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Biomedical subjects

M Freedman

Publications and source records attributed to M Freedman.

At least 19 recordsLinked to original sources
PubMed1992

Transforming growth factor-beta 1 differentially regulates proliferation and MHC class-II antigen expression in forebrain and brainstem astrocyte primary cultures.

To facilitate investigation of cytokine regulation of reactive astrogliosis, primary astrocyte cultures from neonatal murine forebrain and brainstem were established. Forebrain and brainstem astrocytes proliferated at a similar rate under basal culture conditions, and both were growth-inhibited by treatment with recombinant murine interferon-gamma. The growth of cultured brainstem astrocytes was significantly enhanced by exposure to recombinant human transforming growth factor-beta 1. In contrast, proliferation of forebrain astrocytes was not significantly affected by transforming growth factor-beta 1. The disparate responses of brainstem and forebrain astrocytes to transforming growth factor-beta 1 treatment were not limited to effects on cell growth, since transforming growth factor-beta 1 could block interferon-gamma-induced MHC class-II antigen expression on cultured brainstem astrocytes but not on forebrain cells. Results could not be attributed to use of an heterologous cytokine/cellular target system, since similar variability in transforming growth factor-beta 1 modulation of major histocompatibility complex antigen expression could be demonstrated using two human astrocytoma cell lines. This report is the first to document mitogenic response to transforming growth factor-beta 1 for neuroepithelial cells. The role of transforming growth factor-beta 1 in regulating aspects of reactive astrogliosis, particularly in the context of inflammatory demyelination, requires further investigation. Furthermore, these studies may provide insight into regional variability in the sequelae of inflammation within the central nervous system.

Animals↗
PubMed1992

IL-7 receptor mediates tyrosine phosphorylation but does not activate the phosphatidylinositol-phospholipase C-gamma 1 pathway.

IL-7 is a glycoprotein involved in the regulation of lymphocyte precursor growth. In addition, it has a comitogenic effect on mature T cells but not on mature B cells. The exact mechanism whereby IL-7R mediates these cell growth properties remains unknown. Because many growth factor receptor systems on various cell types transduce signals by activating a tyrosine kinase, we have studied here the effect of IL-7R ligation on protein tyrosine phosphorylation. We found that human rIL-7 consistently induced tyrosine phosphorylation of five major proteins, of 175, 155, 135, 110, and 85 kDa, and five minor proteins. The effect of human rIL-7 on tyrosine phosphorylation of these substrates was concentration and time dependent. One of the known substrates that is phosphorylated on tyrosine residues after binding of growth factors to their receptors is the phosphoinositide-specific phospholipase C. Several phospholipase C isozymes have been recently recognized; one isozyme, phospholipase C-gamma 1, was demonstrated to be phosphorylated rapidly after ligand binding to the platelet-derived growth factor receptor and the T cell Ag receptor. We show here that, in contrast to Ag receptor ligation, activation of IL-7R does not induce tyrosine phosphorylation on phospholipase C-gamma 1. Consistent with these results, human rIL-7 failed to increase phosphatidylinositol turnover and did not induce a rise in cytosolic free Ca2+ in the thymocytes, mature T cells, or pre-pre-B cells. The results indicate that the IL-7R mediates the activation of the tyrosine phosphorylation pathway but does not induce the phosphatidylinositol-phospholipase C pathway.

Antibodies, Monoclonal↗
PubMed1992

PACS clinical experience at Georgetown University.

Georgetown University Hospital has been operating an image management and communications system (IMACS or PACS) for 3.5 years. This work was initially funded under the Army Medical Research and Development Command Digital Imaging Network Systems (DINS) project. The system was taken from a research system supporting only radiology tasks to one extended to clinical use, and has been used in clinical work for 3 years. This paper will summarize our PACS clinical experience and will describe the operational features implemented and those still necessary.

