Inflammatory cytokines such as interleukin (IL)-1 beta and IL-18 play an important role in the development of atherosclerosis and restenosis. Apoptosis-associated speck-like protein containing a ...caspase recruitment domain (ASC) is an adaptor protein that regulates caspase-1-dependent IL-1 beta and IL-18 generation; however, the role of ASC in vascular injury remains undefined. Here, we investigated the contribution of ASC to neointimal formation after vascular injury in ASC-deficient (ASC(-/-)) mice.
Wire-mediated vascular injury was produced in the femoral artery of ASC(-/-) and wild-type mice. Immunohistochemical analysis revealed that ASC was markedly expressed at the site of vascular injury. Neointimal formation was significantly attenuated in ASC(-/-) mice after injury. IL-1 beta and IL-18 were expressed in the neointimal lesion in wild-type mice but showed decreased expression in the lesion of ASC(-/-) mice. To investigate the contribution of bone marrow-derived cells, we developed bone marrow-transplanted mice and found that neointimal formation was significantly decreased in wild-type mice in which bone marrow was replaced with ASC(-/-) bone marrow cells. Furthermore, in vitro experiments showed that the proliferation activity of ASC(-/-) vascular smooth muscle cells was not impaired.
These findings suggest that bone marrow-derived ASC is critical for neointimal formation after vascular injury and identify ASC as a novel therapeutic target for atherosclerosis and restenosis.
•In Japan, 66.8% atrial fibrillation patients were prescribed non-vitamin K oral anticoagulants (NOACs), well beyond the global average.•About 15% of patients received NOAC with a non-standardized ...dose reduction (NSDR).•Patients with CHA2DS2-VASc score ≥2 had the highest proportion of NSDRs.•The physician's apprehension for bleeding should be balanced with stroke risk.
Non-vitamin K antagonist oral anticoagulants (NOACs) have been widely used to prevent stroke in non-valvular atrial fibrillation (NVAF) patients. Stringent monitoring is not required for NOACs, albeit dose adjustments are needed based on specific patient factors, such as renal function, body weight and age, or concomitant medications. We investigated the NOAC dosing patterns and evaluated the predictors of the non-standardized dose reduction (NSDR).
A total of 2452 newly diagnosed NVAF patients were consecutively recruited from secondary- and tertiary-care hospitals between 2012 and 2017. The NOAC doses were classified as one of three: (1) full dose; (2) standardized dose reduction (SDR); or (3) NSDR, consistent with Japanese package inserts.
Overall, 66.8% (N=1637) of the NVAF patients (median age: 69 years, interquartile range IQR: 60–76; 70% male; median CHA2DS2-VASc score of 2, IQR: 1–3) received NOACs. NOAC use dramatically increased during the study period (51.2% in 2012–13 to 74.4% in 2016–17). The percentages of SDR and NSDR were 19.6% and 14.4%, respectively; a proportion of SDR and NSDR did not alter drastically. Older age, concomitant antiplatelet therapy, impaired renal function, and prior heart failure or left ventricular dysfunction were independently associated with NSDR. Of note, patients with a high risk (CHA2DS2-VASc score ≥2) had the highest proportion of NSDRs.
Nearly half of the NOAC dose reductions in our registry were deemed “non-standardized,” which were seen mostly in patients at significant risk for ischemic stroke. The physician's apprehension regarding excessive bleeding under NOAC use should be appropriately balanced with concern for an increased risk of embolic events.
A 61-year-old man had a Stanford type A acute aortic dissection, and the total aortic arch was replaced with 22-mm knitted Dacron graft in 1996. In 2006, he underwent mitral valve replacement and ...tricuspid valve repair due to severe mitral and tricuspid valve regurgitation. Although preoperative computed tomography (CT) scan suggested pseudoaneurysm around the Dacron graft replaced with aortic arch, it could not be repaired concomitantly. Four months later, in view of the technical difficulties of an open surgical procedure, the prosthetic graft failure was repaired by endovascular stent graft consisting of a Gianturco Z stent covered with an UBE woven Dacron graft. However, during a follow-up, aneurysm sac diameter increased without any sings of endoleak in follow-up CT scans. Redo endovascular stent graft placement using a Gore-TAG device was performed. Subsequently, shrinkage of the pseudoaneurysmal sac could be observed.
We studied the response of porcine vascular smooth muscle cells (PVSMCs) to cyclic sinusoidal stretch at a frequency of 1 Hz. Cyclic stretch with an area change of 25% caused an increase in PVSMC ...apoptosis, which was accompanied by sustained activation of c-Jun NH(2)-terminal kinases (JNK) and the mitogen-activated protein kinase p38. Cyclic stretch with an area change of 7% had no such effect. Infection of PVSMCs with recombinant adenoviruses expressing constitutively active forms of upstream molecules that activate JNK and p38 also led to apoptosis. The simultaneous blockade of both JNK and p38 pathways with adenovirus-mediated expression of dominant-negative mutants of c-Jun and p38 caused a significant decrease (to 1/2) of the apoptosis induced by 25% cyclic stretch. The 25% stretch also caused sustained clustering of tumor necrosis factor-alpha (TNF-alpha) receptor-1 and its association with TNF-alpha receptor-associated factor-2 (TRAF-2). Overexpressing the wild-type TRAF-2 in PVSMCs caused an increase in apoptosis. In contrast, the expression of a dominant-negative mutant of TRAF-2 attenuated stretch-induced apoptois. These results support the hypothesis that circumferential overload under hypertensive conditions induces a clustering of death receptors that cause vascular smooth muscle cell apoptosis.
