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Biomedical subjects

M Moran

Publications and source records attributed to M Moran.

At least 19 recordsLinked to original sources
PubMed2000

Galectin-1 induces partial TCR zeta-chain phosphorylation and antagonizes processive TCR signal transduction.

Galectin-1 is an endogenous lectin with known T cell immunoregulatory activity, though the molecular basis by which galectin-1 influences Ag specific T cell responses has not been elucidated. Here, we characterize the ability of galectin-1 to modulate TCR signals and responses by T cells with well defined hierarchies of threshold requirements for signaling distinct functional responses. We demonstrate that galectin-1 antagonizes TCR responses known to require costimulation and processive protein tyrosine phosphorylation, such as IL-2 production, but is permissive for TCR responses that only require partial TCR signals, such as IFN-gamma production, CD69 up-regulation, and apoptosis. Galectin-1 binding alone or together with Ag stimulation induces partial phosphorylation of TCR-zeta and the generation of inhibitory pp21zeta. Galectin-1 antagonizes Ag induced signals and TCR/costimulator dependent lipid raft clustering at the TCR contact site. We propose that galectin-1 functions as a T cell "counterstimulator" to limit required protein segregation and lipid raft reorganization at the TCR contact site and, thus, processive and sustained TCR signal transduction. These findings support the concept that TCR antagonism can arise from the generation of an inhibitory pp21zeta-based TCR signaling complex. Moreover, they demonstrate that TCR antagonism can result from T cell interactions with a ligand other than peptide/MHC.

Adjuvants, Immunologic↗
PubMed2000

Long-term adaptive life functioning in relation to initiation of treatment with antipsychotics over the lifetime trajectory of schizophrenia.

BACKGROUND: There is evidence that the stage of illness at which antipsychotic treatment is initiated in schizophrenia may have consequences for its subsequent course. How this might relate to impaired adaptive life functioning in the long-term is poorly understood. METHODS: Thirty-eight inpatients, many of whom had been admitted in the preneuroleptic era, were assessed using the Social-Adaptive Functioning Evaluation (SAFE); constituent clinical and medication phases of the lifetime trajectory of their illnesses were then analyzed to identify predictors of SAFE score using multiple regression modeling. RESULTS: The primary, independent predictor of SAFE score was duration of initially unmedicated psychosis, which accounted for 22% of variance (p<.001) therein. Conversely, duration of subsequently treated illness, although decades longer, failed to predict SAFE score. CONCLUSIONS: These findings are consistent with some form of "progressive" process, particularly over the first several years following the emergence of psychosis, which is associated with accrual of deficits in adaptive life functioning.

Adaptation, Psychological↗
PubMed2000

Treatment of sialorrhea with glycopyrrolate: A double-blind, dose-ranging study.

OBJECTIVE: To determine the safety and efficacy of glycopyrrolate in the treatment of developmentally disabled children with sialorrhea. DESIGN: Placebo-controlled, double-blind, crossover dose-ranging study. SETTING: Outpatient facilities in 2 pediatric hospitals. PATIENTS: Thirty-nine children with both developmental disabilities and excessive and bothersome sialorrhea. MAIN OUTCOME MEASURES: Parent and investigator evaluation of change in sialorrhea and adverse effects. RESULTS: Glycopyrrolate in doses of 0.10 mg/kg per dose is effective at controlling sialorrhea. Even at low doses, 20% of children may exhibit adverse effects severe enough to require discontinuation. CONCLUSIONS: Glycopyrrolate is effective in the control of excessive sialorrhea in children with developmental disabilities. Approximately 20% of children given glycopyrrolate may experience substantial adverse effects, enough to require discontinuation of medication. Arch Pediatr Adolesc Med. 2000;154:1214-1218.

Adolescent↗
PubMed1999

Galectin-1 specifically modulates TCR signals to enhance TCR apoptosis but inhibit IL-2 production and proliferation.

