Biomedical subjects

J Nunes

Publications and source records attributed to J Nunes.

At least 19 recordsLinked to original sources

PubMed1999

Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling.

We evaluated the importance of CD3-zeta ITAMs in T cell responses by breeding the P14 transgenic TCR into mice in which CD3-zeta chains lacking all or part of their ITAMs were genetically substituted for wild-type CD3-zeta chains. In contrast to the H-Y TCR, the P14 TCR permitted the development of peripheral CD8+ T cells harboring signaling-defective CD3-zeta subunits. The absence of functional CD3-zeta ITAMs did not reduce the spectrum of activation events and effector functions that constitute the normal attributes of mature CD8+ T cells. The only detectable differences were quantitative and noted only when T cells were challenged with suboptimal peptide concentrations. Therefore, the ITAMs present in the CD3-gammadeltaepsilon module are sufficient for qualitatively normal TCR signaling and those present in CD3-zeta have no exclusive role during T cell activation.

Animals↗

PubMed1999

Actigraphic predictors of depressed mood in a cohort of non-psychiatric adults.

OBJECTIVE: Depressed mood is one of the essential features for the diagnosis of major depression. Evidence from the three-site Epidemiologic Catchment Area study (ECA, Baltimore, Durham and Los Angeles) suggests a prevalence of 4.4% of depressive symptoms in the community. In this study, we examined whether depressed mood, as coded in the Alzheimer's Disease Assessment Scale, would be correlated with actigraphic-derived daytime activity and sleep/wake parameters in a non-psychiatric sample. METHOD: Consenting volunteers were monitored at home for 5 days with a wrist actigraph. On the last day of the recording, they were given a neuropsychological battery including the Alzheimer's Disease Assessment Scale. RESULTS: Daytime activity level was the best predictor of depressed mood as indicated by a logistic regression analysis. The regression model further suggested that sleep onset latency, total time asleep, and time in bed were also significant predictors of depressed mood. CONCLUSION: This investigation demonstrates that daytime activity level could be used as an index of depressed mood even in a non-psychiatric sample. Further, the results support the notion that depression should be considered more as a continuum rather than as a set of rigid categories.

Adolescent↗

PubMed1999

Assessment of physical activity and sleep by actigraphy: examination of gender differences.

Research evidence suggests that actigraphy is a very important instrument in documenting sleep/wake patterns of people with a variety of sleep disorders or motor dysfunctions. The present actigraphic investigation examined physical activity and sleep profiles as a function of gender in volunteers monitored in their natural environment. Irrespective of age, women exhibited better sleep quality than did men. This was demonstrated by higher sleep efficiency index and lower frequency of transitions between sleep and wakefulness. Additionally, women slept more than men and had shorter sleep onset latency. However, no significant gender effect on daytime activity level and circadian activity amplitude was observed.

Adult↗

PubMed1998

Intracarotid pressure measurements in the evaluation of a computer model of the cerebral circulation.

BACKGROUND: It is difficult to predict which patients will tolerate occlusion of the internal carotid artery. This difficulty arises primarily because of uncertainties in the prediction of the adequacy of collateral circulation. Because of these uncertainties, balloon test occlusion and other methods have been developed to determine a priori the safety of carotid occlusion. However, all the methods are associated with significant false-positive and false-negative rates, as well as other neurologic complications. Because of these problems, more accurate and less invasive methods for predicting tolerance of carotid occlusion are needed. METHODS: In this report, we present the initial clinical evaluation of a new method for assessing the collateral circulation aided by a mathematical model of the cerebral vasculature. Data from the angiograms of 14 patients who underwent carotid endarterectomy were used to create individualized simulations of their cerebral circulations. As a test of the accuracy of the simulations, we compared values of the intracarotid stump pressures predicted by the model to those measured at surgery during the period of carotid occlusion. RESULTS: The pressure predictions of the model correlated well with those measured at surgery. Linear regression analysis of measured versus predicted values yielded a line with slope 1.05. The line with slope 1.00, which denotes perfect agreement between predictions and measurements, is within the 95% confidence interval of the slope determined from the regression analysis. CONCLUSIONS: Mathematical models of the cerebrovascular circulation can provide good predictions of intravascular pressure in the collateral circulation, and may provide accurate predictions of the flow as well. The present study reveals several areas that need further development, such as the models of the microvasculature, measurement of the arterial dimensions from angiograms, and consideration of other collateral sources such as the leptomeningeal and retrograde ophthalmic sources of flow. Incorporation of these improvements may lead to a clinically useful, noninvasive assessment of the state of the cerebrovascular collateral circulation in the individual patient.

