Donor MHC and adhesion molecules in transplant arteriosclerosis.

Transplant-associated arteriosclerosis remains an obstacle to long-term graft survival. To determine the contribution to transplant arteriosclerosis of MHC and adhesion molecules from cells of the donor vasculature, we allografted carotid artery loops from six mutant mouse strains into immunocompetent CBA/CaJ recipients. The donor mice were deficient in either MHC I molecules or MHC II molecules, both MHC I and MHC II molecules, the adhesion molecule P-selectin, intercellular adhesion molecule (ICAM)-1, or both P-selectin and ICAM-1. Donor arteries in which ICAM-1, MHC II, or both MHC I and MHC II were absent showed reductions in neointima formation of 52%, 33%, and 38%, respectively, due primarily to a reduction in smooth muscle cell (SMC) accumulation. In P-selectin-deficient donor arteries, neointima formation did not differ from that in controls. In donor arteries lacking both P-selectin and ICAM-1, the size of the neointima was similar to that in those lacking ICAM-1 alone. In contrast, neointima formation increased by 52% in MHC I-deficient donor arteries. The number of CD4-positive T cells increased by 2.8-fold in MHC I-deficient arteries, and that of alpha-actin-positive SMCs by twofold. These observations indicate that ICAM-1 and MHC II molecules expressed in the donor vessel wall may promote transplant-associated arteriosclerosis. MHC I molecules expressed in the donor may have a protective effect.

The combined role of P- and E-selectins in atherosclerosis.

P- and E-selectins are adhesion molecules mediating the first step in leukocyte extravasation. Because their function in leukocyte adhesion is overlapping, we hypothesized that there might be a combined effect of these selectins on the development of atherosclerotic lesions. We bred P- and E-selectin-double-deficient mice onto the low-density lipoprotein receptor (LDLR)-deficient background (LDLR-/- P/E-/-) and compared lesion development in these mice to that in mice wild type for both selectins (LDLR-/- P/E+/+). After 8 wk on atherogenic diet, the LDLR-/- P/E-/- mice developed fatty streaks in the aortic sinus that were five times smaller than those in LDLR-/- P/E+/+ mice. The density of macrophages in the fatty streaks was comparable between LDLR-/- P/E+/+ and LDLR-/- P/E-/- mice. After 22 wk on the diet, the lesions spread throughout the aorta but this process was delayed in LDLR-/- P/E-/- mice. At 37 wk on diet, the lesions progressed to the fibrous plaque stage in both genotypes. However, the lesions in the aortic sinus in LDLR-/- P/E-/- mice were 40% smaller and less calcified than those of LDLR-/- P/E +/+ mice. Our results suggest that P- and E-selectins together play an important role in both early and advanced stages of atherosclerotic lesion development.

Inhibins, activins, and follistatins: expression of mRNAs and cellular localization in tissues from men with benign prostatic hyperplasia.

BACKGROUND: The transforming growth factor beta (TGF beta) superfamily of growth factors includes activins and inhibins, which have been shown to be present in the rat ventral prostate, and human prostate tumor cell lines, although their localization in benign prostatic hyperplasia (BPH) tissue is currently unknown. METHODS: BPH tissues were obtained at surgery, and the mRNA expression for the inhibin alpha, beta A, beta B subunits, the putative activin beta C subunit, the activin type II receptor (ActRII), and the activin binding protein, follistatin, was determined by reverse transcription polymerase chain reaction (RT-PCR) and Southern blot analysis. Antibodies specific for alpha, beta A, beta B, activin A, and follistatin were used to determine the localization of these proteins in BPH tissue specimens. RESULTS: Southern blot analysis confirmed that mRNA for ActRII, beta C subunit, and follistatin was present in all biopsy samples assayed. However, alpha, beta A, and beta B subunit mRNA expression was variable between patient samples. Immunohistochemistry demonstrated the predominant localization of beta A, beta B, and activin A proteins to the epithelium of BPH tissues. No immunoreactivity for the inhibin alpha subunit was detected; follistatin immunoreactivity was localized to the fibroblastic stroma. CONCLUSIONS: The compartmentalization of activin subunit proteins to the epithelium, and of follistatin to the stroma, suggests that a paracrine interaction occurs between the activin ligands and follistatin-binding proteins in BPH tissue.