Galectin-1 is an endogenous lectin expressed by thymic and lymph node stromal cells at sites of Ag presentation and T cell death during normal development. It is known to have immunomodulatory activity in vivo and can induce apoptosis in thymocytes and activated T cells (1-3). Here we demonstrate that galectin-1 stimulation cooperates with TCR engagement to induce apoptosis, but antagonizes TCR-induced IL-2 production and proliferation in a murine T cell hybridoma and freshly isolated mouse thymocytes, respectively. Although CD4+ CD8+ double positive cells are the primary thymic subpopulation susceptible to galectin-1 treatment alone, concomitant CD3 engagement and galectin-1 stimulation broaden susceptible thymocyte subpopulations to include a subset of each CD4- CD8-, CD4+ CD8+, CD4- CD8+, and CD4+ CD8- subpopulations. Furthermore, CD3 engagement cooperates with suboptimal galectin-1 stimulation to enhance cell death in the CD4+ CD8+ subpopulation. Galectin-1 stimulation is shown to synergize with TCR engagement to dramatically and specifically enhance extracellular signal-regulated kinase-2 (ERK-2) activation, though it does not uniformly enhance TCR-induced tyrosine phosphorylation. Unlike TCR-induced IL-2 production, TCR/galectin-1-induced apoptosis is not modulated by the expression of kinase inactive or constitutively activated Lck. These data support a role for galectin-1 as a potent modulator of TCR signals and functions and indicate that individual TCR-induced signals can be independently modulated to specifically affect distinct TCR functions.

Adjuvants, Immunologic↗
PubMed1999

Blood testing in biathlon: observation of hematocrit values during competitive periods 1994-1997.

The International Biathlon Union, through its own Medical Commission, has undertaken a three-year program aimed at identifying the hematocrit levels of athletes who participate in biathlons. The purpose was to check for hematocrit levels exceeding normal physiological values as well as for any significant modifications within individuals during the course of the competitive season. All of the athletes registered in international biathlon races were, therefore, subjected to venous blood sampling (1 cc) three times a year prior to competition, in the days preceding two World Cup races (December and January) and the World Championships (February). The blood was centrifuged, the micro-hematocrit determined, and the value (rendered anonymous) recorded. This procedure was repeated for three consecutive competitive seasons (Dec. 1994-Feb. 1995, Dec. 1995-Feb. 1996, Dec. 1996-Feb. 1997). During this three-year period, the collected data showed a significant lowering of the average hematocrit level. In fact, from the first February sampling to the third February sampling, the average hematocrit value for the male population dropped from 48.04 +/- 2.36 to 46.33 +/- 1.91, and for the female population from 44.05 +/- 2.44 to 42.52 +/- 1.92. Even the distribution of the absolute hematocrit values was modified from the first to the third competitive season, especially for the February sampling, with a > or = 50% reduction for males and a > or = 48% reduction for females.

Adolescent↗
PubMed1999

Chronic photodamage in skin of mast cell-deficient mice.

Solar elastosis is a hallmark of photoaged human skin and a prominent feature in experimentally produced photoaging in murine skin. The products of mast cells have been implicated in the development of photoaged skin. We evaluated whether products from mast cells mediate chronic UVB-induced changes in murine skin by employing a strain of mast cell-deficient mice, WWv. The responses in these mice were compared to those in BALB/c, another albino mouse strain. Mice were exposed three times per week to UVB radiation for 11 weeks; the total dose was 18.8 J/cm2. Irradiated WWv mice showed greater epidermal alterations than the irradiated BALB/c mice. In the dermis, a 3.6-fold increase in elastin content, as measured by desmosine, was produced in the UVB-treated BALB/c mice; in contrast, no difference was observed in elastin between UVB-treated and untreated WWv mice. Collagen content was not increased by UVB treatment in either strain, and the glycosaminoglycan content increased a similar amount in UVB-treated mice in both strains. The number of mast cells increased two-fold and the number of neutrophils increased six-fold in UVB-treated BALB/c mice compared to age-matched unirradiated controls. Neutrophils, as well as mast cells, were absent in untreated and UVB-treated WWv mouse skin. These results suggest that products of mast cells are important in the development of solar elastosis in murine skin either by directly inducing elastin production by fibroblasts or indirectly by mediating the presence of other cell types that produce products that increase fibroblast elastin production.

