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Heterogeneity of helper/inducer T lymphocytes. IV. Stimulation of resting and activated B cells by Th1 and Th2 clones.

To test the hypothesis that resting and previously activated B lymphocytes differ in their proliferative and differentiative responses to various Th cell-derived stimuli, we have examined the interactions of purified small (resting) and large (activated) murine B cells with rabbit Ig-specific Th1 and Th2 clones in the presence of the Ag analogue, rabbit anti-mouse Ig antibody. Small numbers of Th2 cells induce strong Ag-dependent proliferation of and Ig secretion by both resting and activated B lymphocytes. In contrast, Th1 clones stimulate lower responses of activated B cells and fail to stimulate small resting B cells. An interaction with Th1 clones does make small B cells responsive to the Th2-derived cytokine, IL-4, indicating that Th1 clones are capable of delivering some but not all the stimuli necessary for the induction of humoral immunity. Finally, in order to compare the responses of small and large B cells to cognate interactions and secreted cytokines, we used an autoreactive I-Ak-specific Th2 line. This line induces proliferation of and Ig secretion by I-Ak expressing but not H-2d resting and activated B cells as a result of cognate interactions. However, when the H-2d B cells are bystanders in the presence of cytokine secretion by this Th2 line, or are directly exposed to Th2-derived cytokines, both small and large B cells are induced to proliferate but only the large B cells secrete antibody. These results indicate that the magnitude and nature of antibody responses depend on three principal factors: the cytokines produced by Th cells, the state of activation of the responding B lymphocytes, and whether the B cells are recipients of cognate help or are bystanders at the site of T cell stimulation. Our findings also confirm the view that cognate T-B interactions are most efficient for initiating B cell responses and may allow B cells to subsequently respond to a variety of T cell-derived cytokines.

Animals↗

Central hemodynamic effects at rest and during exercise of acute and chronic treatment with nisoldipine in essential hypertension.

The acute and chronic hemodynamic effects of nisoldipine were studied in 19 patients (17 men, 2 women; mean age 43 years) with essential hypertension at rest supine and sitting and during steady state 100 W bicycle exercise. At rest supine, the first dose response (1 h) was reduction of intraarterial (IA) pressure (9%) and total peripheral vascular resistance (TPR; 19%) and rise in heart rate (HR; 9%) and cardiac output (CO; 12%). Thereafter, the effect leveled off: at 3 h, IA pressure, CO, and TPR were reduced 6%, 1%, and 4%, respectively. Similar results were seen at rest and during exercise. After 1 year treatment, the changes were more marked: at rest, IA pressure and TPR fell (16% and 20%, respectively) while stroke volume and CO rose slightly (4% and 6%, respectively). There was no reflex tachycardia. During 100 W exercise, IA pressure fell (14%) due to reduction both in TPR (7%) and CO (6%). Thus, at rest, nisoldipine lowers blood pressure by reduction of TPR both acutely and chronically. The initial rise in CO is lost after long-term therapy. During exercise, falls in both TPR and CO contribute to the hypotensive effect.

Adult↗

Decreases in resting plasma beta-endorphin/-lipotropin after endurance training.

The purpose of the present study was to investigate changes in the resting plasma beta-endorphin/-lipotropin (beta E/beta-LPH) concentration that may occur with exercise training. A treatment group (N = 10) of previously sedentary, psychologically normal, and medically healthy middle-aged men trained for 4 months in a structured fitness program. The treatment group was compared with two age-matched groups: a jogger group (N = 10) and a sedentary group (N = 10). Venous blood was collected in the early morning after the subjects had been fasting for at least 12 h. The subjects were also resting at the time of blood collection. Resting plasma beta E/beta-LPH (measured by radioimmunoassay) decreased (P less than 0.05) following the 4 months of exercise training in the treatment group, from 11.01 +/- 1.62 (SE) to 7.22 +/- 0.99 pmol.1-1. The jogger and sedentary groups demonstrated no changes in the resting plasma beta E/beta-LPH concentration following the 4 months. Aerobic fitness, measured by the maximal oxygen uptake (VO2max), increased (P less than 0.01) from 36.56 +/- 2.58 (SE) to 44.85 +/- 1.34 ml.kg-1.min-1 in the treatment group after the 4 months of training. There were no changes in VO2max for either the jogger group or the sedentary group following the 4 months. In conclusion, beta E/beta-LPH in the plasma of resting middle-aged men appeared to be decreased after 4 months of aerobic training.