Angiography↗

PubMed1998

Mood states and sleepiness in college students: influences of age, sex, habitual sleep, and substance use.

Survey and laboratory evidence suggests several factors affecting sleep-wake patterns of college students. These factors include social and academic demands, diminution of parental guidance, reduction of total sleep time, delayed bedtime, and increased nap episodes. In this study, we examined the problem of falling asleep in school as a correlate of negative moods in this population (N = 294). A multivariate analysis showed significant main effects of sleepiness on mood states based on the Profile of Mood States. Students who fell asleep in school reported higher negative mood states. Significant interactions were observed among sleepiness and age, sex, race, and duration of sleep. Specifically, younger men reported higher negative moods. No interactions were noted for alcohol and marijuana consumption; however, students who fell asleep in school consumed more alcoholic beverages and smoked more than those who did not. Perhaps falling asleep in school could be used as an index that characterizes students who manifest adaptive or psychological difficulty.

Achievement↗

PubMed1996

Insomnia.

The series of cases presented here should illustrate that the complaint "I can't sleep" is deceptively simple. The clinician must be prepared to gather information from many disparate aspects of the patient's history and present circumstances. Diagnostic considerations are complicated further by the significant night-to-night variation in the manifestations of the insomnia. Too often, the result of this hidden complexity is a tendency either to prescribe hypnotic drugs as a first intervention or to give signals to patients with insomnia that not much can be done and that difficulty sleeping is simply a fact of life. The sleep log can help to bring order to the jumble of insomniac experiences. It leads both the clinician and patient away from assigning too much weight to a specific instance, instead allowing more general patterns to be discerned. As order is created out of the factors contributing to the insomnia, a treatment plan can be designed that goes beyond mere symptomatic treatment.

Adult↗

PubMed1996

Determination of sleep and wakefulness with the actigraph data analysis software (ADAS).

Current evidence has shown that, overall, actigraphy is an excellent tool for unobtrusive documentation of sleep/wake activity in normal individuals. However, a number of methodological issues remain to be resolved to warrant its use in clinical research. In this paper, we report the results of a study aimed at the development of a new scoring software that can accurately identify sleep and wakefulness. Using total sleep time as an index of comparison, the software was optimized on a calibration sample and prospectively tested on a validation sample. A strong correlation coefficient (r = 0.93, p < 0.008), with an average discrepancy value of 10 minutes, was observed for the calibration sample. The application of the optimal software to the validation sample revealed an even higher correlation coefficient (r = 0.97, p < 0.0001), with an average discrepancy value of 12 minutes.

Adult↗

PubMed1994

Binding of phosphatidylinositol-3-OH kinase to CD28 is required for T-cell signalling.

The engagement of CD28 with its ligand B7.1/CD80 results in potent costimulation of T-cell activation initiated through the CD3/T-cell receptor complex. The biochemical basis of CD28 costimulatory function is poorly understood. The signalling pathways used by CD28 are unlike those used by the CD3/T-cell receptor in that they are resistant to cyclosporin A and independent of changes in cyclic AMP concentrations. These differences suggest that each pathway provides unique biochemical information which is required for T-cell activation. We report here that CD28 becomes tyrosine-phosphorylated following interaction with B7.1/CD80, which induces formation of a complex with phosphatidylinositol-3-OH kinase, mediated by the SH2 domains of the p85 subunit of the kinase. Phosphatidylinositol-3-OH kinase is a heterodimer of this 85K regulatory subunit and a 110K catalytic subunit, and is a common substrate for most receptor tyrosine kinases and some cytokine receptors, binding through its SH2 domain to phosphotyrosine in the motif Tyr-X-X-Met in the CD28 sequence, which is highly conserved between human, mouse and rat and lies in the intracellular domain. We show that CD28 mutants that have their kinase-binding site deleted or the tyrosine at position 173 substituted by phenylalanine do not associate with the kinase after CD28 stimulation and cannot stimulate production of interleukin-2. Our results suggest that phosphatidylinositol-3-OH kinase is critical for signalling by CD28.