Computer Systems↗
PubMed1992

Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a severely disabling illness of uncertain aetiology. It is characterized by a chronic, sustained or fluctuating sense of debilitating fatigue without any other known underlying medical conditions. It is also associated with both somatic and neuropsychological symptoms. Both physical and laboratory findings are usually unremarkable. Regional cerebral blood flow (rCBF) was assessed in 60 clinically defined CFS patients and 14 normal control (NC) subjects using 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO) single photon emission computed tomography (SPECT). Compared with the NC group, the CFS group showed significantly lower cortical/cerebellar rCBF ratios, throughout multiple brain regions (P < 0.05). Forty-eight CFS subjects (80%) showed at least one or more rCBF ratios significantly less than normal values. The major cerebral regions involved were frontal (38 cases, 63%), temporal (21 cases, 35%), parietal (32 cases, 53%) and occipital lobes (23 cases, 38%). The rCBF ratios of basal ganglia (24 cases, 40%) were also reduced. 99Tcm-HMPAO brain SPECT provided objective evidence for functional impairment of the brain in the majority of the CFS subjects. The findings may not be diagnostic of CFS but 99Tcm-HMPAO SPECT may play an important role in clarifying the pathoaetiology of CFS. Further studies are warranted.

Adolescent↗
PubMed1991

Assessment of competency: the role of neurobehavioral deficits.

We present a practical set of guidelines for assessing competency in patients with cognitive deficits due to neurologic disorders such as stroke, head injury, Alzheimer disease, and multi-infarct dementia. Our focus is the evaluation of cognitive processes underlying the ability to make competent decisions, with an emphasis on the identification of areas of preserved function that may be used to bypass intellectual deficits. The assessment of the cognitive processes underlying competency involves a series of steps designed to evaluate attention, language, memory, and frontal lobe function. The examiner must first show that the patient has an adequate level of attention for participation in the further testing of specific cognitive functions; second, that the patient is able to comprehend relevant instructions, retain information long enough to evaluate it in relation to relevant recent and remote experiences, and express his or her wishes; and finally, that the patient has sufficiently intact judgment and awareness. The examiner must determine whether the patient's preserved cognitive abilities are sufficient for him or her to make an adequate judgment in relation to the specific question being asked. If cognitive function is found to be significantly impaired, the examiner should do a detailed assessment for the presence of compensatory abilities that can be used to bypass the deficits. For example, the examiner should assess whether patients who cannot speak are still able to express their wishes by pointing, using gesture, or even by drawing pictures. Unless such an assessment has been done, patients should not be considered incompetent.

Attention↗
PubMed1991

Selective delayed alternation deficits in dominantly inherited olivopontocerebellar atrophy.

In order to characterize more completely the nature of the frontal lobe-type cognitive changes in patients with dominantly inherited olivopontocerebellar atrophy (OPCA) we administered two tasks sensitive to frontal system dysfunction, delayed alternation (DA) and delayed response (DR), to 12 patients from one OPCA family. Affected members from this family have previously been shown to have a marked and widespread cerebral (including frontal) cortical cholinergic reduction as severe as that observed in Alzheimer's disease. Performance on DA, but not on DR, was significantly impaired in the OPCA patients compared to that in the controls. We suggest that the DA deficits in OPCA could be a consequence of a loss of cholinergic innervation to orbitofrontal or possibly temporal cortical areas and/or damage to the integrity of the cerebello-frontal neuronal connections.

Adult↗
PubMed1991

Assessment of cognitive impairment: the role of CT.

The value of CT as a routine screening procedure in the investigation of cognitive impairment is being increasingly challenged. To address this issue, we reviewed the records of 175 patients with intellectual deficits admitted to a Behavioural Neurology Unit over a two-year period. In the vast majority of cases, ie. 82%, the CT served essentially to confirm the clinical impression and added no new diagnostic information that impacted the management of the presenting problem. In 15% of cases the CT scan was helpful for diagnosis, especially in the differentiation between Alzheimer's disease and multi-infarct dementia.

Adult↗
PubMed1990

Hodgkin's disease in children: treatment with MOPP and low-dose, extended field irradiation without laparotomy. Late results and toxicity.

