Similar co-stimulation requirements of CD4+ and CD8+ primary T helper cells: role of IL-1 and IL-6 in inducing IL-2 secretion and subsequent proliferation.

Primary murine CD4+ and CD8+ T helper (Th) cells provide help for various immune responses by secreting lymphokines which activate effector cells. The purpose of the present study was to investigate the co-stimulatory signals that, together with T cell receptor (TCR) cross-linking, induce phenotypically distinct primary Th cells to secrete IL-2 and proliferate. We isolated highly purified populations of primary CD4+ or CD8+ T cells and stimulated them in vitro with platebound anti-CD3 mAb. TCR cross-linking by anti-CD3 mAb induced both IL-2 receptor expression and responsiveness to exogenous IL-2, but was not sufficient to induce either IL-2 secretion or T cell proliferation. Rather, for both CD4+ and CD8+ primary Th cells, IL-2 secretion and proliferation required both TCR cross-linking and antigen presenting cell (APC)-derived co-stimulatory signals. Based on G-10 adherence and sensitivity to gamma-irradiation, the APC populations able to induce primary CD4+ Th cells and primary CD8+ Th cells to secrete IL-2 were indistinguishable. In addition, we found that either IL-1 or IL-6 could replace the requirement for APC-derived co-stimulatory signals for IL-2 secretion and proliferation by both primary CD4+ Th cells and primary CD8+ Th cells. Thus, the present study has examined and compared the co-stimulatory requirements of rigorously purified subsets of IL-2-secreting primary CD4+ and primary CD8+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Surgical considerations in bypassing coronary arteries with 100% proximal occlusion.

Objective data on the ability of cineangiography to predict the size of reconstituted totally occluded coronary arteries, as well as the clinical outcome of such revascularization, are sparse. Accordingly, we reviewed 200 consecutive cases of coronary revascularization to determine the answers to these questions. Group I patients (n = 57, with 86 totally occluded coronary arteries) had at least one coronary artery with a 100% proximal occlusion that reconstituted distally. Group II patients (n = 143, with 205 subtotally occluded coronary arteries) had 50% to 99% proximal stenosis of at least one coronary artery. Cineangiograms were blindly reviewed to measure the size of the coronary arteries, which were compared with the actual vessel size at operation. In group I, the totally occluded coronary arteries had a cineangiographic size of 1.9 +/- 0.7 mm and an actual size of 1.6 +/- 0.4 mm (p = 0.00004). In group II, the subtotally occluded coronary arteries had a cineangiographic size of 1.8 +/- 0.4 mm compared with an actual size of 1.8 +/- 0.3 mm (p = not significant). The site of bypass grafting was significantly smaller in group I (1.6 +/- 0.4 mm versus 1.8 +/- 0.3 mm; p = 0.00008). The two groups were similar with respect to preoperative and intraoperative parameters. Operative mortalities were similar (group I, 1.8%; group II, 3.5%; p = 0.68). Creatine kinase isoenzyme profiles and electrocardiographic changes were similar, except for a significant late rise of creatine kinase-MB in group I (56.1 +/- 14.7 versus 30.7 +/- 33.7 MIU/mL; p < 0.001). In conclusion, cineangiography significantly overestimates the size of totally occluded coronary arteries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Native genomic blotting: high-resolution mapping of DNase I-hypersensitive sites and protein-DNA interactions.

DNase I-hypersensitive sites are observed in the promoter regions of actively expressed genes, potentially active genes, and genes that were once active. We have developed an approach that greatly increases the resolution for mapping these sites by electrophoresing genomic DNA on native polyacrylamide gels prior to electroblotting and hybridization. This improved method has been used to scan the promoter and coding region of a cell-cycle-dependent human histone H4 gene with an accuracy of +/-5-10 base pairs. Protein-DNA interactions can be seen in the autoradiograph as light areas and DNase I-hypersensitive sites as dark bands. Therefore, this method provides a rapid and relatively simple means to accurately localize protein-DNA interactions as well as DNase I-hypersensitive sites, thus directly displaying DNase I hypersensitivity and protein-DNA complexes on one autoradiograph. It also potentially allows the analysis of small changes in DNase I-hypersensitive sites under various biological conditions. With this technique rather large regions of DNA can be screened to determine areas that should be analyzed by more sophisticated methods, such as genomic sequencing or gel retardation assays.     

Bilateral malignant glaucoma.

Two cases of bilateral malignant glaucoma are presented. In one case the condition developed sequentially in the two eyes; pars plana vitrectomy was eventually needed in the operated eye, whereas the condition responded to medical treatment in the fellow eye. In the second case the two eyes were involved simultaneously nearly 1 year after surgery, and the glaucoma responded to medical treatment.     

Salvage radical prostatectomy after failure of curative radiotherapy for adenocarcinoma of prostate.

