G2 arrest following fractionated irradiation in the mouse jejunal crypt

Infection by human T-cell lymphotrophic virus type I (HTLV-I) is associated with a myelopathy known as tropical spastic paraparesis (TSP). The prevalence of HTLV-I infection was found to be high in a pilot study in Bahia, Brazil. In the present study, among patients with myelopathy of unclear etiology, 27% (17/62) were immunoblot reactive to HTLV-I/II (serum and CSF), but none of 40 consecutive patients seen at the neurological clinic and having a well-established neurological diagnosis had detectable antibodies against those viruses (discrimination between HTLV-I and HTLV-II was not possible with the tests we used). The clinical syndrome of typical TSP with upper limb hyperreflexia was found to be a significant feature among the HTLV-I/II-seropositive patients compared to seronegative individuals. The 17 HTLV-I/II-reactive individuals had negative tests for syphilis, toxoplasmosis and schistosomiasis. TSP was also associated with female gender (P = 0.001). We conclude that TSP is strongly associated with HTLV-I/II infection in women in Bahia.     

Fibrin induction of ICAM-1 expression in human vascular endothelial cells

In acute and chronic inflammatory processes, fibrin deposition, and leukocyte accumulation are classic histopathologic hallmarks. Previous studies have shown that fibrin and fibrin degradation products can have biologic effects on vascular endothelial cells and can induce the expression of several endothelial cell-derived factors that may be important in regulating inflammation and tissue repair. We now demonstrate that coculture of human vascular endothelial cells (EC) with fibrin results in the up-regulation of intercellular adhesion molecule-1 (ICAM-1), thus providing a first link between fibrin deposition and adhesion molecule expression, which may lead subsequently to leukocyte accumulation and extravasation. Increased ICAM-1 expression was demonstrated by ELISA, flow cytometry, and functional adhesion assays. EC ICAM-1 expression increased in a time and dose response fashion. Cell surface levels of ICAM-1 induced by fibrin were comparable to, or exceeded, levels induced by IL-1beta. ICAM-1 expression increased beginning at 4 h post-fibrin formation with sustained elevated expression at 48 h. Fibrin-stimulated EC also bound increased numbers of polymorphonuclear neutrophils in cellular adhesion assays. This increase in adhesion could be blocked by Ab to ICAM-1. Inhibition of fibrin polymerization also inhibited the up-regulation of ICAM-1. Culture medium from fibrin-stimulated EC contained elevated levels of soluble ICAM-1. These data suggest that fibrin deposition on vascular EC, in addition to other reported effects on EC metabolism, may also lead to leukocyte accumulation and extravasation through the induction of leukocyte adhesion molecules such as ICAM-1.     

Alterations in ICAM-1 and ELAM-1 expression in psoriatic lesions following various treatments

In long-term hypertension, hemodynamic alterations are associated with functional and structural changes in the cardiovascular system. The technique of arterial impedance spectral analysis has long been used to characterize the arterial hemodynamics of steady and pulsatile components in human hypertension. Although rats with spontaneous hypertension (SHR) are the most common model for studies of primary hypertension, characterization of complete hemodynamic parameters has not been accomplished in this animal model. In the present experiment, aortic flow and pressure waves were recorded in anesthetized, open-chest and ventilated rats. Arterial impedance spectral analysis was employed to obtain steady and pulsatile hemodynamic parameters. A total of 26 SHRs (22-24 wk) and 22 age-matched normotensive WKYs was used. The purpose was to provide a comprehensive analysis of arterial hemodynamics in rats with established hypertension. The SHR had higher arterial pressure (50% increase over the control) than WKY. The total peripheral resistance was elevated by 57%. Stroke volume was decreased by 23% and heart rate increased by 18% without a significant change in cardiac output. The characteristic impedance was increased by 43%, while arterial compliance was decreased by 52%. There were also big rises in ventricular work and wave reflection. The results provide quantitative analysis of the alteration in arterial hemodynamics of steady and pulsatile components in rats with established hypertension. In long-term hypertension, the hemodynamics reflect functional abnormalities in the resistance and Windkessel vessels.     

