Biomedical subjects

M Freedman

Publications and source records attributed to M Freedman.

At least 55 records · Page 3Linked to original sources

PubMed1999

Pulmonary sarcoidosis: comparison of patients at a university and a municipal hospital.

Charts and radiographs of sarcoidosis patients seen at a private university hospital and at a municipal hospital were reviewed to determine whether there was a difference in the severity of disease retrospectively. A standardized abstract form was used to identify and abstract information on new and continuing sarcoidosis patients seen at either Georgetown University Medical Center (GUMC) or District of Columbia General Hospital (DCGH) during a 2-year period. Because there were too few white sarcoidosis patients for comparison, analysis was done for African-American patients only. African-American patients at GUMC were slightly older, with a higher percentage of women. For GUMC patients, 76% had private insurance and 21% had public insurance, and for DCGH patients, one-half had public insurance and 29% had no insurance. Significantly fewer GUMC patients (7% versus 36%) reported moderate to severe dyspnea. Chest radiographs showed a larger percentage of patients with stage 1 disease at GUMC and more patients with stage 4 disease at DCGH. Spirometry showed more impairment of forced expired volume in one second (FEV1) in GUMC patients, but diffusing capacity of the lung for carbon monoxide (DLCO) values were significantly lower among DCGH patients. Less than 8% of GUMC patients showed disease progression compared with almost one-third of DCGH patients. These results demonstrate that substantially less severe pulmonary sarcoidosis was seen in African-American patients treated at a private, nonprofit university hospital compared with a municipal hospital. Factors that determine the use of municipal hospitals, such as limited financial access to care and sources of patients, may have played a major role in the differences seen.

Adult↗

PubMed1998

Serendipity in diagnostic imaging: magnetic resonance imaging of the breast.

BACKGROUND: Magnetic resonance imaging (MRI) of the breast has been proposed as a noninvasive diagnostic test for evaluation of suspicious ("index") lesions noted on mammography and/or clinical breast examination (CBE). However, women may have incidental ("serendipitous") lesions detected by MRI that are not found on mammography or CBE. To understand better whether or not biopsy procedures should be performed to evaluate serendipitous lesions, we estimated the breast cancer risk for women with this type of lesion. METHODS: A decision analysis model was used to estimate the positive predictive value (i.e., the chance that a woman with a serendipitous lesion has cancer) of MRI for serendipitous lesions in women who had an abnormal mammogram and/or CBE suspicious for cancer (where a biopsy procedure is recommended). We restricted the analysis to data from women whose index lesions were noncancerous and used meta-analysis of published medical literature to determine the likelihood ratios (measures of how test results change the probability of having cancer) for MRI and the combination of CBE and mammography. The positive predictive value of MRI was calculated using the U.S. population prevalence of cancer (derived from registry data) and the likelihood ratios of the diagnostic tests. RESULTS: Under a wide variety of assumptions, the positive predictive value of MRI was extremely low for serendipitous lesions. For instance, assuming sensitivity and specificity values for MRI of 95.6% and 68.6%, respectively, approximately four of 1000 55- to 59-year-old women with serendipitous lesions would be expected to have cancer (positive predictive value = 0.44%, 95% confidence interval = 0.24%-0.67%). CONCLUSION: In women with a suspicious lesion discovered by mammography and/or CBE that is found to be benign, serendipitous breast lesions detected by MRI are extremely unlikely to represent invasive breast cancer. Immediate biopsy of such serendipitous lesions may, therefore, not be required.

Adult↗

PubMed1998

Absence of association between Alzheimer disease and the -491 regulatory region polymorphism of APOE.

A novel polymorphism (-491 A/T) within the regulatory region on the apolipoprotein E gene has recently been reported to be associated with risk for Alzheimer disease (AD). To test this association in an independent data set, we have examined this polymorphism in a sample of 88 well-characterized AD cases and compared the allele frequency and genotype frequencies for this polymorphism with those observed in 112 cognitively normal subjects drawn from the same ethnic group. These results suggest that in the current data set at least, the -491 A/T polymorphism is not associated with risk for AD, but may be in partial linkage disequilibrium with the APOE epsilon2/epsilon3/epsilon4 polymorphism.

Aged↗

PubMed1998

Structural and functional meta-analytic evidence for fronto-subcortical system deficit in progressive supranuclear palsy.

Meta-analytic methods were used to determine the most sensitive indexes to fronto-subcortical deficit in progressive supranuclear palsy (PSP) and to further characterize the neurocognitive and related features of PSP that can provide a basis of comparison to other disorders with prominent subcortical brain lesions. Studies dating back to 1984 were gathered and calibrated to compare the neuropsychological, neuroimaging, and neurophysiological test results from 229 patients with PSP, and 357 healthy controls. The tests most sensitive to fronto-subcortical deficit in PSP were mostly neuropsychological measures that include such tests as the Stroop Task, Trail Making Test Part A, and Purdue pegboard performance. We conclude that although neuropsychological measures may be most sensitive to deficits in PSP, they are also less specific and valid indicators of fronto-subcortical brain system integrity.