Adult↗

[DNA synthesis in the nuclei of stimulated NIH 3T3 cells in heterodikaryons obtained by the fusion of these cells with resting cells treated with cycloheximide].

Serum-deprived (0.2%) resting NIH 3T3 mouse fibroblasts preincubated with cycloheximide (7.5 micrograms/ml) were fused with stimulated cells taken 10 hours after changing the medium to the one containing 10% serum, and DNA synthesis was investigated in nuclei of heterodikaryons, homodikaryons, and monokaryons, using radioautography with double-labeling technique. Preincubation of resting cells with the inhibitor of protein synthesis cycloheximide for 4, 3, 2, but not for 1 or 0.5 hours abolishes their ability to suppress DNA synthesis in stimulated nuclei in heterodikaryons. Three hours after the removal of cycloheximide from the media, the resting cells acquire once again the inhibitory effect towards the entry of stimulated nuclei into the S-period. The data suggest that the resting cells may produce a labile endogenous inhibitor of cell proliferation, and support the idea on the active metabolic processes occurring in the resting cells.

Animals↗

Rest and exercise evaluation of St. Jude Medical and Medtronic Hall prostheses. Influence of primary lesion, valvular type, valvular size, and left ventricular function.

To compare St. Jude Medical and Medtronic Hall mechanical prosthetic heart valves, we prospectively randomized 90 consecutive patients requiring mechanical valve replacement and studied their rest and exercise hemodynamics by Doppler echocardiography. Fifty-six aortic and 42 mitral valves were implanted. All patients were examined preoperatively and postoperatively, and follow-up studies were obtained at rest and immediately after upright, treadmill exercise at 6 months (n = 68). Clinical parameters (mortality, morbidity, and congestive heart failure classification), as well as rest and exercise hemodynamics (valvular area, gradients, and left ventricular ejection fraction), were examined, and their relation to exercise duration was defined. Mortality (perioperative, 8.8% and late, 2.4%) was similar between patients in the two valve groups (five in each group). There was one late thromboembolic episode with each valve. Improvement in New York Heart Association congestive heart failure class was seen in 85% of patients at 6 months. There were no significant differences in calculated aortic valve areas (2.2 vs. 2.0 cm2), resting (24 vs. 21 mm Hg) and exercise (41 vs. 35 mm Hg) peak aortic gradients, and exercise duration between patients with the St. Jude Medical and Medtronic Hall aortic prostheses. In patients with aortic prostheses, valvular size was correlated with exercise duration (r = 0.41, p less than 0.05). In patients with mitral prostheses, we observed no significant differences between St. Jude Medical and Medtronic Hall prostheses in calculated mitral valve areas (3.4 cm2 vs. 3.4 cm2) and rest (2.5 vs. 3.0 mm Hg) and exercise (5.1 vs. 7.0 mm Hg) mean gradients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Effect of gamma radiation on resting B lymphocytes. II. Functional characterization of the antigen-presentation defect.