An exopolygalacturonase exo-PGase; poly (1,4-α-D-galacturonide) galacturonohydrolase, EC 3.2.1.67 was found to be extracellularly produced by Bacillus sp. strain KSM-P443. The exo-PGase was purified ...to homogeneity, as judged by polyacrylamide gel electrophoresis, through sequential column chromatographies. The enzyme had a molecular weight of approximately 45,000 and an isoelectric point of pH 5.8. The N-terminal sequence was Ser-Met-Gln-Lys-Ile-Lys-Asp-Glu-Ile-Leu-Lys-Thr-Leu-Lys-Val-Pro-Val-Phe and had no sequence similarity to those of other petinolytic enzymes reported to date. Maximum activity toward polygalacturonic acid (PGA) was observed at 60°C and at pH 7.0 in 100 mM Tris-HCl buffer without requiring any metal ions. When the chain length of oligogalacturonic acids increased, the apparent Km for them decreased, but the kcat values increased. This is the first bacterial exo-PGase that releases exclusively mono-galacturonic acid from PGA, di-, tri-, tetra-, and penta-galacturonic acids.
Weekly pulsed low-dose methotrexate (MTX) is a standard regimen for rheumatoid arthritis (RA). Severe adverse reactions to MTX, such as pneumonia and cytopenia, sometimes occur; however, it is ...difficult to predict the development of these adverse reactions. In this article, we examine the serum concentrations of orally administered MTX of 69 Japanese patients with RA in the clinical setting. The maximum serum concentration (C (max)) after the first dose of the weekly administration and the time at which C (max) was obtained (T (max)) were analyzed. C (max) correlated with the administered dose before measurement. The average T (max) was 2.0 +/- 0.8 h, and none of the patients showed a T (max) of more than 4 h. In addition, we demonstrated that the weekly MTX dosage and the mean dosage of steroids were significantly higher in patients with adverse reactions than in those without them, and the C (max) after the first dose of the weekly administration particularly correlated with the incidence of adverse reactions (P < 0.001). In fact, the cut-off point of C (max) (0.16 micromol/l) was a sensitive predictor of the adverse reactions (sensitivity 81% and specificity 67%). We concluded that C (max) after the first dose of weekly administration is a useful parameter for predicting the development of adverse reactions to MTX.
We report a case of abdominal aortic aneurysm invaded by periaortic malignant lymphoma. An 86-year-old woman who had had persistent abdominal pain for several days was urgently admitted to our ...hospital with suspected ruptured abdominal aortic aneurysm. An enhanced computed tomography scan showed an infrarenal aortic aneurysm with an area of soft tissue density in the retroperitoneal region, suggestive of hematoma. We performed emergency abdominal aortic reconstruction under a diagnosis of impending rupture of an abdominal aortic aneurysm. The intraoperative diagnosis was inflammatory abdominal aortic aneurysm, but the specimen from the abdominal wall revealed diffuse large B-cell lymphoma. She underwent chemotherapy, but died of multiple organ failure during the course of treatment.
Since the macrophage colony-stimulating factor (M-CSF) has been shown to stimulate differentiation and proliferation of monocyte/macrophage lineage and to be involved in the process of neointimal ...formation after vascular injury, we tested the effects of M-CSF on the recruitment of bone marrow-derived progenitor cells in neointimal formation after vascular injury in mice.
Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. Recombinant human M-CSF 500 microg/(kg x day) or saline (control) was administered for 10 consecutive days, starting 4 days before the injury. Treatment with M-CSF accelerated neointimal formation in the early phase after injury, and this neointimal lesion mainly consisted of bone marrow-derived cells. M-CSF treatment had no effect on the mobilization of endothelial progenitor cells (EPCs: CD34+/Flk-1+) and reendothelialization after injury. The stromal cell-derived factor-1 (SDF-1) was markedly expressed in the neointima and media after injury, whereas CXCR4+ cells were observed in the neointima. Further, a novel CXCR4 antagonist, AMD3100, significantly attenuated the M-CSF-induced neointimal formation.
These findings suggest that M-CSF accelerated neointimal formation after vascular injury via the SDF-1-CXCR4 system, and the inhibition of this system has therapeutic potential for the treatment of cardiovascular diseases.
The present study investigated the metabolic fate of dietary TAG and DAG and also their digestion products in the stomach and small intestine. A diet containing 10% TAG or DAG oil, enriched in ...1,3‐DAG, was fed to Wistar rats ad libitum for 9 d. After 18 h of fasting, each diet was re‐fed ad libitum for 1 h. The weights of the contents of the stomach and small intestine were measured, and the acylglycerol and FFA levels were analyzed by GC at 0, 1, and 4 h after the 1‐h re‐feeding. The amounts of re‐fed diet ingested and the gastric and small intestinal content were not different between the two diet groups. In the TAG diet group, the main products were TAG and DAG, especially 1(3),2‐DAG. In addition, 1,3‐DAG and 1(3)‐MAG were present in the stomach, and the 1,3‐DAG levels increased over time after the re‐feeding period. In the DAG diet group, the main products in the stomach were DAG, MAG, FFA, and TAG. There were significantly greater amounts of 1,3‐DAG, 1(3)‐MAG, and FFA in the DAG diet group in the stomach compared with the TAG diet group. The amount of FFA in the stomach relative to the amount of ingested TAG plus DAG in the DAG diet group was higher than that in the TAG diet group. Acylglycerol and FFA levels were considerably lower in the small intestine than in the stomach. These results indicate that, in the stomach, where acyl migration might occur, the digestion products were already different between TAG and DAG oil ingestion, and that DAG might be more readily digested by lingual lipase compared with TAG. Furthermore, almost all of the dietary lipid was absorbed, irrespective of the structure of the acylglycerol present in the small intestine.
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