Aged↗

PubMed1998

Clustering and switching on verbal fluency tests in Alzheimer's and Parkinson's disease.

Two components of verbal fluency performance--clustering (i.e., generating words within subcategories) and switching (i.e., shifting between subcategories)--were examined in patients with dementia of the Alzheimer type (DAT), patients with dementia with Parkinson's disease (DPD), nondemented patients with Parkinson's disease (NPD), and demographically matched controls. The DAT and DPD groups were impaired in the number of words generated on both phonemic and semantic fluency. The DAT group produced smaller clusters on both tasks and switched less often on semantic fluency than controls. The DPD group switched less often on both tasks and produced smaller clusters on phonemic fluency than controls. The NPD group was not impaired on any fluency variable. Thus, the total number of words generated on phonemic and semantic fluency did not discriminate the dementia groups from their respective control groups, but measures of clustering and switching did. This differential pattern of performance provides evidence for the potential usefulness of measures of switching and clustering in the assessment of dementia.

Aged↗

PubMed1998

L-deprenyl in Alzheimer's disease: cognitive and behavioral effects.

BACKGROUND: Short-term studies of L-deprenyl in Alzheimer's disease (AD) suggest a beneficial effect, whereas longer-term studies are less convincing. Accordingly, we undertook a 6-month, randomized, double-blind, placebo-controlled clinical trial to assess the potential benefit of L-deprenyl in AD. METHODS: Sixty subjects were assigned to L-deprenyl (10 mg daily) or placebo. After 4 weeks of single-blind placebo, 51 subjects entered the double-blind phase. The Brief Psychiatric Rating Scale (BPRS) was the primary outcome measure. Secondary outcome measures were the Mini-Mental State Examination, Global Deterioration Scale, Alzheimer's Disease Assessment Scale (noncognitive), Cornell Scale for Depression in Dementia, Buschke Selective Reminding Test (BSRT), Relative's Assessment of Global Symptomatology-Elderly (RAGS-E), Controlled Oral Word Association Test, and Modified Continuous Performance Test. In addition, several exploratory tasks were included for future hypothesis testing. RESULTS: We found no significant differences between the L-deprenyl and placebo groups on the primary or secondary measures. However, several measures appeared to be sensitive to change over time, including the total score on the BPRS and some of its components as well as parts of the BSRT and the RAGS-E. CONCLUSION: Oral L-deprenyl provides no detectable benefit on general behavior, neuropsychiatric symptoms, or cognitive function in AD after 6 months of treatment. Protocols for future drug studies should utilize measures that are sensitive to change over time such as the BPRS.

Aged↗

PubMed1998

Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.

OBJECTIVE: To improve clinical recognition and provide research diagnostic criteria for three clinical syndromes associated with frontotemporal lobar degeneration. METHODS: Consensus criteria for the three prototypic syndromes-frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia-were developed by members of an international workshop on frontotemporal lobar degeneration. These criteria build on earlier published clinical diagnostic guidelines for frontotemporal dementia produced by some of the workshop members. RESULTS: The consensus criteria specify core and supportive features for each of the three prototypic clinical syndromes and provide broad inclusion and exclusion criteria for the generic entity of frontotemporal lobar degeneration. The criteria are presented in lists, and operational definitions for features are provided in the text. CONCLUSIONS: The criteria ought to provide the foundation for research work into the neuropsychology, neuropathology, genetics, molecular biology, and epidemiology of these important clinical disorders that account for a substantial proportion of cases of primary degenerative dementia occurring before the age of 65 years.

Dementia↗

PubMed1998

Clock tests in depression, Alzheimer's disease, and elderly controls.

OBJECTIVE: While clock-drawing tests are commonly used to screen for cognitive impairment in the elderly, little is known about the performance of elderly depressives. METHODS: We compared thirty-three patients with major depression to forty-two Alzheimer's disease and thirty age-matched controls on clock-drawing, copying, and reading. RESULTS: Patients with Alzheimer's disease had significantly lower scores on clock-drawing, copying, and reading than patients with depression or the controls (p < 0.05). Patients with depression did not differ significantly from controls on quantitative scores or qualitative errors. CONCLUSIONS: Clock tests may be useful for identifying depressed patients with underlying dementia.

Aged↗

PubMed1998

Age-related changes in D2 receptor binding with iodine-123-iodobenzofuran SPECT.