The effect of radiation on three discrete Ag-presentation functions in resting B cells was examined: 1) Ag uptake and processing, 2) expression of processed Ag in the context of functional class II molecules, and 3) provision of necessary co-stimulatory, or "second," signals. Analysis of radiation's effect on B cell presentation of intact vs fragmented Ag or its effect on presentation by Ag-pulsed B cells indicated that damage to Ag uptake and processing could not account for the bulk of the radiation-induced Ag-presentation defect. Experiments with phosphatidylinositol hydrolysis as an indirect measure of TCR occupancy suggested that irradiation caused a fairly rapid (within 1 to 2 h) decrease in the ability of the B cell APC to display a stimulatory combination of Ag and class II molecule. Ag dose-response analyses demonstrated that when presenting a fragment of the Ag pigeon cytochrome c to a T cell clone, 3000 rad-treated B cell APC were able to stimulate approximately 50% as much phosphatidylinositol turnover as unirradiated B cells. It was also found that, in contrast to their inability to initiate T cell proliferation, and similarly to chemically cross-linked splenocytes, heavily irradiated resting B cells plus Ag induced a state of Ag hyporesponsiveness in T cell clones. This effect on T cells had the same Ag- and MHC-specificity as did receptor occupancy required for proliferation, indicating that heavily irradiated resting B cells bear functional class II molecules. Co-culture of T cells with allogeneic B cells and syngeneic heavily irradiated B cells or chemically cross-linked splenic APC plus Ag resulted in T cell proliferation and interfered with the induction of the hyporesponsive state. This co-stimulatory function was radiosensitive in resting allogeneic B cells. Together, these data support the hypothesis that the major functional consequences of radiation to resting B cell APC are a reduction in the effective display of Ag plus class II molecules and, probably what is more important, a loss in the ability to provide APC-derived co-stimulatory signals.

Animals↗

B cell activating factor(s) (BCAF) containing supernatant can induce all classes of immunoglobulin and IgG switches in resting B cells.

We have previously shown (L. Leclercq et al., Proc. Nat. Acad. Sci. 1984, 81:6491) that the supernatants of activated T helper cells can stimulate resting B cells to proliferate and to express early activation markers. The corresponding activity has been called B Cell Activating Factor or BCAF. Here we show that BCAF-containing supernatants can induce resting B cells to produce immunoglobulins of all isotypes as measured by enzyme linked immunoabsorbent assay. The isotype pattern obtained is similar to the one obtained when TH cells are cocultured with unprimed resting B cells. Furthermore, BCAF-containing supernatants induce IgG switches as measured by the secretion of IgG3, IgG1, IgG2a and IgG2b immunoglobulin by cell sorted surface IgG- resting B cells. These investigations confirm that BCAF-containing supernatants can act on resting B cells.

Animals↗

Direct activation of human resting T cells by IL 2: the role of an IL 2 receptor distinct from the Tac protein.

High concentrations of interleukin 2 (IL 2) were shown to produce a delayed but pronounced proliferation of purified resting T cells in the apparent absence of other activation signals. Because these stimulatory effects of IL 2 occurred in the absence of detectable Tac+ cells, the possibility that IL 2 might be initially interacting with an IL 2 binding protein distinct from the Tac protein was studied. Chemical cross-linking studies with 125I-IL 2 revealed the presence of an IL 2 binding protein distinct from the Tac protein on the surface of these unstimulated T cells. This second IL 2 receptor has an estimated molecular size of 70,000 daltons, lacks reactivity with the anti-Tac antibody, and appears to be identical to the p70 protein recently proposed as a component of the high affinity IL 2 receptor. Scatchard analysis of IL 2 binding assays performed with the unactivated T cells revealed approximately 600 to 700 p70 sites per cell and an apparent Kd of 340 pM. These data indicate that the p70 protein present on resting T cells binds IL 2 with an intermediate affinity compared with the previously recognized high and low affinity forms of the receptor and may account for the high concentration of IL 2 needed to induce resting T cell proliferation. To investigate the early biologic consequences of IL 2 binding to the p70 protein, potential changes in the expression of genes involved in T cell activation were examined. Northern blotting revealed the rapid induction of c-myc, c-myb, and Tac mRNA after stimulation of resting T cells with a high concentration of IL 2. The anti-Tac antibody did not inhibit IL 2 induced expression of these genes, suggesting that the p70 protein rather than the Tac antigen or the high affinity IL 2 receptor complex mediated this signal. However, in contrast to these early activation events, the anti-Tac antibody significantly inhibited IL 2 induced T cell proliferation. This finding implicates the high affinity form of the IL 2 receptor in the proliferative response of the IL 2 activated T cells. Thus these data support a two step model for the induction of resting T cell proliferation by high doses of IL 2 involving the initial generation of an activation or "competence" signal through the p70 protein and a subsequent proliferation or "progression" signal through the high affinity form of the receptor.

Antigens, Surface↗

[Effects of a new beta-blocker (CI 775) on left ventricular hemodynamics at rest and during exercise (author's transl)].

