC950, completely abrogated the enhanced IR in O-HFD. However, ex vivo caspase-1 activity in eWAT revealed no difference between the two groups. In contrast, noncanonical inflammasome activation of caspase-11 was significantly augmented in O-HFD compared with O-ND, suggesting that membrane pore formation, but not cleavage of pro-IL-1β by caspase-1, is augmented in O-HFD. To examine the membrane pore formation, we performed metabolic activation of bone marrow-derived macrophages (BMDMs). The percentage of pore formation assessed by ethidium bromide staining was significantly higher in BMDMs of O-HFD, accompanied by an enhanced active caspase-11 expression. Consistently, the concentration of IL-1β in culture supernatants was significantly higher in the BMDMs from O-HFD than those from O-ND. Conclusions: These findings demonstrate that maternal HFD exaggerates diet-induced IR in adult offspring by enhancing noncanonical caspase-11-mediated inflammasome activation.

Depression is an independent risk factor for cardiovascular disease and is significantly associated with the prevalence of abdominal aortic aneurysm (AAA). We investigated the effect of repeated social defeat (RSD) on AAA development. Eight-week-old male wild-type mice were exposed to RSD by being housed with larger CD-1 mice in a shared cage. They were subjected to vigorous physical contact. After the confirmation of depressive-like behavior, calcium chloride was applied to the infrarenal aorta of the mice. At one week, AAA development was comparable between the defeated and control mice, without any differences being observed in the accumulated macrophages or in the matrix metalloproteinase activity. At two weeks, the maximum diameter and circumference of the aneurysm were significantly increased in the defeated mice, and a significant decrease in periaortic fibrosis was also observed. Consistently, the phosphorylation of the extracellular signal-regulated kinase and the incorporation of 5-bromo-2′-deoxyuridine in the primarily cultured aortic vascular smooth muscle cells were significantly reduced in the defeated mice, which was accompanied by a substantial increase in mitogen-activated protein kinase phosphatase-1 (MKP-1). The MKP-1 mRNA and protein expression levels during AAA were much higher in the defeated mice than they were in the control mice. Our findings demonstrate that RSD enhances AAA development by suppressing periaortic fibrosis after an acute inflammatory response and imply novel mechanisms that are associated with depression-related AAA development.

Depression is an independent risk factor for cardiovascular disease (CVD). We have previously shown that repeated social defeat (RSD) exaggerates atherosclerosis development by enhancing neutrophil extracellular trap (NET) formation. In this study, we investigated the impact of RSD on arterial thrombosis. Eight-week-old male wild-type mice (C57BL/6J) were exposed to RSD by housing with larger CD-1 mice in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days. After confirming depression-like behaviors, mice underwent FeCl3-induced carotid arterial injury and were analyzed after 3 h. Although the volume of thrombi was comparable between the two groups, fibrin(ogen)-positive areas were significantly increased in defeated mice, in which Ly-6G-positive cells were appreciably co-localized with Cit-H3-positive staining. Treatment with DNase I completely diminished exaggerated fibrin-rich clot formation in defeated mice. Flow cytometric analysis showed that neutrophil CD11b expression before FeCl3 application was significantly higher in defeated mice than in control mice. In vitro NET formation induced by activated platelets was significantly augmented in defeated mice, which was substantially inhibited by anti-CD11b antibody treatment. Our findings demonstrate that RSD enhances fibrin-rich clot formation after arterial injury by enhancing NET formation, suggesting that NET can be a new therapeutic target in depression-related CVD.

Maternal high-fat diet (HFD) modulates vascular remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) development. Female wild-type mice were fed an HFD or normal diet (ND). AAA was induced in eight-week-old pups using calcium chloride. Male offspring of HFD-fed dams (O-HFD) showed a significant enlargement in AAA compared with the offspring of ND-fed dams (O-ND). Positive-staining cells for tartrate-resistant acid phosphate (TRAP) and matrix metalloproteinase (MMP) activity were significantly increased in O-HFD. The pharmacological inhibition of osteoclastogenesis abolished the exaggerated AAA development in O-HFD. The in vitro tumor necrosis factor-α-induced osteoclast-like differentiation of bone marrow-derived macrophages showed a higher number of TRAP-positive cells and osteoclast-specific gene expressions in O-HFD. Consistent with an increased expression of nuclear factor of activated T cells 1 (NFATc1) in O-HFD, the nuclear protein expression of interferon regulatory factor 8 (IRF8), a transcriptional repressor, were much lower, with significantly increased H3K27me3 marks at the promoter region. The enhancer of zeste homolog 2 inhibitor treatment restored IRF8 expression, resulting in no difference in NFATc1 and TRAP expressions between the two groups. Our findings demonstrate that maternal HFD augments AAA expansion, accompanied by exaggerated osteoclast-like macrophage accumulation, suggesting the possibility of macrophage skewing via epigenetic reprogramming.