Animals↗
PubMed1998

Lobular carcinoma in situ as a component of breast cancer: the long-term outcome in patients treated with breast-conservation therapy.

PURPOSE: The purpose of this study is to assess the long-term outcome of breast cancer patients with a component of lobular carcinoma in situ (LCIS) treated with conservative surgery and radiation therapy. METHODS AND MATERIALS: The pathology reports of all patients treated with conservative surgery and radiation therapy at our institution prior to 1992 were reviewed to identify patients who had LCIS as a histologic component. A total of 51 patients were identified. Primary histology of the 51 patients was as follows: 53% infiltrating lobular, 20% invasive and intraductal, 18% invasive ductal, 10% intraductal. There were no patients treated who had LCIS only. One thousand forty-five patients treated conservatively during the same time interval without LCIS served as a control group. All patient characteristics, staging, treatment and outcome variables were entered into a computer database. RESULTS: As of 3/96, the median follow-up for the LCIS-containing group and control group was 10.6 and 11.4 years, respectively. There were no significant differences in age of presentation, clinical stage, nodal status, estrogen receptor status, or adjuvant therapy received between the two groups. Twenty-two patients (43%) in the LCIS group underwent reexcision. Of those, 69% had residual LCIS in the reexcision specimen. LCIS was characterized as focal in 29%, diffuse in 25%, and not specified in all other cases. The primary histology of the two populations differed significantly with a larger percentage of infiltrating lobular primaries in the LCIS group (53 vs. 5%, p < 0.001). The LCIS group also differed from the control group with respect to the percentage of patients with bilateral disease (17 vs. 8%, p = 0.05), and the percentage of patients with "false negative" mammograms (20 vs. 10%, p = 0.02). There was no statistically significant difference between the LCIS group and control group in the 10-year overall survival (67 vs. 72%), distant disease-free survival (62 vs. 79%), or ipsilateral breast tumor recurrence-free survival (77% LCIS vs. 84% control). CONCLUSION: Patients with LCIS as a histologic component of breast cancer do not carry a worse prognosis than breast cancer patients without an LCIS component. Furthermore, the comparable local control rates between conservatively treated patients with or without LCIS suggests that patients with a histologic component of LCIS are suitable candidates for conservative surgery and radiation therapy.

Adult↗
PubMed1998

Engagement of GPI-linked CD48 contributes to TCR signals and cytoskeletal reorganization: a role for lipid rafts in T cell activation.

GPI-linked proteins coassociate with intracellular tyrosine kinases in "lipid rafts" proposed to function as platforms for signal transduction and cytoskeletal reorganization. TCR activation requires both tyrosine kinase signals and cytoskeletal reorganization. How receptor engagement initiates cytoskeletal changes remains poorly understood. We investigated the consequences of recruiting GPI-linked CD48 and associated rafts to the site of T cell:APC contact by stimulating T cells with APCs that express the CD48 ligand CD2. We demonstrate that CD2:CD48 interactions enhance TCR-mediated functions. CD48/TCR coengagement qualitatively and quantitatively enhances lipid raft-dependent zeta association with the actin cytoskeleton and zeta tyrosine phosphorylation. This implicates lipid rafts as sites where receptor-induced signals and cytoskeletal reorganization are integrated and reveals a novel component of accessory molecule function.

Actins↗
PubMed1998

Endogenous skin fluorescence includes bands that may serve as quantitative markers of aging and photoaging.

