Concentrations of immunoreactive tonin in submandibular glands and saliva of the rat

The submandibular gland (SMG) of the rat contains tonin, an enzyme of serine proteases, which specifically cleaves angiotensinogen and angiotensin I to yield angiotensin II directly. Using a specific RIA for rat tonin, the present study was performed to examine the concentrations of immunoreactive (IR) tonin in SMG of normal Wistar male rats with various ages, those in SMG and saliva of normal adult males and females, and also its SMG levels of castrated males and testosterone-treated females. The concentrations of IR-tonin in SMG of immature 4 week old male rats were very low but rose exponentially with increasing age to reach adult levels (3-6 micrograms/mg wet tissue) in male rats after 6 week old or more. SMG of the adult male rat contained 10-fold more IR-tonin than that of the female rat and male saliva contained 5-fold more IR-tonin than that of females. The concentrations of SMG IR-tonin in the castrated males fell to about one-tenth the levels of normal males, whereas SMG IR-tonin levels in the testosterone-treated females increased about ten times more than those of normal females. These data confirm the sexual dimorphism of rat SMG with respect to the concentrations of tonin and indicate that androgens play an important role in regulating the synthesis and/or storage of tonin in rat SMG. It is also suggested that tonin is secreted into saliva in concentrations reflecting its SMG levels. However, biological significance of tonin in SMG and saliva remains obscure.     

Effects of laser irradiation on human erythrocytes: Considerations concerning clinical laser angioplasty

Recent studies demonstrate the potential use of laser to vaporize human coronary atherosclerotic plaques. The laser energy is transmitted through flexible quartz fiber and discharged intravascularly. Since red blood cells could be exposed to intense heat, we examined effects of laser irradiation on human erythrocytes. Blood was obtained and placed in 5 ethylene diaminetetracidic acid (EDTA) vials for each normal donor. A flexible 400 diameter core quartz fiber coupled to an argon-ion laser source was positioned 1 cm above the surface of 1.5 ml blood. Four vials were exposed to 5 W laser beam for 5, 10, 15, or 20 s; the remaining vial was left untreated. Packed cell volume fell primarily during the first 5 s of laser exposure (p<0.01) and plateaued beyond 5 s. Plasma hemoglobin (Hgb) rose progressively with each increased duration of exposure (p<0.01). This study indicates that lysis of erythrocytes occurs in cells exposed directly to the laser beam. However, beyond the direct beam, damage to red cell membrane took place as evident by progressive Hgb leakage into plasma despite no further cell lysis. These observations require consideration during clinical laser angioplasty.     

Interleukin 6 expression in coronary circulation after coronary angioplasty as a risk factor for restenosis

OBJECTIVE—To investigate changes in cytokine expression in the coronary circulation induced by percutaneous transluminal coronary angioplasty (PTCA).
METHODS—The study involved 32 patients with ischaemic heart disease who underwent elective PTCA for isolated stenotic lesions of the left coronary artery. Ten patients had plain old balloon angioplasty, 10 had percutaneous transluminal rotational atherectomy, and 12 had stent implantation. Blood samples were drawn from the coronary sinus before and immediately after PTCA. Plasma concentrations of interleukin 6 (IL-6), platelet derived growth factor (PDGF), monocyte chemoattractant protein 1 (MCP-1), and macrophage coronary stimulating factor (M-CSF) were measured. The patients were scheduled for follow up angiography six months after PTCA. Late loss index was calculated using quantitative coronary angiography.
RESULTS—IL-6 concentrations in coronary sinus blood increased immediately after PTCA (p < 0.001), but there was no change in PDGF, MCP-1, or M-CSF. There was a positive correlation between changes in IL-6 concentrations immediately after PTCA and late loss index six months after PTCA (r = 0.73, p < 0.001). IL-6 concentrations in coronary sinus blood were higher in patients with late restenosis than in those without restenosis (p < 0.001).
CONCLUSIONS—PTCA induces IL-6 production in the coronary circulation. This may induce subsequent inflammatory responses in injured vessels and play an important role in late restenosis after PTCA.


Keywords: inflammation; cytokine; restenosis     

Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial

Background

Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial.

Methods

The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e’) assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study.

Conclusions

The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

     

Illegitimate recombination mediated in vitro by DNA gyrase of Escherichia coli: structure of recombinant DNA molecules.

