Activation of microvascular endothelial cells in active ulcerative colitis and detection of inducible nitric oxide synthase.

Endothelial nitric oxide (NO) synthase (NOS) that is expressed constitutively on microvascular endothelium is believed to be essential to systemic and/or local vascular integrity. Endothelial cells (ECs) were reported to express inducible NOS (iNOS) under some conditions iNOS expression indicates vascular activation. In this study we examined microvascular activation using ECs obtained from patients with ulcerative colitis (UC). We cultured ECs from the mesenteries of surgical UC patients and assayed NOS activity by NADPH-diaphorase cytochemistry and immunocytochemistry with an anti-iNOS antibody. Strong NOS activity was demonstrated on the cells from UC patients (5/5), whereas no activity was detected on the cells from cancer patients and human umbilical vein endothelial cells (HUVEC 0/5, 0/5). Strong iNOS activity was detected by immunoreaction, and large amounts of NO generated were detected by the conversion from [14C]arginine to [14C]citrulline (HUVEC 624+/-376 vs. EC-UC 1,492+/-233 dpm). These results suggest the possibility that ECs express spontaneous and continuous iNOS in active UC. They indicate a close relationship of vascular activation with the pathogenesis of UC.

Gay men and HIV in Japan.

Unique aspects of Japanese culture have shaped the response of homosexual men to HIV infection in Japan. Japan is a relatively homogeneous society that has, by and large, felt invulnerable to AIDS, viewing it primarily as a Western phenomenon. This attitude has been common in the gay community as well and has resulted in some gay men engaging in high-risk behavior. Among those who have contracted HIV, there is often a sense of denial, so men often do not seek help until they develop AIDS. However, many motivated gay men in Japan are establishing prevention programs geared toward the gay community. In many cases, these programs are modeled on those developed by community groups in the United States but are adapted to Japanese culture. Cooperation and collaboration with governmental prevention programs, a new concept to the gay community in Japan, is proving to be mutually beneficial in reaching a high-risk population.

High nitric oxide synthase activity in endothelial cells in ulcerative colitis.

Endothelial nitric oxide (NO) synthase, a unique NO synthase (NOS) isoform that is expressed constitutively by the vascular endothelium both in vivo and in vitro, is believed to be essential to systemic and/or local vascular integrity. NOS expression by endothelial cells may indicate vascular activation. We successfully established a simple method for the culture of microvascular endothelial cells from a small amount of tissue and investigated ulcerative colitis (UC), in which condition vascular factors have not been studied extensively. We cultured endothelial cells from the mesenteries of surgical patients with UC and assayed NOS activity by reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. Strong NOS activity was demonstrated in the cells from all UC patients (5/5), whereas no activity was detected in the cells from human umbilical veins and the mesenteries of colon cancer patients (0/10 and 0/5, respectively). This strong NOS activity was not diminished by incubation with a high concentration of glucocorticoid, suggesting that it was constitutive. These results indicate a close relationship of vascular activation (high NOS activity) with the pathogenesis of UC.

N-[2-[N'-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl]- (2-methyl-1-naphthylthio)acetamide (FY-087). A new acyl coenzyme a:cholesterol acyltransferase (ACAT) inhibitor of diet-induced atherosclerosis formation in mice.

FY-087 (N-[2-[N'-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl]- (2-methyl-1-naphthylthio)acetamide) was found to be a competitive inhibitor of human microsomal acyl coenzyme A:cholesterol acyltransferase (ACAT) with an IC50 value of 0.11 microM. Under our assay conditions, other ACAT inhibitors tested, specifically YM-750, E-5324, and melinamide, all of which are now in phase I clinical trials or in clinical use in Japan, inhibited this enzyme with IC50 values of 0.18, 0.14, and 3.2 microM, respectively. FY-087 also inhibited ACAT in acetyl-low density lipoprotein loaded human macrophages (THP-1 cells) with an IC50 of 0.17 microM. Following the oral administration of FY-087 (30 mg/kg) to rats, the plasma concentration of FY-087 reached 0.42 microgram/mL after 2 hr. This concentration of FY-087 was enough to inhibit blood vessel ACAT activity. Cholesterol-lowering and anti-atherogenic effects of FY-087 were examined using C57BL/6J mice fed an atherogenic diet. In this mouse model, treatment with FY-087 (28 mg/kg) inhibited the increase in plasma cholesterol levels by about 20% and decreased the hepatic accumulation of free and esterified cholesterol by 61 and 67%, respectively. FY-087 also significantly inhibited the atherogenic diet-induced increase in the fatty-streak lesion area of the proximal aorta by 57% in C57BL/6J mice. These results indicate that FY-087 is not only a therapeutically bioavailable ACAT inhibitor that lowers plasma cholesterol levels, but also an effective anti-atherogenic agent in mice fed an atherogenic diet.