Aging and photoaging cause distinct changes in skin cells and extracellular matrix. Changes in hairless mouse skin as a function of age and chronic UVB exposure were investigated by fluorescence excitation spectroscopy. Fluorescence excitation spectra were measured in vivo, on heat-separated epidermis and dermis, and on extracts of mouse skin to characterize the absorption spectra of the emitting chromophores. Fluorescence excitation spectra obtained in vivo on 6 wk old mouse skin had maxima at 295, 340, and 360 nm; the 295 nm band was the dominant band. Using heat separated tissue, the 295 nm band predominantly originated in the epidermis and the bands at 340 and 360 nm originated in the dermis. The 295 nm band was assigned to tryptophan fluorescence, the 340 nm band to pepsin digestable collagen cross-links fluorescence and the 360 nm band to collagenase digestable collagen cross-links fluorescence. Fluorescence excitation maxima remained unchanged in chronologically aged mice (34-38 wk old), whereas the 295 nm band decreased in intensity with age and the 340 nm band increased in intensity with age. In contrast, fluorescence excitation spectra of chronically UVB exposed mice showed a large increase in the 295 nm band compared with age-matched controls and the bands at 340 and 350 nm were no longer distinct. Two new bands appeared in the chronically exposed mice at 270 nm and at 305 nm. These reproducible changes in skin autofluorescence suggest that aging causes predictable alterations in both epidermal and dermal fluorescence, whereas chronic UV exposure induces the appearance of new fluorphores.

Animals↗
PubMed1998

Spontaneous dyskinesia in subjects with schizophrenia spectrum personality.

OBJECTIVE: The study of spontaneous dyskinesia in schizophrenia is confounded by the widespread use of neuroleptics. The authors hypothesized that spontaneous dyskinesia would be present in subjects with schizophrenia spectrum personality (schizoid, paranoid, or schizotypal). They also tested the hypothesis that dyskinetic-like movements would increase after repeated dextroamphetamine challenge to the dopaminergic system. METHOD: Dyskinetic-like movements were assessed in 34 spectrum subjects and 22 normal subjects; nine subjects from each group were administered both placebo and repeated dextroamphetamine challenges. RESULTS: Spectrum subjects had more dyskinetic-like movements than normal subjects. Spontaneous dyskinesia was present in 12% of the spectrum subjects but was not seen in the normal subjects. Subjects with schizotypal personality had more dyskinetic-like movements than subjects with schizoid personality or normal subjects. Dyskinesia was present in 24% of the schizotypal subjects but not in the other groups. Dyskinetic movement scores correlated with positive symptom scores. With repeated amphetamine challenge, normal subjects showed a pattern of behavioral sensitization (an increase in dyskinetic-like movements), but spectrum subjects showed an abnormal response (fewer dyskinetic-like movements). CONCLUSIONS: Dyskinesia and dyskinetic-like movements are more common in subjects with schizophrenia spectrum personality (primarily schizotypal) than in normal subjects and are related to positive symptoms. A failure of normal behavioral sensitization mechanisms after dextroamphetamine challenge is seen in subjects with schizophrenia spectrum personality.

Comorbidity↗
PubMed1997

The Lck SH2 phosphotyrosine binding site is critical for efficient TCR-induced processive tyrosine phosphorylation of the zeta-chain and IL-2 production.

The lymphocyte-specific tyrosine kinase Lck is essential for TCR-mediated signal transduction. This is in part due to its enzymatic activity as a tyrosine kinase responsible for TCR-induced tyrosine phosphorylation of zeta and CD3 receptor subunits. In addition to its catalytic domain, the Lck protein contains SH3 and SH2 domains capable of associating with other signaling molecules. It has been proposed that phosphotyrosine binding by the Lck SH2 domain may enhance substrate tyrosine phosphorylation by facilitating the processive phosphorylation of multiple sites within the TCR complex. Alternatively or additionally, it may function in adapter activity for facilitating required protein-protein interactions. Previous experiments demonstrate that overexpression of a constitutively activated form of Lck (F505) in the BI-141 T cell hybridoma leads to the Lck kinase activity-dependent enhancement of TCR-mediated signals. Here we demonstrate that mutation of amino acids important for SH2 phosphotyrosine binding significantly compromises the ability of F505 to enhance TCR-mediated protein tyrosine phosphorylation and Ag-induced IL-2 production in BI-141. Examination of the effects of TCR-regulated phosphorylation of the Lck substrate zeta provides in vivo evidence for a role for the Lck SH2 domain in the processive phosphorylation of a multiply phosphorylated substrate.

Binding Sites↗
PubMed1997

Computed tomography scanning and delirium in elder patients.