The effects of a new beta-blocking agent (CI 778) were studied in 8 patients in whom non-invasive data suggested absence of significant organic heart disease. The left ventricular hemodynamics at rest and during bicycle exercise were measured before and after intravenous administration of 0,9 mg/kg body weight. With exercise there was a significantly smaller increment of heart rate (18%) after beta-blockade. Stroke volume index at rest was significantly lower (17%) after administration of CI 775; the difference disappeared with exercise. There was an 18% decrease of the resting cardiac output after CI 775 and a 23% decrease with exercise. Significant changes at rest and with exercise indicating a negative inotropic action of CI 775 were noted for max dP/dt and peak measured velocity of circumferential fiber shortening (Vpm). The left ventricular enddiastolic pressure with exercise increased with borderline significance by 41% after CI 775. Also left ventricular stroke work index at rest and with exercise decreased moderately (n.s.), the systemic arterial resistance changed to the same extent as cardiac output decreased. Also the arterial venous oxygen difference increased after CI 775 only according to the decrease of cardiac output. The data suggest the hemodynamic properties of CI 775 are located between propranolol and practolol within the spectrum of available beta-blockers.

Adrenergic beta-Antagonists↗

Respiratory airflow patterns in ponies at rest and during exercise.

The exercise-induced changes in the equine breathing pattern were studied by analyzing tidal breathing flow-volume loops recorded in ten ponies both at rest and during a standardized exercise. Airflow, tidal volume, esophageal pressure and mask pressure were simultaneously recorded before, during and after a treadmill exercise. From the collected data, respiratory frequency and total pulmonary resistance were calculated, tidal breathing flow-volume loops were retraced using a computerized method and loop indices were measured for each period of the experimental protocol. For each pony, results of three consecutive daily measurements were averaged. The exercise loop indices were compared with the corresponding resting values using a one-way analysis of variance. The significantly changed indices were correlated with respiratory frequency and total pulmonary resistance. Several types of respiratory patterns were observed at rest as well as during exercise, although each pony was relatively constant in its own pattern of breathing. Most resting inspiratory and expiratory airflow curves were found to be biphasic. When ponies started running, the airflow developed an increasingly rectangular pattern. During strenuous exercise, both inspiratory and expiratory airflow curves showed a substantial increase of the volume acceleration and tended to a plateau. The loop indices relating the expiratory to the inspiratory airflow were significantly increased compared with their rest values. Correlations of these indices with respiratory frequency and total pulmonary resistance were weak.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

The effect of verapamil on potentiated rest contractions in the rat ventricular myocardium.

The effects of verapamil (0.3 to 30 microM) on potentiated rest contractions (PRC) were studied in isometric contractions of left ventricular papillary muscles of the rat. The post-rest potentiation was studied after rest periods of 5, 10, 15, 30, 60 and 120 s. Verapamil reduced the steady-state force and PRC in a dose-dependent manner. However, PRC were less depressed and the magnitude of this depression decreased as the rest period increased. The time constant of the recovery of steady state force after rest potentiation was shortened. These results indicate that the first PRC are less dependent on calcium entering the cell through the slow channels and apparently more dependent on an intracellular calcium store.

Animals↗

Characterization of antigen processing and presentation by resting B lymphocytes.