Cardiac graft intercellular adhesion molecule-1 (ICAM-1) and interleukin-1 expression mediate primary isograft failure and induction of ICAM-1 in organs remote from the site of transplantation

During the first few hours after heart transplantation, the occurrence of graft failure is unpredictable and devastating. An explosive cascade of inflammatory events within the reperfused graft vasculature is likely to be mediated, at least in part, by the local expression of the leukocyte adhesion receptor intercellular adhesion molecule-1 (ICAM-1, CD54). Furthermore, although proinflammatory cytokines such as interleukin-1 (IL-1) are known to autoinduce their own (and ICAM-1) expression in vitro, there are no data to identify their functional in vivo cross talk in the setting of isograft transplantation. To determine the role of ICAM-1 in primary graft failure, we used an isogeneic vascularized model of heterotopic cardiac transplantation. ICAM-1 mRNA and protein increased in grafts during the early posttransplant period and were predominantly localized in the endothelium. The functional significance of this was established using donor hearts obtained from either ICAM-1-deficient (ICAM-1 -/-) or control (ICAM-1 +/+) mice. ICAM-1 +/+ grafts exhibited increased neutrophil infiltration, reduced left ventricular compliance, and poorer survival than did ICAM-1 -/- grafts. Increased ICAM-1 expression was not limited to ICAM-1 +/+ grafts but also occurred in unmanipulated recipient organs located remote from the site of surgery (but only after transplantation of ICAM-1 +/+, not ICAM-1 -/-, cardiac grafts). This expression of ICAM-1 in remote organs appeared to be triggered by IL-1alpha released from the graft, because (1) in situ hybridization revealed increased IL-1 mRNA within cells of the reperfused graft, including myocytes and endothelial cells; (2) ICAM-1 expression in remote organs coincided with a significant increase in serum levels of IL-1alpha after transplantation of ICAM-1 +/+ grafts; both remote organ ICAM-1 expression and IL-1alpha levels were blunted by implantation of ICAM-1 -/- grafts; and (3) remote organ ICAM-1 expression and neutrophil infiltration and IL-1 levels could be blocked by the administration of an IL-1 receptor antagonist. These data demonstrate an apparent positive-feedback loop in which local ICAM-1 and IL-1 expression leads to a mutual amplification of each other's expression within the reperfused graft, promulgating inflammatory events that are likely to be an important cause of primary cardiac graft failure. Because IL-1 receptor blockade reduces the IL-1-mediated autoinduction of IL-1, reduces the expression of ICAM-1 in both the graft and remote organs, and improves graft survival, it may provide a new and effective strategy to prevent the occurrence of primary cardiac graft failure.     

Inhibition of TNFalpha attenuates infarct volume and ICAM-1 expression in ischemic mouse brain

The family physician occupies a front-line position in the detection and treatment of emotional problems and psychiatric illnesses. The practice pattern of the family physician necessitates an efficient, effective model of psychotherapy The BATHE technique is a brief psychotherapeutic method that addresses the patient's background issues, affect and most troubling problem. The emphasis of the interview then shifts to how the patient is handling the problem and a demonstration of empathy by the physician. Some of the challenges in psychotherapy are presented, and cases in which the BATHE technique was used are described.     

Neuropsychological effects of preventive CNS irradiation in adult tumor patients

Prophylactic cranial irradiation (PCI) has led to marked prolongation of survival, but also to intellectual and neuropsychological retardation in children with ALL. PCI has also been conducted in adult patients with small-cell bronchial carcinoma in the stage of minimal disease or with breast cancer. There are no studies assessing cognitive or other neuropsychological consequences of PCI in adult cancer patients. We report on a longitudinal prospective study of the effects of PCI on five major neuropsychological domains (intelligence, concentration, attention, memory and psychomotor performance). We report on our ongoing study, in which up to now 11 patients with small-cell lung cancer undergoing PCI have been investigated. Patients are assessed immediately before therapy started as well as 4 weeks and 3 months after onset of PCI. The used instruments are Standard Progressive Matrices (SPM), d2 Concentration Test, Minimental State, Verbal Learning Test and Psychomotor Tests (Steadiness, Aiming, Tapping, Tracking, Pursuit Rotor Test). Although our sample is small, results indicate that there is no evidence for a decrease in neuropsychological abilities in adults after three months. This is in contrast to the observed results after PCI in children. As compared to baseline measures, differences in memory, intelligence, concentration and attention were marginal over time. Moreover the progress of motor performance skills showed no clear tendency.     

Drug modification of hypothermia induced by CNS glucopenia in the mouse

The long-term effects of elective induction of labor at term by amniotomy and the intravenous infusion of prostaglandin F2alpha were studied in 40 children. No untoward effect of this procedure on the psychomotor development of the children during the first 30 months could be demonstrated.     