Radical prostatectomy with curative intent was performed in 13 patients with prostate cancer after local failure of radiotherapy. Of these patients, 2 underwent cystoprostatectomy for bladder neck involvement by the prostatic tumor. Local recurrence had been diagnosed twenty-one to one hundred sixty-eight months (mean 65.4 months) after completion of radiotherapy (6,000-7,000 cGy; mean 6,136 cGy). Three patients had radioactive implants. Rising prostate-specific antigen (PSA) was part of the indication for surgery in 5 patients. Complications included minor rectal injury (1 patient) and total incontinence (2/13 patients). Two patients had positive surgical margins and 6/13 patients had involvement of seminal vesicles, 2 of whom also had positive lymph nodes. The authors conclude that salvage prostatectomy is feasible after radiation failure. Transrectal ultrasound and careful monitoring of PSA after irradiation treatment may improve patient selection and minimize the risk of complications and incomplete excision.     

Salmon calcitonin prevents cyclosporin-A-induced high turnover bone loss

Cyclosporin-A (CsA) has greatly influenced the outcome of organ transplantation and has also been effective in the treatment of many autoimmune diseases. Unfortunately, it has deleterious effects on bone remodelling, causing a high turnover bone loss, with bone resorption exceeding bone formation. Salmon calcitonin (SCtn) has been shown to inhibit bone resorption in high turnover states such as Paget's disease and postmenopausal osteoporosis. In an attempt to attenuate the high turnover bone remodelling caused by CsA alone, we studied the bone mineral effects of CsA in combination with SCtn in male Sprague-Dawley rats. Group A (n = 20) received vehicle as control, group B (n = 20) received CsA (15 mg/kg BW) by daily gavage and SCtn vehicle sc, group C (n = 20) received SCtn (1.3 IU/kg BW) daily sc and CsA vehicle, and group D (n = 20) received a combination of CsA and Ctn daily, as described above. Rats were bled weekly for determination of circulating biochemical bone parameters. Eight rats from each group were killed on day 14 (short term), and the remaining rats were killed on day 28 (long term). Tibiae were removed for bone histomorphometry after death, which revealed a reduction of trabecular bone volume and an increase in osteoclast number induced by CsA alone. These changes were significantly attenuated by the combination of CsA and SCtn to resemble the histomorphometry of the control group. The inhibition of osteoclast number by SCtn is the most plausible mechanism by which the combination therapy attenuates the high turnover bone loss induced by CsA alone.     

Duodenoesophageal reflux and the development of esophageal adenocarcinoma in rats.

BACKGROUND. The carcinogenic effect of duodenoesophageal reflux, gastroesophageal reflux, and nitrosamines was studied in the rat esophagus. METHODS. Twenty male Sprague-Dawley rats underwent esophagogastroplasty to produce gastroesophageal reflux and 60 underwent duodenoesophageal anastomosis to produce duodenoesophageal reflux. Forty-three animals underwent no operation and acted as controls. Carcinogens known to produce squamous tumors in the rat esophagus (2,6-dimethylnitrosomorpholine [DMNM] or methyl-n-amylnitrosamine [MNAN]) were tested in each group. RESULTS. The rate of squamous carcinoma was 25% for rats with DMNM alone, 30% for rats with MNAN alone, and 20% for rats with induced gastroesophageal reflux plus DMNM. The rate of malignant change rose to 80% in rats with induced duodenoesophageal reflux and DMNM and 67% with duodenoesophageal reflux and MNAN. With duodenoesophageal reflux, 50% of tumors were adenocarcinoma, in contrast to 100% squamous differentiation of tumors in rats given the carcinogens with esophagogastroplasty or no operation. CONCLUSION. The presence of duodenoesophageal reflux increased the frequency and changed the histologic type of esophageal cancer in nitrosamine-treated rats. This indicates that duodenoesophageal reflux plays a role in the development of esophageal adenocarcinoma.     

Congenital toxoplasmosis—prenatal aspects of Toxoplasma gondii infection

Toxoplasma gondii (T. gondii) is the cause of toxoplasmosis. Primary infection in an immunocompetent person is usually asymptomatic. Serological surveys demonstrate that world-wide exposure to T. gondii is high (30% in US and 50–80% in Europe). Vertical transmission from a recently infected pregnant woman to her fetus may lead to congenital toxoplasmosis. The risk of such transmission increases as primary maternal infection occurs later in pregnancy. However, consequences for the fetus are more severe with transmission closer to conception. The timing of maternal primary infection is, therefore, critically linked to the clinical manifestations of the infection. Fetal infection may result in natural abortion. Often, no apparent symptoms are observed at birth and complications develop only later in life. The laboratory methods of assessing fetal risk of T. gondii infection are serology and direct tests.Screening programs for women at childbearing age or of the newborn, as well as education of the public regarding infection prevention, proved to be cost-effective and reduce the rate of infection.The impact of antiparasytic therapy on vertical transmission from mother to fetus is still controversial. However, specific therapy is recommended to be initiated as soon as infection is diagnosed.