The production of antibody to a thymus-dependent Ag requires cooperation between the B cell and an Ag-specific Th cell. MHC restriction of this interaction implies that the Th cell recognizes Ag on the B cell surface in the context of MHC molecules and that the Ag-specific B cell gets help by acting as an APC for the Th cell. However, a number of studies have suggested that normal resting B cells are ineffective as APC, implying that the B cell must leave the resting state before it can interact specifically with a Th cell. Other studies, including our own with rabbit globulin-specific mouse T cell lines and hybridomas, show that certain T cell lines can be efficiently stimulated by normal resting B cells. One possible explanation for the above contradiction is that our B cells have become activated before presentation. Here we show that presentation by size-selected small B cells is not the result of nonspecific activation signals generated by the T cells or components of the medium. Also, although LPS activation does increase the efficiency of presentation by small B cells, use of large cells in place of small cells or preincubation of resting B cells with mitogenic doses of anti-Ig does not. Another possibility that we considered was that small B cells are unable to process Ag and that we had selected T cell lines that were capable of recognizing native Ag on the B cell surface. In the majority of cases, experiments with B cell lines and macrophages have shown that Ag presentation requires Ag processing, a sequence of events that includes internalization of Ag into an acid compartment, denaturation or digestion of Ag into fragments, and its return to the cell surface in the context of class II MHC molecules. The experiments reported here show that our T cell lines require an Ag processing step and that small resting B cells, like other APC, process Ag before presenting it to T cells. Specifically, we show that an incubation of 2 to 4 h is required after the Ag pulse before Ag presentation becomes resistant to irradiation. Shortly after the pulse, the Ag enters a pronase-resistant compartment. Although efficient Ag presentation requires initial binding to membrane Ig, Ag is no longer associated with membrane Ig at the time of presentation and is not presented in its intact form, because removal of membrane Ig by goat anti-Ig blocks presentation before but not after the Ag pulse.

Animals↗

Resting B lymphocytes can be triggered directly through the CDw40 (Bp50) antigen. A comparison with IL-4-mediated signaling.

Resting tonsillar B lymphocytes were shown to enlarge and become more buoyant when exposed to either IL-4 or a mAb (G28-5) to the 50-kDa CDw40 Ag. A striking feature of activation through CDw40 was the promotion of strong homotypic adhesions which did not occur in populations cultured with IL-4. Whereas the CDw40 antibody down-regulated its target Ag, an increased expression of CDw40 accompanied IL-4 stimulation. Similarly, only IL-4, and not the CDw40 antibody, was able to induce the appearance of CD23 on the resting B cell surface. Functionally, the major consequence of ligating CDw40 on resting B cells was that they remained alert to subsequent mitogenic signaling--cells incubated with IL-4 developed the same sluggish response as noted in control cultures. Together, IL-4 and the CDw40 antibody provoked a small, but significant, level of DNA synthesis in tonsillar B cells which was enhanced dramatically by the inclusion of low m.w. B cell growth factor. This latter agent had no discernible direct effect on resting B lymphocytes. The different pathways which have been observed for triggering resting B cells are discussed.

Antibodies, Monoclonal↗

Influence of whole body protein turnover rate on resting energy expenditure in patients with cancer.

Whole body protein turnover and resting energy expenditure are measured simultaneously in weight stable and weight losing patients with lung (n = 22) or colorectal cancer (n = 38). These results were compared with those from weight stable and weight losing non-cancer controls (n = 22). Rates of whole body protein turnover were calculated from the plateau isotopic enrichment of urinary ammonia and urea following a primed, continuous, 24-h infusion of [15N]glycine. Resting energy expenditure was measured by indirect calorimetry. All groups of cancer patients had significantly elevated rates of whole body protein turnover (P less than 0.05) and synthesized, on average, 1.9 g/kg/day more protein compared with weight stable non-cancer controls. In contrast, the resting energy expenditure of cancer patients and controls was similar. Moreover, there was no correlation between individual rates of whole body protein turnover. Thus, although cancer patients had rates of whole body protein turnover which were 50-70% greater than controls, this did not result in a measurable increase in resting energy expenditure. The assumption that elevation of whole body protein turnover or resting energy expenditure causes weight loss in cancer patients must be an oversimplification. An acute phase protein response was observed in the majority of cancer patients. Although the presence of such an inflammatory response did not correlate with the rate of whole body protein turnover, the role of inflammatory mediators in the pathogenesis of disturbed protein metabolism in cancer patients merits further investigation.

Aged↗

[The development of the activity-rest cycle in the rabbit fetus].

On 25-30-day rabbit foetuses, in chronic experiments using constant synchronous recording of the motor activity and heart rate, studies have been made of temporal organization of the activity-rest cycle. Already in 25-day foetus, three functional conditions may be distinguished: active, intermediate and resting ones, the duration of the latter increasing to the end of gestation up to 8-10 min, whereas the duration of the intermediate phase decreases, reaching its minimum to the 30th day if not being completely reduced. Cyclic pattern of active and resting phases is observed in 28-day foetuses; to the 29th-30th day, these phases from a unique activity-rest cycle, its duration reaching 20-30 min to the end of intrauterine period. It is suggested that the resting phase in foetal rabbits serves as a basis for the development of polyphasic sleep in adult animals.