LFA-1 interaction with ICAM-1 and ICAM-2 regulates Th2 cytokine production

The role of CD28/B7 and LFA-1/ICAM costimulation in proliferation and Th1/Th2 differentiation of naive CD4+ T cells was addressed using T cells from DO11.10 TCR transgenic mice stimulated by dendritic cells. The blockade of either CD28/B7 or LFA-1/ICAM interactions partially inhibited T cell proliferation. By comparison, blocking CD28/B7 costimulation inhibited IL-4 and IL-5 (Th2 cytokine) production, whereas blocking LFA-1/ICAM-1 or LFA-1/ICAM-2 led to a significant increase (15- to 40-fold) of Th2 cytokines. The combination of anti-ICAM-1 and anti-ICAM-2 mAbs had a synergistic effect with a 100- to 1000-fold increase of Th2 cytokine production. Thus, these two costimulatory pathways have opposing roles in the regulation of Th2 development.     

T cell interaction with ICAM-1-deficient endothelium in vitro: essential role for ICAM-1 and ICAM-2 in transendothelial migration of T cells

Transendothelial migration is a crucial step in the complex process of lymphocyte extravasation during lymphocyte homing, immunosurveillance and inflammation. However, little is known about the precise role of cell adhesion molecules (CAM) involved in this particular event. To define the CAM involved in T cell adhesion versus transendothelial migration, we have previously established an in vitro transendothelial migration system using mouse T cells and mouse endothelioma cells. We demonstrate here that, using ICAM-1-deficient endothelioma cells derived from ICAM-1 mutant mice, transendothelial migration of T cells was inhibited to a much greater extent when compared to migration across wild-type cells treated with a blocking anti-ICAM-1 monoclonal antibody. This unexpected result was confirmed by a rescue experiment using retroviral transfer of wild-type ICAM-1 into ICAM-1-deficient endothelial cells. Additional experiments showed that, in the absence of functional ICAM-1, only ICAM-2 was involved in transendothelial migration, but not PECAM-1, VCAM-1, or E-selectin. Taking this novel approach, we show that ICAM-1 and ICAM-2 are essential for transendothelial migration of T cells.     

Arterial changes following single-dose irradiation

In this reported experiment, the serial morphologic changes in the rabbit ear central artery, following a single dose of 45 Gy 60Co gamma-ray irradiation, were investigated using light and scanning electron microscopy. Under light microscopy, mild intimal proliferation, disorganization of smooth muscle, and severe perivascular fibrosis were observed. These appeared to be caused by increased intimal cell death and lower repair capability after large single-dose irradiation. Under scanning electron microscopy, the endothelial cells did not show significant morphologic changes during the first 4 weeks. At 6 and 10 weeks after irradiation, the endothelial cells shrank in all directions and detached from the basement membrane. These changes accord with the theory that radiation damage following therapeutic dosage occurs within the DNA of the cell, and that there is no significant change until the cell attempts to divide.     

Suppression of mouse-killing in rats following irradiation

Suppression of mouse-killing was produced following pairings of mouse-presentations (CS) with 96 roentgens of ionizing radiation (US) at O ( less than 2 min.) and 30 min. US-CS interstimulus intervals. No suppression was found at CS-US intervals of 30 min., 1hr., and 2 hr., or at US-CS intervals of 1 hr. and 2 hr.     

Pharmacokinetics and CNS pharmacodynamics of the 5-HT1A agonist buspirone in humans following acute L-tryptophan depletion challenge