The 10 year results of a trial of bimodal treatment of Hodgkin's disease in children with 6 cycles of MOPP and low-dose extended field irradiation, without staging laparotomy, were for 57 children in all stages as follows: survival 85%, relapse-free survival 80%, and survival-free of second relapse 86%. There were three fatal toxic events, two due to viral infection and one to a second malignant tumor (NHL). Three other patients developed a second malignant tumour, and one developed a thyroid adenoma. No patient developed acute leukemia. These results are compared with the results of treatment of surgically staged children by extended field irradiation alone, with bimodal treatment reserved for relapse or advanced disease at diagnosis. Initial bimodal treatment improved the overall 10 year survival free from a second relapse rate by 20% (86% vs. 66%). No major difference in treatment toxicity between these two groups has emerged during the first 10 years of follow-up. We conclude that, except for favourable CS-1 presentations, children with Hodgkin's disease confined to the lymphatic system should be given bimodal treatment, but that the least morbid effective combination remains to be determined.

Adolescent↗
PubMed1990

Object alternation and orbitofrontal system dysfunction in Alzheimer's and Parkinson's disease.

Previous performance on measures of frontal system function have suggested prominent orbitofrontal system damage in Alzheimer's disease, but not in Parkinson's dementia. Object alternation (OA), a task sensitive to orbitofrontal system dysfunction in non-human animals, was therefore administered to determine whether this measure would distinguish Alzheimer's from Parkinson's dementia. OA was significantly impaired in Alzheimer's disease compared to Parkinson's dementia, even though both groups were equated for severity of dementia. Although the patients with Parkinson's dementia also showed impairment on OA compared to normals, an error analysis revealed that the performance of the Alzheimer's patients, but not the Parkinson's patients, was characterized by abnormal response perseveration. The marked perseverative deficit in Alzheimer's disease may reflect orbitofrontal system dysfunction whereas the milder, and qualitatively different, deficits in Parkinson's disease may reflect dorsolateral frontal system involvement.

Aged↗
PubMed1990

Further observations on the doubling time of human chorionic gonadotropin in early asymptomatic pregnancies.

The doubling time (DT) of human chorionic gonadotropin (hCG) in serum was investigated retrospectively using serial serum hCG values that had been obtained from asymptomatic pregnant women with a prior history of infertility. The DT of hCG did not increase significantly as pregnancy advanced during the period in gestation when the serum hCG concentration was less than 10,000 mIU/mL (International Reference Preparation). Serum hCG concentrations increased subnormally in 2 of 60 women with normal intrauterine pregnancies, 5 of 8 women with asymptomatic ectopic pregnancies (EPs), and in 2 of 8 asymptomatic women who subsequently aborted their pregnancies. Neither the sensitivity nor the specificity of serial hCG testing for EP was enhanced by adopting different test criteria at different serum hCG concentrations.

Chorionic Gonadotropin↗
PubMed1989

Non-Alzheimer-type pattern of brain cholineacetyltransferase reduction in dominantly inherited olivopontocerebellar atrophy.

We recently reported reduced activity of the cholinergic marker enzyme cholineacetyltransferase (ChAT) in several brain regions of patients with dominantly inherited olivopontocerebellar atrophy (OPCA). To document the regional extent of these changes we performed a comprehensive examination of the behavior of ChAT throughout both cerebral cortical and subcortical brain areas in 5 patients from one large OPCA pedigree. As compared with the controls, mean ChAT activities in OPCA were reduced by 39 to 72% in all (n = 27) cerebral cortical areas examined and in several thalamic subdivisions, caudate head, globus pallidus, red nucleus, and medial olfactory area. In contradistinction to findings in Alzheimer's disease (AD), mean ChAT levels in OPCA amygdala and hippocampal subdivisions were either normal or only mildly reduced. The lack of severe disabling dementia in our OPCA patients compared with AD patients having a similar cortical cholinergic reduction could be explained by an absence of either a marked cholinergic loss in amygdala or hippocampus or significant loss of noncholinergic cerebral cortical and limbic neurons as occurs in AD brain. We suggest that this and other OPCA pedigrees having a cortical cholinergic reduction represent a unique model for the study of behavioral consequences of a more selective cerebral cortical cholinergic lesion rather than a limbic cholinergic lesion.