We have developed a cell-free system from Escherichia coli for studying illegitimate recombination between nonhomologous DNA molecules. The recombination is stimulated by oxolinic acid, an inhibitor of DNA gyrase. The stimulation is abolished by coumermycin A1 and is not found in extracts of nalidixic acid-resistant (gyrA) mutants. We therefore inferred that DNA gyrase directly participates in illegitimate recombination, at least in the presence of oxolinic acid [Ikeda, H., Moriya, K. & Matsumoto, T. (1981) Cold Spring Harbor Symp. Quant. Biol. 45, 399--408]. The structure of recombinant DNA molecules formed in the presence of oxolinic acid from a cross between phage lambda and plasmid pBR322 DNAs was analyzed by heteroduplex mapping. Among nine isolates tested, two recombinants were formed by the insertion of the plasmid into the lambda genome. The seven other recombinants had more complicated genome structures. Insertion of pBR322 was accompanied by a deletion on one of the genomes. In all cases, the end points of deletions coincided with one end of the pBR322 insertion. Recombination sites seemed to be distributed randomly on the lambda and pBR322 genomes. Analysis of nucleotide sequences of the recombination junctions proved that the crossover took place between nonhomologous DNA sequences. A model for DNA gyrase-mediated illegitimate recombination is discussed.     

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome in Nagano, Japan: clinical, radiological, and cytokine studies of 13 patients

OBJECTIVE: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) has so far been reported almost exclusively from the USA and Europe. We carried out this study to define the clinical characteristics of this syndrome in Japanese patients. METHODS: Prospectively, we identified 13 Japanese patients with RS3PE (5 men and 8 women, age 72.7 +/- 11.8 years (mean +/- SD)) without underlying neoplasm. Their clinical features were summarized, pertinent laboratory data including serum/synovial interleukin-6 (IL-6) concentrations were obtained, and extensive radiologic studies using magnetic resonance imaging and 67gallium-citrate (67Ga) whole body scintigram were performed. RESULTS: All patients suffered from proximal arthralgia/myalgia in addition to typical distal symptoms of RS3PE, and all experienced systemic symptoms such as fever, malaise, and weight loss. In laboratory examinations, anemia and elevated inflammatory markers were often remarkable. Magnetic resonance imaging showed severe tenosynovitis of the hands. 67Ga-scintigram revealed radioisotope accumulation in both proximal and distal joints of the extremities. IL-6 activity was markedly elevated both in the serum (mean 82.4 +/- 62.1 (SD) pg/ml, normal range 0.157-2.94) and in the synovial fluid (mean 3350 +/- 633 (SD) pg/ml). CONCLUSION: Compared with cases reported previously from the USA/Europe, Japanese patients with RS3PE are characterized by more prominent systemic symptoms/signs associated with marked inflammatory responses including elevated IL-6 activity. All patients had proximal as well as distal synovitis which could be demonstrated by 67Ga-scintigram. These clinical features were very similar to those of polymyalgia rheumatica, suggesting that RS3PE and polymyalgia rheumatica are closely related disorders which may have a common pathogenesis.     

Conformal radiation therapy for liver metastasis of esophageal carcinoma

Recently, aggressive hepatectomies or hepatic arterial infusion chemotherapy for liver metastasis from gastric or colorectal carcinoma have been performed, and the number of successful studies of liver metastasis have increased. However, there have been few successful cases of liver metastasis from esophageal carcinoma by surgery or chemotherapy. Herein, we show the benefits of radiation therapy for the treatment of liver metastasis from esophageal carcinoma. A 60-year-old woman with a 5-cm solitary liver metastasis from esophageal squamous cell carcinoma was treated with radiation therapy. The treated volume was encompassed by the anteroposterior and right lateral opposing fields, shaped by a multileaf collimator. The daily fraction size was 1.8 Gy, 5 days per week, for a total dose of 54 Gy. During the course of treatment, the patient did not experience any complications. After radiotherapy, abdominal computed tomography showed that the enhanced solid tumor had changed to a very low-density mass lesion with a clear margin, and the size was decreasing gradually between the 6 months. Radiotherapy could be a treatment of choice in patients with liver metastasis from esophageal squamous cell carcinoma.     