Animals↗

PubMed1994

Intracranial aneurysms: size, risk of rupture, and prophylactic surgical treatment.

Intracranial saccular aneurysms frequently cause devastating neurologic injury when they rupture. With recent improvements in diagnostic imaging, however, an increasing number of aneurysms are now diagnosed in the unruptured state. Controversy exists regarding the appropriate management of these lesions. We have retrospectively examined a group of 86 patients from Connecticut with 104 intracranial aneurysms to determine whether small (less than 10 mm in greatest diameter) aneurysms have potential for rupture, and whether there is a role for prophylactic surgical therapy for these unruptured aneurysms. The majority of ruptured and unruptured aneurysms in the series measured less than 10 mm in greatest diameter. Out of a total of 82 patients who underwent surgical therapy, 44 had surgery for unruptured aneurysms. The major surgical morbidity in this group was 2%. We conclude that surgical therapy for small unruptured intracranial aneurysms may be beneficial since these lesions likely have substantial potential for rupture and because surgical treatment carries an acceptable risk.

Aneurysm, Ruptured↗

PubMed1993

Signalling through CD28 T-cell activation pathway involves an inositol phospholipid-specific phospholipase C activity.

Stimulation of the human T-cell line, Jurkat, by a monoclonal antibody (mAb) directed against the CD28 molecule leads to sustained increases in intracellular levels of Ca2+ ([Ca2+]i); the initial rise in Ca2+ comes from internal stores, followed by Ca2+ entry into the cells. The CD28 molecule also appears to activate polyphosphoinositide (InsPL)-specific phospholipase C (PLC) activity in Jurkat cells, as demonstrated by PtdInsP2 breakdown, InsP3 and 1,2-diacylglycerol generation and PtdIns resynthesis. We also observed that interleukin-2 (IL2) production induced via CD28 triggering was sensitive to a selective protein kinase C inhibitor. Of the four other anti-CD28 mAbs (CD28.2, CD28.4, CD28.5, CD28.6) tested, only one (CD28.5) was unable to generate any InsPL-specific PLC or IL2 secretion. However, the cross-linking of cell-bound CD28.5 with anti-mouse Ig antibodies led to an increase in [Ca2+]i. CD28-molecule clustering in itself appears to be a sufficient signal for induction of PLC activity.

Antibodies, Monoclonal↗

PubMed1993

Regulation of CD2-mediated human T cell activation: anti-CD8 monoclonal antibodies inhibit CD2-mediated rise in intracellular calcium.

The human CD8 glycoprotein regulates the function of cytotoxic T cells activated by antigenic peptide as well as via CD3 or CD2 mAbs. Activation of T cells by CD2 mAbs requires two mAbs directed against distinct CD2 epitopes and induces tyrosine phosphorylation, PI-PLC activity generating the second messengers, IP3 and DAG, and finally lymphokine secretion. We have investigated the role of the CD8 alpha molecule in CD2-mediated activation of human cytotoxic T cell clones and CD8+ resting T cells. CD8 alpha-specific mAb inhibited 60% of the allospecific cytotoxicity of the CD8+ clone against its target cell and 86% of the CD2-redirected killing against the HLA Class I-negative Daudi target cell. In addition, CD8 alpha-specific mAb inhibited CD2-mediated TNF alpha and IL2 secretion by the CD8+ clone. Furthermore, CD8 alpha-specific mAb inhibited the increase in intracellular ionized calcium mediated by CD2 mAbs in the CD8+ clone and in purified T cells. Since the [Ca2+]i recruitment from internal stores induced by CD2 mAbs was inhibited, the inhibitory effect induced by the CD8 alpha-specific mAb probably acts on the PI-PLC activation pathway. This inhibition mechanism involves neither a decrease in affinity of CD2 mAb for its target nor a decrease in CD2 cell surface expression or a rise in cAMP known as an inhibitor of the CD2-mediated PI-PLC activity. These results suggest that the inhibitory mechanism induced by the CD8 mAb may prevent the activation of the PI-PLC activity, probably through the CD8 alpha-associated protein tyrosine kinase p56lck.