Absence of P-selectin delays fatty streak formation in mice.

P-selectin is expressed on activated endothelium and platelets where it can bind monocytes, neutrophils, stimulated T cells, and platelets. Because recruitment of these cells is critical for atherosclerotic lesion development, we examined whether P-selectin might play a role in atherosclerosis. We intercrossed P-selectin-deficient mice with mice lacking the low density lipoprotein receptor (LDLR) because these mice readily develop atherosclerotic lesions on diets rich in saturated fat and cholesterol. The atherogenic diet stimulated leukocyte rolling in the mesenteric venules of LDLR-deficient mice, and the increase in adhesiveness of the vessels was P-selectin-dependent. Most likely due to the reduced leukocyte interaction with the vessel wall, P-selectin-deficient mice on diet for 8-20 wk formed significantly smaller fatty streaks in the cusp region of the aortae than did P-selectin-positive mice. This difference was more prominent in males. At 37 wk on diet, the lesions in the LDLR-deficient animals progressed to the fibrous plaque stage and were distributed throughout the entire aorta; their size or distribution was no longer dependent on P-selectin. Our results show that P-selectin-mediated adhesion is an important factor in the development of early atherosclerotic lesions, and that adhesion molecules such as P-selectin are involved in the complex process of atherosclerosis.

Classical Kaposi's: a rare cause of gastrointestinal haemorrhage.

Classical Kaposi's sarcoma (KS) is an indolent neoplasm involving mucocutaneous sites predominantly in elderly Mediterranean or Jewish persons. Whilst gastrointestinal involvement is common, it is usually asymptomatic. This case report presents a case of massive gastrointestinal haemorrhage in a patient with stable cutaneous disease and outlines options for the investigation and management of this rare complication.

Ondansetron use in a major university teaching hospital.

A drug-use evaluation of ondansetron was conducted. Literature-based criteria for the use of ondansetron were developed by an oncology specialty resident and a clinical pharmacy specialist in oncology. Orders for ondansetron written in the hospital or in the outpatient oncology clinic were reviewed over a nine-week period. After an interval of education, the use of ondansetron was re-evaluated. The data collected included the indication for use, dosage, route of administration, and, for inpatient orders during the first evaluation, therapeutic outcome. In the first evaluation, 100 orders were reviewed. Some 87% of the orders for inpatients and 80% of the outpatient orders met the criteria for therapeutic indication. Criteria for dosage and administration were met by 76% of the inpatient orders and 83% of the outpatient orders. The inpatient orders met the criteria for therapeutic outcome in 93% of cases. In the follow-up evaluation, 50 orders were reviewed. Some 96% of the inpatient orders and 100% of the outpatient orders met the criteria for therapeutic indication. Dosage and administration criteria were met by 92% of the inpatient orders but only 24% of the outpatient orders. A considerable potential for cost avoidance was identified. An evaluation of ondansetron use led to general improvements in prescribing patterns, but continued monitoring is necessary to reduce the use of inappropriate dosages and routes of administration for outpatients.

A controlled magnetic resonance imaging study of corpus callosum thickness in schizophrenia.

Two previous postmortem studies reported an increased thickness of the corpus callosum in schizophrenic patients compared to psychiatric controls. We report an in vivo study of the corpus callosum in schizophrenic patients (n = 38) and healthy controls (n = 41) using magnetic resonance (MR) brain imaging. A significant increase in mean callosal thickness was found in the middle and anterior, but not the posterior, parts of the callosal body. However, when the patients and controls were compared by gender and handedness, schizophrenic men were found not to differ from control men in callosal thickness, regardless of handedness, whereas schizophrenic women were found to have a highly significant increase in callosal middle and anterior thickness compared to control women. The data suggest that increased callosal thickness in schizophrenia is gender related, a factor that is not considered by postmortem studies. The implications of increased callosal dimensions in female schizophrenics are discussed.