Duality of n-3 Polyunsaturated Fatty Acids on Mcp-1 Expression in Vascular Smooth Muscle: A Potential Role of 4-Hydroxy Hexenal

N-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have protective effects against atherosclerosis. Monocyte chemotactic protein (MCP)-1 is a major inflammatory mediator in the progression of atherosclerosis. However, little is known about the regulation of Mcp-1 by DHA and EPA in vessels and vascular smooth muscle cells (VSMCs). In this study, we compared the effect of DHA and EPA on the expression of Mcp-1 in rat arterial strips and rat VSMCs. DHA, but not EPA, suppressed Mcp-1 expression in arterial strips. Furthermore, DHA generated 4-hydroxy hexenal (4-HHE), an end product of n-3 polyunsaturated fatty acids (PUFAs), in arterial strips as measured by liquid chromatography-tandem mass spectrometry. In addition, 4-HHE treatment suppressed Mcp-1 expression in arterial strips, suggesting 4-HHE derived from DHA may be involved in the mechanism of this phenomenon. In contrast, Mcp-1 expression was stimulated by DHA, EPA and 4-HHE through p38 kinase and the Keap1-Nuclear factor erythroid-derived 2-like 2 (Nrf2) pathway in VSMCs. In conclusion, there is a dual effect of n-3 PUFAs on the regulation of Mcp-1 expression. Further study is necessary to elucidate the pathological role of this phenomenon.     

Influence of power setting on superior vena cava potential during right pulmonary vein isolation

Purpose

High-power short-duration (HP-SD) ablation could reduce collateral tissue damage by shortening the conductive heating phase. However, it is difficult to evaluate the transmural effect of ablation lesions during pulmonary vein isolation (PVI) procedures. The present study aimed to evaluate the change in superior vena cava (SVC) potential delay as a surrogate marker of collateral tissue damage during right PVI, which is adjacent to SVC.

Methods

Out of 250 consecutive patients who underwent PVI, 86 patients in whom SVC potential during sinus rhythm was recorded both before and after right PVI were analyzed. In 46 of the patients, an HP-SD setting of 45–50 W was used (HP-SD group). In the remaining 40 patients, a conventional power setting of 20–30 W was used (conventional group). We compared the change in SVC potential delay after right PVI, radiofrequency energy, and mean contact force in the anterior–superior right PVI line, which was close to the posterior aspect of SVC, between the two groups.

Results

Although the total delivered radiofrequency energy (2,924 J vs. 2,604 J) and the mean contact force (18.5 g vs. 16.0 g) in the SVC overlapping area did not differ, the change in SVC potential delay after right PVI was significantly longer in the conventional group compared to the HP-SD group (5.0 ms vs. 0.0 ms, p?<?0.001).

Conclusions

The changes in SVC potential delay after right PVI might be a surrogate marker of collateral tissue damage according to the used energy settings.

     

Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation

Caspase-3 is a major cell death effector protease in the adult and neonatal nervous system. We found a greater number and higher density of cells in the cortex of caspase-3(-/-) adult mice, consistent with a defect in developmental cell death. Caspase-3(-/-) mice were also more resistant to ischemic stress both in vivo and in vitro. After 2 h of ischemia and 48 h of reperfusion, cortical infarct volume was reduced by 55%, and the density of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells was decreased by 36% compared with wild type. When subjected to oxygen-glucose deprivation (2 h), cortical neurons cultured from mice deficient in caspase-3 expression were also more resistant to cell death by 59%. Mutant brains showed caspase-specific poly(ADP-ribose) polymerase cleavage product (85-kDa fragment) in vivo and in vitro, suggesting redundant mechanisms and persistence of caspase-mediated cell death. In the present study, we found that caspase-8 mediated poly(ADP-ribose) polymerase cleavage in caspase-3(-/-) neurons in vivo and in vitro. In addition, mutant neurons showed no evidence of compensatory activation by caspase-6 or caspase-7 after ischemia. Taken together, these data extend the pharmacological evidence supporting an important role for caspase-3 and caspase-8 as cell death mediators in mammalian cortex and indicate the potential advantages of targeting more than a single caspase family member to treat ischemic cell injury.     

Changes in plasma atrial natriuretic peptide after angiocardiography

BACKGROUND:

Angiocardiography is an important diagnostic modality for evaluation of heart disease. It is well known that the concentration of plasma atrial natriuretic peptide (ANP) increases after injection of contrast medium. On the other hand, some patients with hypertension, heart failure or cardiac hypertrophy have an increased plasma ANP concentration at baseline; however, whether ANP increases after angiography in these patients is unknown.

OBJECTIVES:

To investigate changes in plasma ANP concentrations after angiocardiography in patients with high ANP concentrations at baseline.

PATIENTS AND METHODS:

Plasma ANP concentrations of 32 patients with angina pectoris were measured before and after angiocardiography. They were then classified into two groups according to their ANP concentration before examination.

RESULTS:

ANP concentration after the injection of contrast medium increased significantly in patients with normal ANP concentrations before angiography but did not change in patients with high ANP concentrations at rest.

CONCLUSIONS:

These results suggest that the absence of an increase in ANP after angiography may in part be due to reduced sensitivity to the angiography stimulus or to an already maximal activation of ANP secretion at baseline.     