[Retrograde systemic venous perfusion with selective jugular cannulation].

46 patients underwent surgery for the ascending aorta and the aortic arch using continuous hypothermic retrograde systemic venous perfusion (RSVP). Good cerebral protection has been obtained by this method in most patients including four in whom periods of retrograde perfusion exceeded 90 minutes (the longest 140 min). In first 19 patients retrograde perfusion was performed through conventional caval cannulae, but one of them sustained serious neurological damage despite a relatively short duration of retrograde perfusion probably due to impediment of retrograde flow to the brain with venous valves at the jugular-subclavian junction. Then we have developed a new technique that employs a cavoatrial cannula inserted selectively into the internal jugular vein beyond the valve at the venous angle and have applied this technique in last 27 patients.

Efficacy and pitfalls of the STATAK soft-tissue attachment device for the Bankart repair.

This report describes the results of Bankart repair with the use of a soft-tissue attachment device in 15 consecutive patients with traumatic, recurrent anterior instability of the shoulder. The mean operative time was 18 minutes shorter when compared with our previous series with the traditional transosseous suture technique. The surgical outcome was satisfactory in 12 patients and unsatisfactory in three. In two of these three patients, incomplete anchoring of the device seemed to have caused subluxation after the operation. Thus this device has the potential to shorten the operative time, but great care must be taken to securely position it below the cortical surface.

[Leukotriene B4, leukotriene C4 and prostaglandin E2 in the serum, synovial fluid and synovium in patients with rheumatoid arthritis].

This study investigated the presence of arachidonic acid metabolites, (leukotriene B4, leukotriene C4 and prostaglandin E2) in the serum, synovial fluid and synovium of rheumatoid arthritis patients (RA). We obtained the serum, synovial fluid and synovium from 16 female patients with RA during knee operations. Leukotriene B4 (LTB4), leukotriene C4 (LTC4) and prostaglandin E2 (PGE2) were detected by RIA analysis. In the patients administered steroids, a positive correlation was found between the concentrations of LTB4 and PGE2 in the synovium. In the patients not administered steroids, significant correlations were found between the concentrations of LTB4 in the synovium and serum, and also between the concentrations of LTB4 and LTC4 in the synovium. The levels of immunoglobulins and LTB4 in the serum were determined and a significant correlation was found between the content of IgG and the concentration of LTB4. In the serum, the concentration of LTB4 was elevated in RA patients relative to the control normal subjects, and the difference was statistically significant. In conclusion, these data suggest that LTB4 in the serum reflects the concentration of LTB4 in the synovium.

Antitumor effect of forphenicinol, a low molecular weight immunomodifier, in combination with surgery on Meth A fibrosarcoma, Lewis lung carcinoma, and adenocarcinoma 755.

Forphenicinol, S-2-(3-hydroxy-4-hydroxymethylphenyl)glycine, prolonged the survival period of mice implanted with Meth A fibrosarcoma or Lewis lung carcinoma. The effect was observed in the mice when the primary tumor was removed by amputation. At autopsy, metastasized tumors were found in all dead mice but no tumor foci were detected in any of the mice still alive at the time of sacrifice. Moreover, forphenicinol suppressed the growth of subcutaneously implanted adenocarcinoma 755. When combined with surgical resection of primary tumors, forphenicinol administration both before and after resection suppressed the growth of recurrent tumors and prolonged the survival period of the mice.

Antitumor effect of forphenicinol, a low molecular weight immunomodifier, on murine transplantable tumors and microbial infections.

The antitumor activities of forphenicinol against murine transplantable tumors were examined. Ehrlich carcinoma was suppressed by treatment with 0.08 approximately 0.31 mg/kg/day of forphenicinol given for 10 days starting 5 days after tumor inoculation. IMC carcinoma was also suppressed by treatment with 0.5 approximately 5 mg/kg/day given for 5 days starting 8 days after the inoculation. The antitumor activity was dependent on the number of tumor cells inoculated, schedule of administration and dose. However, even in case of fast growing tumors such as L1210 and inoculation with a large number of tumor cells, forphenicinol markedly enhanced the antitumor effect of 6-mercaptopurine, aclacinomycin and cyclophosphamide. Forphenicinol showed a protective effect on Pseudomonas infection in mice.