Adult↗
PubMed1989

Spatial and visual learning deficits in Alzheimer's and Parkinson's disease.

Experimental paradigms adopted from animal models were used to compare the neuropsychological mechanisms underlying the dementias of Alzheimer's and Parkinson's diseases. Two tasks were selected because characteristic profiles of impairment in nonhuman primates are seen following selective lesions of frontal cortex, temporal cortex, and fornix. The tasks consisted of a spatial and a visual learning problem, each with two components: (1) original learning and (2) reversal of the original learning. The Alzheimer's patients were significantly impaired on original learning and reversal learning in the visual modality compared with demented Parkinson's patients, even though both groups were equated for severity of dementia. On the spatial tasks, both the Alzheimer's and the demented Parkinson's patients were impaired on reversal learning but not on original learning. The profile of deficits on the visual tasks may serve to differentiate Alzheimer's from Parkinson's dementia and may reflect selective orbitofrontal system lesions in the former.

Aged↗
PubMed1989

Airway obstruction due to goiter in older patients.

It has been shown that goiters can progressively enlarge to compress the surrounding trachea or esophagus and result in incapacitating obstructive symptoms or potentially fatal airway obstruction. The potential of a goiter to become hyperactive also exists. Recently, we have seen three older patients with longstanding untreated "benign" goiters who presented difficult management decisions. Given the likelihood of progressive growth of a goiter and the increased life expectancy of these patients with goiters, it is essential to perform flow-volume loop studies while following these patients.

Aged↗
PubMed1989

Hypersegmented neutrophils and vitamin B12 deficiency. Hypersegmentation in B12 deficiency.

The sensitivities and specificities of the mean cell volume (MCV), the red cell distribution width (RDW), and blood smear hypersegmentation for B12 deficiency were reviewed in 515 patients whose B12 levels were determined. 61 patients had B12 levels less than 200 pg/ml. 43 patients were defined as B12 deficient (n = 13) or non-B12 deficient (n = 30). Hypersegmentation was more sensitive (91%) than MCV greater than 95 fl (62%) or RDW greater than 15% (54%) in detecting B12 deficiency. The MCV and the RDW should not be relied on when screening for B12 deficiency; examination of the blood smear for hypersegmentation is essential.

Anemia↗
PubMed1989

Characterization of lymphoid cells isolated from human gliomas.

To analyze the phenotypic profile of lymphoid cells freshly isolated from surgically resected human gliomas, a double-immunostaining technique was developed which permitted the investigators simultaneously to distinguish between hematogenous and tumor cell populations and to detect expression of lymphocyte-monocyte subset-specific antigens on hematogenous cells. With this technique, the profiles of tumor-infiltrating lymphocytes (TIL's) derived from high- and low-grade gliomas were compared with phenotypes of lymphocytes concurrently isolated from peripheral blood. The total leukocyte cell yield from high-grade glioma cases exceeded that of low-grade cases. In nine high-grade glioma cases the proportion of CD8-positive cells was increased within the TIL population (41.2% +/- 1.9%, mean +/- standard error of the mean) as compared to the corresponding peripheral blood lymphocyte (PBL) population (30.8% +/- 4.1%, p less than 0.05). The proportion of natural killer HNK-positive cells, some of which bear the CD8 antigen (although not necessarily the pan T cell antigens CD2 and CD3), was also increased in the TIL's (41.9% +/- 4.2%) compared to that found in PBL's (32.1 +/- 5.6%, p less than 0.05) of high-grade glioma cases. The observed phenotypic pattern of high-grade glioma TIL's is similar to that reported based on immunohistochemical analysis of tumor tissue sections, suggesting that the techniques described here resulted in isolation of lymphoid cells representative of TIL's.

Antigens, CD↗