Haptoglobin therapy for acute favism: a Japanese boy with glucose-6-phosphate dehydrogenase Guadalajara

Summary. We report the case of a 2-year-old Japanese boy with acute favism who was treated with human haptoglobin products. He had been exhibiting chronic nonspherocytic haemolytic anaemia until the diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency when 14 months old. He suffered a favic crisis at 24 months of age, when the administration of haptoglobin was effective for relieving bilirubinaemia and haemoglobinuria. Serum-free Hb rapidly decreased to normal levels despite the sustained level of serum lactate dehydrogenase. His G6PD gene was G6, Guadalajara. This is the first application of haptoglobin therapy for acute favism and the first reported case of Japanese G6PD deficiency with typical favic crisis. Haptoglobin treatment might be helpful for managing the haemolytic crisis in the disease.     

Usefulness of preheparin lipoprotein lipase mass as a parameter for predicting the efficacy of colestimide

This study was conducted to clarify the characteristics of colestimide responders. Forty-seven non-diabetic patients with high levels of low-density lipoprotein cholesterol (LDL-C) received colestimide at 3,000 mg/day and were followed up for 4 months. After 4 months, body weight was reduced but the change was not statistically significant. Total serum cholesterol (TC) and LDL-C levels significantly decreased from 280 to 232 mg/dl and from 195 to 150 mg/dl, respectively (p<0.01 versus before colestimide was administered). Serum triglyceride (TG) levels increased, but the change was not significant. Preheparin lipoprotein lipase mass (preheparin LPL mass) at baseline was significantly higher in colestimide responders (greater than a 20% decrease of LDL-C: n=28) than non-responders (76.2 ng/ml versus 50.3 ng/ml, p<0.05: n=19). Next, the subjects were divided into those with a high (n=33) and low (n=14) preheparin LPL mass at baseline. LDL-C levels were significantly decreased in patients with a high preheparin LPL mass while TG levels were significantly increased in patients with a low preheparin LPL mass. These results suggest that baseline preheparin LPL mass may be a marker of the response to colestimide.     

Increased Serum Type IV Collagen 7-S Levels in Patients with Hepatic Metastasis

Objective: The purpose of this study was to assess scrum type IV collagen 7-S domain (IV 7-S) levels in colorectal cancer patients with hepatic metastasis and to investigate the relation between serum IV 7-S levels and type IV collagenase activities in tumor tissue. Methods: Tissue type IV collagena.se activity and serum IV 7-S were measured in 50 colorectal cancer patients without hepatic metastasis and in 26 patients with hepatic metastasis. Results: Type IV collagenase showed significantly higher activities in colorectal cancer (n = 36) than in colorectal normal mucosa (n = 36) ( p < 0.001), but significantly lower activities were shown in the hepatic metastatic tumor (n = 18) than in the primary tumor (n = 36) and normal liver tissue (n = 18) ( p < 0.001). No significant correlation was (bund between type IV collagenase activities in the tumor and serum IV 7-S levels. Colorectal cancer patients with hepatic metastasis (n = 26) had significantly higher serum IV 7-S levels than those without hepatic metastasis (n = 50) ( p < 0.001). Moreover, serum IV 7-S levels correlated significantly with hepatic metastatic tumor volume in patients with synchronous ( r = 0.719, p < 0.001, n = 26) and in patients with metachronous ( r = 0.910, p < 0.001, n = 16) hepatic metastasis. Conclusion: We suggest that serum IV 7-S levels may increase in hepatic metastasis, not by the degradation of type IV collagen in the primary and secondary tumors, but by the enhanced production of type IV collagen responsive to hepatic metastasis. The measurement of serum IV 7-S levels might be a useful tumor marker of hepatic metastasis reflecting hepatic metastatic tumor volume.     

Two cases of atypical femoral fracture in cancer patients administered with bone-modifying agents

Objective: We report two cases of atypical femoral fracture (AFF) in patients with cancer.Patients: Two patients, a 53-year-old woman with breast cancer and a 77-year-old man with prostate cancer, could not walk after being injured in a fall. They used bone-modifying agents (BMA) for the prevention of bone metastasis for three and four years, respectively.Results: Intramedullary nails were placed to fix the femoral fractures in each patient. Neither of them had pathological metastatic femoral fractures based on fracture site specimens; however, severe suppression of bone turnover at the fracture site was suspected. Both patients could ambulate with a T-cane and were free of hip pain after surgery. Radiographs showed no callus formation at the fracture site.Conclusion: Based on the two cases of AFF in patients with cancer related to BMA use, we should consider that the incidence of AFF may be associated with long-term BMA use.     

Concerted interaction between origin recognition complex (ORC), nucleosomes and replication origin DNA ensures stable ORC–origin binding

Chromosomal replication origins, where DNA replication is initiated, are determined in eukaryotic cells by specific binding of a six‐subunit origin recognition complex (ORC). Many biochemical analyses have showed the detailed properties of the ORC–DNA interaction. However, because of the lack of in vitro analysis, the molecular architecture of the ORC–chromatin interaction is unclear. Recently, mainly from in vivo analyses, a role of chromatin in the ORC–origin interaction has been reported, including the existence of a specific pattern of nucleosome positioning around origins and of a specific interaction between chromatin—or core histones—and Orc1, a subunit of ORC. Therefore, to understand how ORC establishes its interaction with origin in vivo, it is essential to know the molecular mechanisms of the ORC–chromatin interaction. Here, we show that ORC purified from yeast binds more stably to origin‐containing reconstituted chromatin than to naked DNA and forms a nucleosome‐free region at origins. Molecular imaging using atomic force microscopy (AFM) shows that ORC associates with the adjacent nucleosomes and forms a larger complex. Moreover, stable binding of ORC to chromatin requires linker DNA. Thus, ORC establishes its interaction with origin by binding to both nucleosome‐free origin DNA and neighboring nucleosomes.