A 67-year-old male, with a known diagnosis of myelodysplastic syndromes with multilineage dysplasia (MDS-MLD) was admitted to our hospital with a primary complaint of subcutaneous bleeding in his left thigh. Laboratory data showed anaemia and prolongation of activated partial thromboplastin time (85.8 s, normal range 24–39 s) without thrombocytopenia. Coagulation factor VIII (FVIII) activity was less than 1% (normal range 60–150%), and a FVIII inhibitor was identified and quantified at 166 BU/mL to indicate a diagnosis of acquired haemophilia A (AHA). A recent, but sustained circulating monocytosis (>1 × 109/L) was observed, which combined with elevated numbers of neutrophil and monocytic cells in the marrow, suggested evolution of MDS-MLD to chronic myelomonocytic leukaemia (CMML), coinciding with AHA. Further analysis revealed a karyotype of 46, XY, i(14) (q10), which was the same abnormality previously identified in the patient. To treat bleeding caused by AHA, steroid and activated prothrombin complex concentrate were administered. Azacitidine (AZA) was used to treat CMML. During the clinical course, bleeding partially improved; however, subsequent acute myocardial infarction occurred on day 87. Worsening bone marrow failure was observed 4 months after the original admission, despite administration of AZA therapy, and the patient died due to bleeding from AHA. This case suggests that the evolution of MDS to CMML status can be associated with AHA conferring a bleeding tendency.

Social stress (SS) has been linked to the development of cardiovascular disease (CVD), which is closely associated with insulin resistance (IR); however, the causal effect of SS on IR remains unclear. The 8-week-old male C57BL/6 mice were exposed to SS by housing with a larger CD-1 mouse in a shared home cage without physical contact for 10 consecutive days followed by high-fat diet (HFD) feeding. Control mice were housed in the same cage without a CD-1 mouse. After 6 weeks of HFD, insulin sensitivity was significantly impaired in stressed mice. While the percentage of classically activated macrophages in epididymal white adipose tissue (eWAT) was equivalent between the two groups, the percentage of lymphocyte antigen 6 complex locus G6D (Ly-6G)/neutrophil elastase (NE)-double positive cells markedly increased in stressed mice, accompanied by augmented NE activity assessed by ex vivo eWAT fluorescent imaging. Treatment with an NE inhibitor completely abrogated the insulin sensitivity impairment of stressed mice. In vitro NE release upon stimulation with a formyl peptide receptor 1 agonist was significantly higher in bone marrow neutrophils of stressed mice. Our findings show that SS-exposed mice are susceptible to the development of HFD-induced IR accompanied by augmented NE activity. Modulation of neutrophil function may represent a potential therapeutic target for SS-associated IR.

Introduction: In percutaneous coronary intervention (PCI) with a retrograde approach, successful guide wire passage through the collateral channels is indispensable. However, success of the procedure depends on the quality of collateral channels, and vascular tortuosity is one of the most common obstacles for successful guidewire passage. Case Presentation: Herein, we present a case of PCI with retrograde approach for chronic total occlusion at the ostium of the left anterior descending coronary artery. A highly tortuous morphology of the right posterior descending artery (PDA) and septal channels bifurcating from the right PDA with marked angulations were recognized in angiographic images from multiple directions. We could advance a guidewire to the optimal route of the septal collateral channel with guidance provided by these images and successfully completed all PCI procedures. Conclusions: To pass a guidewire through collateral arteries in PCI with a retrograde approach, careful inspection of angiographic images for thoroughly understanding the optimal route through the collateral vasculature is of great significance.

Introduction: In practical settings of endovascular treatment,wesometimes encounter difficulties in treating lesions with massive thrombi, which may cause distal thromboembolism. Case Presentation: We encountered a case of severe critical limb ischemia involving in-stent iliac occlusion with massive thrombi. We had to overcome the critical issue of how to treat the massive thrombi in the iliac artery while avoiding thromboembolism. Therefore, we devised a very simple but possibly very useful protection system without any special devices based on the concept of the Optimo® balloon-tipped occlusion catheter. Conclusions: Although various endovascular treatment (EVT) devices and techniques have since been developed, little tips and tricks during EVT procedures are sometimes markedly useful.