OBJECTIVE: 1) To examine the ordering of head CT scans in elder patients with delirium and cognitive impairment; and 2) to report CT scan findings associated with these conditions. METHODS: This was a 2-part study. Part 1 was a prospective, observational study of 560 adults > 70 years of age evaluated at 3 separate EDs using a 200-hour stratified sampling process at each ED. During Part 1, the frequencies of specific findings (i.e., delirium, impaired consciousness, and impaired cognition) and CT scan rates for these groups were determined. Part 2 was a retrospective analysis of CT scan reports and medical records (n = 279) for patients > 70 years of age in the prospective sample (n = 79) and from a sample (n = 200) of CT scans obtained at a fourth ED. Part 2 examined clinical findings detected in the ED to determine those factors that were associated with acute findings on CT scan. RESULTS: Part 1: There were 333 (59.4%) patients prospectively classified as having impaired cognition, impaired consciousness, or delirium; 79 (23.7%) of these patients had a head CT scan. Of these 3 groups, delirious patients were more frequently scanned (p < 0.001). Part 2: Of 279 CT scans, 42 (15.0%) were positive for an acute condition (hemorrhage, hematoma, space-occupying lesion, infarct). Of 42 positive scans, 40 (95.1%) were found in the 102 (36.6%) patients with either impaired consciousness or a new focal neurologic finding detected in the ED. CONCLUSIONS: Considerable variability in ED CT scan ordering exists for elder patients with neurologic findings. Impaired consciousness and/or new focal neurologic signs are associated with acute findings on CT scan in elder patients. Acute CT abnormalities are uncommon in elder ED patients with other neurologic findings. Additional prospective evaluation is warranted prior to guideline development for CT scans in this patient population.

Acute Disease↗
PubMed1997

Visual information-processing impairments in deficit and nondeficit schizophrenia.

OBJECTIVE: Previous studies of covert visuospatial attention in schizophrenia suggest a subtle form of right hemispatial neglect in acutely ill patients but not in chronic, stable patients. Because of previous work documenting various visual information-processing abnormalities in deficit schizophrenia, the authors investigated whether the deficit/nondeficit categorization would help clarify the presence of visual attentional asymmetries in schizophrenia. METHOD: Performance on a covert visuospatial attention task was examined in clinically stable outpatients with schizophrenia (17 in a deficit subgroup and 28 in a nondeficit subgroup) and 25 normal subjects. Peripheral cue and central cue versions of the covert visuospatial attention task, at 100-, 200-, and 800-msec intervals between cue and target, were administered a week apart. RESULTS: The nondeficit patients exhibited a significant and abnormal asymmetry, with slower reaction time to targets presented in the right visual field than in the left visual field. This right visual field disadvantage was found with both versions of the task, but only at the 100-msec cue-target interval. The deficit patients were slowest in overall reaction time but, similar to the normal subjects, showed no asymmetry. CONCLUSIONS: The results are consistent with slower visual information processing in the left compared to the right cerebral hemisphere in nondeficit schizophrenia. This finding cannot be accounted for by differences between the deficit and nondeficit subgroups in demographic characteristics, chronicity, or medication effects, nor is it secondary to generalized cognitive impairment.

Adolescent↗
PubMed1996

The effects of human hippocampal resection on the serial position curve.

The purpose of this study was to examine the contribution of the human hippocampal formation to the classic serial position curve. Seventy-seven patients who underwent anterior temporal lobectomy (ATL) (47 left, 30 right) were administered a list learning task before and after surgery, and changes in the serial position curve were examined. Forty nonsurgical patients with complex partial seizures were tested at comparable intervals and served as controls. Changes in the serial position curve were seen only after left ATL, and almost exclusively among patients without hippocampal sclerosis. Patients without left hippocampal sclerosis, and who therefore underwent resection of hippocampus that was to a considerable degree structurally (and presumably functionally) intact, showed significant declines in recall from the primacy and middle portions of the list compared to all other groups. There was no change in the recency portion of the list. Patients with left hippocampal sclerosis showed only a modest decline in recall from the middle region compared only to the control group, and the right ATL groups did not show any significant changes in serial position recall. These findings demonstrate the contribution of the left hippocampus to those discrete portions of the serial position curve which rely on secondary memory, and have implications for assessing the effects of ATL on memory function.

Adult↗