Antibodies, Monoclonal↗

PubMed1993

Anti-T11.1 and -T11.2 monoclonal antibodies play a different role in CD2-mediated signal transduction.

We comparatively evaluated (Ca2+)i mobilization after triggering with a stimulatory pair of CD2 (CD2.9, anti-T11.1 + CD2.1, anti-T11.2) or CD3 mAbs in the differentiated T-cell line Jurkat, using INDO-1 labeling and cytofluorimetry. The results obtained showed different (Ca2+)i mobilization kinetics following CD2 or CD3 stimulation (the former being slower than the latter), not due to different association kinetics of mAbs. In a nonreciprocal manner, however, preliminary interaction with CD2.1 (anti-T11.2) followed by CD2.9 (anti-T11.1) induces a rapid (Ca2+)i rise, similar to CD3 stimulation, as shown by preincubation experiments. There is no interference between CD2.9 and CD2.1 mAb binding. CD2.1 mAb by itself is unable to induce (Ca2+)i mobilization; in addition, preincubation with CD2.1 mAb did not modify the CD2, CD3, CD45, or CD28 immunoprecipitation patterns. Triggering of the epitope recognized by CD2.1 mAb may favor, possibly via conformational changes of CD2 molecule or (Ca2+)i-unrelated metabolic effect(s), optimal signal transduction.

Antibodies, Monoclonal↗

PubMed1993

Spatial dose-rate distribution for an 194Ir point source in water.

The spatial dose-rate distribution arising from a unit activity point source of 194Ir embedded in an infinite water medium has been calculated. These results may prove to be both useful and timely; 194Ir is a beta-particle-emitting radionuclide that is a suitable candidate for radioimmunotherapy, and a means for producing it fairly easily has recently been made available. Calculation of the beta-ray dose-rate distribution is based on a new set of monoenergetic electron dose point kernels which are results from an improved Monte Carlo (ETRAN) calculation. The spatial dose-rate distribution for 32P was also calculated and compared with results from the EGS4-PRESTA and ACCEPT Monte Carlo codes. The ETRAN-based distribution agrees with that from EGS4-PRESTA to within 2% out to 3.6 mm from the source, a distance over which 90% of the source energy is deposited. The ETRAN-based distribution also agrees well with that from ACCEPT between 0.6 and 4 mm from the source; at distances < 0.6 mm, values from ACCEPT are about 6% larger than ones calculated here.

Beta Particles↗

PubMed1989

Monoclonal antibodies against LFA-1 or its ligand ICAM-1 accelerate CD2 (T11.1 + T11.2)-mediated T cell proliferation.

Activation of human-purified T cells can be mediated by pairwise combinations of monoclonal antibodies directed against T11.1 and T11.2 epitopes on the CD2 molecule. Monoclonal antibodies (mAbs) reactive with either the alpha and beta chains of the lymphocyte-function-associated antigen-1 (LFA-1) molecule or one of its ligands, intercellular adhesion molecule-1 (ICAM-1), were found to accelerate anti-CD2-induced proliferation. This effect was seen on thymocytes and resting or preactivated T cells (phytohemagglutinin blasts and alloproliferative T cell clones) and could be observed, following the introduction of anti-LFA-1 or -ICAM-1 mAbs, up to 50 hr after the CD2 stimulatory signal. This effect was equally abrogated by 55 kDa anti-interleukin-2 (IL-2) receptor mAb, but neither the expression of IL-2 receptor nor the production of IL-2 was modified. The effects of anti-LFA-1 or anti-ICAM-1 on T cell activation through the CD2 pathway were therefore opposite to those observed in the CD3 pathway, where both mAbs strongly delayed T cell proliferation.

Antibodies, Monoclonal↗

PubMed1989

T cell activation via the CD2 molecule is associated with protein kinase C translocation from the cytosol to the plasma membrane.