Activity Cycles↗

Lactate production under fully aerobic conditions: the lactate shuttle during rest and exercise.

O2 insufficiency and other factors increase the rate of lactate production. Significant quantities of lactate are produced under postabsorptive as well as postprandial conditions in resting individuals. In humans during postabsorptive rest, 25-50% of the total carbohydrate combusted appears to pass through the lactate pool. During sustained submaximal (in terms of VO2max) exercise, the rates of lactate production (Ri) and oxidation (Rox) are greatly elevated as compared to rest. However, lactate production and oxidation increase relatively less than O2 consumption during moderate-intensity exercise. Because the lactate production index (RiI = Ri/VO2) decreases during submaximal, moderate-intensity exercise compared to rest, it is concluded that skeletal muscle and other sites of lactate production are effectively oxygenated. Alterations in the levels of circulating catecholamines can affect levels and turnover rates of glucose and lactate. In pure red dog gracilis muscle in situ and in the healthy and myocardium in vivo, contraction results in glycolysis and lactate production. This production of lactate occurs despite an apparent abundance of O2. Similarly, glucose catabolism in the human brain results in lactate production. The formation of lactate under fully aerobic conditions of rest and exercise represents an important mechanism by which different tissues share a carbon source (lactate) for oxidation and other processes such as gluconeogenesis. This mechanism has been termed the lactate shuttle.

Aerobiosis↗

Predictive value of the resting electrocardiogram for Mobitz type I atrio-ventricular block on Holter monitoring in Israeli air force personnel.

During 1981-1984, a total of 52 airpersonnel had 24-h continuous ambulatory electrocardiographic (ECG) monitoring at the Israel Air Force Aeromedical Center because of an incidental finding of a first or second degree atrio-ventricular block on a resting 12-lead ECG. There were 230 other airpersonnel without AV block on the resting ECG monitored during the same period. Altogether 17 cases of second degree Mobitz type I (Wenckebach) block were identified. Mobitz type I was detected on Holter monitoring in 2 (0.9%) of the 230 cases with a normal PR interval on the resting ECG, in 6 (15.4%) of 39 cases with a PR interval of 0.22-0.25 s, in 5 (55.5%) of 9 cases with a PR interval of 0.26 s or more, and in all 4 cases with Mobitz type I on the resting ECG. It is concluded that the PR interval on the resting ECG may be useful in predicting an intermittent Mobitz type I AV block on Holter monitoring.

Aerospace Medicine↗

[Significance of the ejection fraction at rest and by stress using radionuclide ventriculography for the prognosis of myocardial infarct patients--comparison with other study methods].

We examined 221 patients with postmyocardial infarctions 8 weeks after MI using radionuclide ventriculography (RNVA) at rest (EFR) and during supine submaximal exercise (delta EF). Mortality rates were evaluated 2 1/2 and 3 1/2 years later by interviewing patients and/or their homephysicians. Sixteen patients were dead (6.7%) 2 1/2 years after MI, 28 (12.7%) were dead after 3 1/2 years. Thirty percent of patients with a resting EF less than 30% had died 2 1/2 years after MI, and 40% were dead within 3 1/2 years. The mortality rate was significantly higher than in patients who had EF greater than or equal to 30% 8 weeks after MI. Patients with a decrease of delta EF (greater than or equal to 5%) showed a 2 1/2 year mortality of 10.8% and after 3 1/2 years of 18.5%. Mortality was significantly higher in patients with decreasing EF during exercise than in those who increased their EF during exercise. This prognostic value of EFR and delta EF was compared with other parameters (angina pectoris, ECG at rest and during exercise, heart volume, Holter ECG, floating catheter PCP [rest and exercise], coronary angiography). Radionuclide ventriculography at rest and during exercise showed a tendency to be the best determining factor for prognosis, and is therefore recommended to determine prognosis in post-MI patients.

Adult↗