This study was designed to evaluate the relationship between the pharmacokinetic(s) (PK) and CNS pharmacodynamic(s) (PD) of buspirone, an antidepressant/anxiolytic, in 6 healthy male volunteers placed on an acute L-tryptophan deficient (ATD) diet. The study was a randomized, double-blind, placebo-controlled, four-period, three-way crossover study. The first study period was a single-blind familiarization period in which all subjects received placebo. During the remaining three study periods, subjects received either placebo, 10 mg or 30 mg oral buspirone. Subjects were administered the ATD diets 5 h prior to buspirone/placebo administration during each study period. All subjects underwent serial measurements of resting electroencephalography (REEG) and vigilance electroence-phalography (VEEG), cognitive tests, subjective rating scales, and blood was sampled for determination of unbound plasma L-tryptophan, serum prolactin, serum cortisol and plasma buspirone and its active metabolite, 1-pyrimdylpiperazine (1-PP). The ATD diet reduced the unbound plasma L-tryptophan concentrations to 20% of their baseline values. The intraindividual and interindividual variability in the unbound L-tryptophan concentration drop was less than 10% and 15%, respectively. Peak L-tryptophan depletion occurred 5 h after ATD diet was administered; L-tryptophan depletion lasted for approximately 11 h, and L-tryptophan concentrations recovered to baseline values approximately 13 h after administration of the ATD diet. PK-PD analysis for buspirone showed that: 1) peak plasma concentration (Cmax) and total area under the plasma concentration-time curve (AUC infinity) for buspirone following the 10 mg dose in this study were higher than those reported previously in the literature; 2) there was a transient response in the neuroendocrine measures, subjective rating scales and the EEG, but no changes in the cognitive tests with increasing doses of buspirone; 3) the PD measures were correlated with the doses of buspirone, but not with plasma concentrations of buspirone and 1-PP; and 4) the subjective rating scales were the most sensitive indicators of buspirone's CNS effects. This study provides evidence that ATD diet is a simple, specific and non-toxic experimental method to lower plasma L-tryptophan concentrations and thereby (indirectly) deplete brain tryptophan and serotonin (5-HT) concentrations. The ATD challenge may serve as a model of depression in healthy volunteers because of its ability to induce transient symptoms of the disease. Comparison of the results from this study to those reported in the literature suggests that the use of the ATD diet decreases the buspirone-induced neuroendocrine response, increases the buspirone-induced changes in subjective rating scales and, at the same time, increases the systemic exposure to buspirone and 1-PP.     

Effects of irradiation on the expression of major histocompatibility complex class I antigen and adhesion costimulation molecules ICAM-1 in human cervical cancer

PURPOSE: We initiated studies to analyze the effects of high doses of gamma irradiation on the surface antigen expression of MHC Class I, Class II, and ICAM-1 on human cervical carcinoma cell lines. METHODS AND MATERIALS: The expression of surface antigens (MHC Class I, Class II, and ICAM-1) was evaluated by FACS analysis on two cervical cell lines at different time points, following their exposure to high doses of gamma irradiation (i.e., 25.00, 50.00, and 100.00 Gy). RESULTS: The CaSki and SiHa cervical cancer cells we analyzed in this study expressed variable levels of MHC Class I and ICAM-1 antigens, while Class II surface antigens were not detectable. Whereas irradiation doses of 25.00 Gy were not sufficient to totally block cell replication in both cell lines, exposure to 50.00 or 100.00 Gy was able to completely inhibit cell replication. Range doses from 25.00 to 100.00 Gy significantly and consistently increased the expression of all surface antigens present on the cells prior to irradiation but were unable to induce neoexpression of antigens previously not expressed by these cells (i.e., MHC Class II). Importantly, such upregulation was shown to be dose dependent, with higher radiation doses associated with increased antigen expression. Moreover, when the kinetic of this upregulation was studied after 2 and 6 days after irradiation, it was shown to be persistent and lasted until all the cells died. CONCLUSIONS: These findings may partially explain the increased immunogenicity of tumor cells following irradiation and may suggest enhanced immune recognition in tumor tissue in patients receiving radiation therapy.     

Tumorigenesis in F1 offspring mice following paternal 12.5 cGy 252Cf fission neutron irradiation

Experiments were conducted to determine whether following genetic damage at germ cell stages induced by paternal exposure to 252Cf fission neutron could lead to tumorigenesis in the offspring. Seven-week-old C3H/HeNCrj male mice were irradiated with 252Cf fission neutrons, at doses of 0 and 12.5 cGy and were mated with nine-week-old C57BL/6NCrj females two weeks after the exposure. Three weeks later, it was found that the proportion of abnormal sperm in the 12.5 cGy-irradiated males was higher than that of 0 cGy-irradiated group. Embryo lethality among the F1 offspring was also found to be higher in the 12.5 cGy group than in the 0 cGy group, while the incidence of liver tumors among the F1 offspring increased in males only. These results suggest that the paternal 12. 5 cGy radiation exposure may have caused genetic transmission of liver tumor-associated traits, which is in line with findings that show steep increase in incidence of tumorigenesis in B6C3F1.