T cell activation via the CD2 molecule involves phospholipase C and phosphoinositide hydrolysis. Here we demonstrate that the triggering of subclones of the human T leukemia Jurkat cell line by anti-CD2 as well as anti-CD3 monoclonal antibodies is able to induce activation (i.e. translocation from cytosol to cell membrane) of protein kinase C (PKC), which is dependent on the formation of 1,2-diacylglycerol from inositol 4-5-bisphosphate. The kinetics of PKC translocation parallels the rise in intracellular calcium following both CD2 and CD3 stimulations. These results further demonstrate that CD2 and CD3 activation pathways use similar signal transduction mechanisms.

Antibodies, Monoclonal↗

PubMed1989

Cholera toxin inhibits the increase in cytoplasmic free calcium induced via the CD2 pathway of human T-lymphocyte activation.

We investigated the action of cholera toxin on the intracellular ionized calcium [Ca2+]i increase induced by anti-CD2 and anti-CD3 monoclonal antibodies in the leukemic human T-cell line Jurkat. Cholera toxin inhibits in a dose-dependent manner these two pathways of human T-lymphocyte activation but with different half maximal inhibition doses (75 ng/ml for CD3, 30 ng/ml for CD2). This effect cannot be accounted for only by the increase in cAMP induced by cholera toxin because forskolin, which raises cellular cyclic adenosine monophosphate (cAMP) to the same levels, induced only a small inhibition of the [Ca2+]i increase in similar conditions. Cholera toxin induced a decrease in the surface expression of the CD3 molecule, suggesting a down-regulation of the CD3 molecules. On the other hand, the expression of CD2 remained unchanged. Cell surface disappearance of the CD3 molecule cannot account for all the inhibitory effects of cholera toxin because CD2 molecule expression was not affected (no modifications in the half maximal binding of anti-CD2 monoclonal antibodies). All together, these results suggest that cholera toxin acts on substrates, possibly G proteins, that could regulate the [Ca2+]i increase induced by anti-CD2 and anti-CD3 mAbs in Jurkat cells. In addition, the present study demonstrated that the rise in cellular cAMP partially inhibits the [Ca2+]i increase induced by anti-CD2 and anti-CD3 mAbs.

Antibodies, Monoclonal↗

PubMed1989

Beta dose point kernels for radionuclides of potential use in radioimmunotherapy.

Beta dose point kernels for 32P, 67Cu, 90Y, 131I, 186Re, and 188Re nuclides appropriate for radioimmunotherapy are calculated based upon Monte Carlo results. The calculations are shown to differ significantly from values based upon solutions to the electron transport equation. Agreement with experiment for 32P is found to be improved for the former as compared with the latter. Values of the scaled dose point kernels are tabulated at 4% intervals of the continuous slowing down approximation range for each of the six radionuclides. Beta dose distributions are also tabulated at corresponding distances from the source. This data may be used to calculate the spatial dose distribution expected following administration of radiolabeled monoclonal antibodies, aiding in optimum selection of the appropriate radionuclide. Parameters for functions providing analytic representation of the calculated scaled dose point kernels of individual beta groups are presented.

Beta Particles↗

PubMed1988

Triggering CD 28 molecules synergize with CD 2 (T 11.1 and T 11.2)-mediated T cell activation.

Pairs of monoclonal antibodies (mAb) defining epitopes T 11.1 and T 11.2 on the CD 2 molecule are mitogenic for purified human T cells in the presence of a submitogenic dose of 12-O-tetradecanoylphorbol 13-acetate (TPA). Anti-CD 28 mAb can substitute for the action of TPA in the anti-CD 2-induced proliferative response of resting T cells, whereas each signal alone is unable to mediate this effect. Co-stimulation by anti-CD 2 plus anti-CD 28 mAb is monocyte independent and besides resting T cells also induces strong proliferation of thymocytes and pre-activated T cells. Modulation of the CD 3-T cell receptor complex does not inhibit the co-stimulatory effects of anti-CD 2 plus anti-CD 28 mAb. The effect is largely dependent on endogenously produced interleukin 2, since the response is strongly inhibited in the presence of mAb against the 55-kDa interleukin 2 receptor chain.

Antibodies, Monoclonal↗