Intraepithelial lymphocytes in colon have similar properties to intraepithelial lymphocytes in small intestine and hepatic intermediate TCR cells

Recently, properties of intraepithelial lymphocytes (IEL) in the colon (C-IEL) have been analyzed in comparison with those of IEL in the small intestine (SI-IEL). We compared the properties of C-IEL with those of SI-IEL and hepatic intermediate TCR cells, two other types of extrathymic T cells. C-IEL and intermediate TCR cells contain many NK1⁺T cells, although SI-IEL contain few. V and V usage of C-IEL was the same as that of SI-IEL, and that of intermediate TCR cells was different. C-IEL responded to Con A while SI-IEL did not. As to adhesion molecules, C-IEL include both extrathymic and thymus-originated type T cells. With age, TCR-⁺CD4⁺CD8⁺ cells do not increase among C-IEL but do increase among SI-IEL. IL-2R⁺ or CD4^–CD8^– C-IEL increase as observed in the liver. These results indicate that these organ-specific T cells have different roles at their respective sites and that they may be of different lineages.     

Circulating advanced glycation end products (AGEs) and soluble form of receptor for AGEs (sRAGE) are independent determinants of serum monocyte chemoattractant protein-1 (MCP-1) levels in patients with type 2 diabetes

BACKGROUND: Atherosclerosis is an inflammatory disease. Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine responsible for the recruitment of monocytes to inflammatory lesions in the vasculature, an initial step of atherosclerosis. Since serum levels of MCP-1 are higher in patients with type 2 diabetes, inhibition of MCP-1 may be a novel therapeutic target for prevention of accelerated atherosclerosis in diabetes. However, little is known about the regulation and determinants of serum MCP-1 levels in patients with diabetes. In this study, we examined the determinants of serum MCP-1 levels in type 2 diabetic patients. METHODS: Eighty-six consecutive outpatients with type 2 diabetes (36 male and 50 female; mean age 68.4+/-9.6) underwent a complete history and physical examination, determination of blood chemistries, MCP-1, tumour necrosis factor-alpha, adiponectin, advanced glycation end products (AGEs), and soluble form of receptor for AGEs (sRAGE). We examined the association between MCP-1 levels and those in anthropometric, metabolic and inflammatory variables in these subjects. RESULTS: Univariate regression analysis showed that serum levels of MCP-1 were positively associated with AGEs (r=0.386, p<0.001) and sRAGE (r=0.315, p<0.001). After adjusting for age and sex, AGEs (p<0.001) and sRAGE (p<0.05) still remained significant. CONCLUSION: The results demonstrate for the first time that circulating levels of AGEs and sRAGE are independent determinants of serum MCP-1 levels in patients with type 2 diabetes. Our present observations suggest the AGEs-RAGE system may be mainly involved in the elevation of MCP-1 in type 2 diabetic patients.     

Atorvastatin induces associated reductions in platelet P-selectin, oxidized low-density lipoprotein, and interleukin-6 in patients with coronary artery diseases

The development and progression of atherosclerosis comprises various processes, such as endothelial dysfunction, chronic inflammation, thrombus formation, and lipid profile modification. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that have pleiotropic effects in addition to cholesterol-lowering properties. However, the mechanisms of these effects are not completely understood. Here, we investigated whether atorvastatin affects the levels of malondialdehyde-modified low-density lipoprotein (MDALDL), an oxidized LDL, the proinflammatory cytokine interleukin-6 (IL-6), or platelet P-selectin, a marker of platelet activation, relative to that of LDL cholesterol (LDL-C). Forty-eight patients with coronary artery disease and hyperlipidemia were separated into two groups that were administered with (atorvastatin group) or without (control group) atorvastatin. The baseline MDA-LDL level in all participants significantly correlated with LDL-C (r = 0.71, P < 0.01) and apolipoprotein B levels (r = 0.66, P < 0.01). Atorvastatin (10 mg/day) significantly reduced the LDL-C level within 4 weeks and persisted for a further 8 weeks of administration. Atorvastatin also reduced the MDA-LDL level within 4 weeks and further reduced it over the next 8 weeks. Platelet P-selectin expression did not change until 4 weeks of administration and then significantly decreased at 12 weeks, whereas the IL-6 level was gradually, but not significantly, reduced at 12 weeks. In contrast, none of these parameters significantly changed in the control group within these time frames. The reduction (%) in IL-6 between 4 and 12 weeks after atorvastatin administration significantly correlated with that of MDALDL and of platelet P-selectin (r = 0.65, P < 0.05 and r = 0.70, P < 0.05, respectively). These results suggested that the positive effects of atorvastatin on the LDL-C oxidation, platelet activation and inflammation that are involved in atherosclerotic processes are exerted in concert after lowering LDL-C.