UNLABELLED: The purpose of this study was to evaluate the effects of age on D2 receptor binding with 123I-iodobenzofuran (IBF) SPECT. METHODS: Subjects were 40 healthy volunteers (age 19-83 yr), including 6 who had test/retest studies. Scans were acquired with a triple-head SPECT camera 3 hr postinjection of IBF (300 MBq). Striatal regions (caudate and putamen) were defined by two different region-of-interest (ROI) sets consisting of large volumes [(CLVs), 2.2 and 6.6 m] and small volumes [(SVs), 0.6 and 1.3 ml]. D2 binding (Rv=V3/V2) was quantified using our previously proposed multilinear regression technique. Effects of age on D2 binding were evaluated by fitting linear, exponential and logarithmic models. RESULTS: The mean Rvs were 26% lower than LV for both putamen and caudate than the corresponding values from the SV due to the partial-volume effect. Although the identifiability of Rv using SV deteriorated slightly, the test/retest reproducibility of Rv measurements was equally excellent for LV and SV. The mean Rvs were 11% higher for putamen compared with those for caudate. D2 binding declined significantly with age (p < 10(-5)) for all three models. The nonlinear models were slightly superior to the linear model in describing the relationship between Rv and age. In these models, D2 binding declined with age, equally for caudate and putamen at 7%-13% per decade; the decline was progressively smaller with age. CONCLUSION: IBF SPECT permitted reliable measurements of D2 binding in the caudate or putamen separately using small ROI volumes that significantly improved the quantitation loss from the partial-volume effect. Our results agreed with previous PET and postmortem findings of D2 binding losses with age. However, these age effects may be nonlinear. Age-related changes in D2 binding must be taken into consideration in clinical IBF SPECT investigations.

Adult↗

PubMed1997

Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison.

OBJECTIVE: To compare the efficacy, safety, and cost of midazolam and propofol in prolonged sedation of critically ill patients. DESIGN: Randomized, prospective study. SETTING: General intensive care unit (ICU) in a 1100-bed teaching hospital. PATIENTS: 67 critically ill, mechanically ventilated patients. INTERVENTIONS: Patients were invasively monitored and mechanically ventilated. A loading dose [midazolam 0.11 +/- 0.02 (SEM) mg.kg-1, propofol 1.3 +/- 0.2 mg.kg-1] was administered, followed by continuous infusion, titrated to achieve a predetermined sedation score. Sedation was continued as long as clinically indicated. MEASUREMENTS AND RESULTS: Mean duration of sedation was 141 and 99 h (NS) for midazolam and propofol, respectively, at mean hourly doses of 0.070 +/- 0.003 mg.kg-1 midazolam and 1.80 +/- 0.08 mg.kg-1 propofol. Overall, 68% of propofol patients versus 31% of midazolam (p < 0.001) patients had a > 20% decrease in systolic blood pressure after the loading dose, and 26 versus 45% (p < 0.01) showed a 25% decrease in spontaneous minute volume. Propofol required more daily dose adjustments (2.1 +/- 0.1 vs 1.4 +/- 0.1, p < 0.001). Nurse-rated quality of sedation with midazolam was higher (8.2 +/- 0.1 vs 7.3 +/- 0.1 on a 10-cm visual analog scale, p < 0.001). Resumption of spontaneous respiration was equally rapid. Recovery was faster after propofol (p < 0.02), albeit with a higher degree of agitation. Amnesia was evident in all midazolam patients but in only a third of propofol patients. The cost of propofol was 4-5 times higher. CONCLUSIONS: Both drugs afforded reliable, safe, and controllable long-term sedation in ICU patients and rapid weaning from mechanical ventilation. Midazolam depressed respiration, allowed better maintenance of sedation, and yielded complete amnesia at a lower cost, while propofol caused more cardiovascular depression during induction.

Adult↗

PubMed1997

Polycythemia secondary to focal nodular hyperplasia.

An otherwise healthy 14-year-old girl presented with polycythemia and elevated serum erythropoietin. A lesion was identified in the liver by ultrasound scan and computerized axial tomography. The pathology findings of the mass excised by hepatic segmentectomy showed focal nodular hyperplasia that stained positively for erythropoietin by immunohistochemistry. Resection resulted in a cure of the polycythemia with serum erythropoietin, hemoglobin, and hematocrit returning to normal range in subsequent follow-up. To our knowledge, this is the first report of focal nodular hyperplasia resulting in secondary polycythemia.

Adolescent↗

PubMed1997

Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia.

Previously, nonsense mutations in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R) have been described in three patients with severe congenital neutropenia (SCN) (Proc Natl Acad Sci USA 1994; 91: 4480; New Engl J Med 1995; 333: 487). The mutations resulted in the truncation of the carboxy-terminal region of G-CSF-R essential for transduction of maturation signals. Two of these patients developed acute myeloblastic leukemia (AML). We present the results of a search among 20 additional cases of congenital neutropenia (CN) and SCN for the presence of mutations in the cytoplasmic domain of G-CSF-R. This series includes patients with familial and nonfamilial forms of CN and SCN. Mutations in the G-CSF-R gene were found in two new SCN cases. These mutations were nonsense mutations, located in the same cytoplasmic region of G-CSF-R as those found earlier, resulting in the truncation of the C-terminus. Both of these patients developed AML. None of the other patients showed clinical symptoms or cytogenetic features indicative of AML or progression to leukemia. The analysis in this extended series of patients thus has revealed five SCN cases with G-CSF-R mutations, four of whom developed AML. These results add support to the notion that mutations in the G-CSF-R gene, affecting the maturation signaling function of the receptor, define a distinct subgroup of SCN with increased susceptibilty to AML.

Adolescent↗

PubMed1997

Orienting of visual attention in Alzheimer's disease: its implication in favor of the interhemispheric balance.

Visual attention in dementia of Alzheimer's disease (AD) has not been investigated as extensively as memory or language. The aim of this research was to study the orienting of attention in patients with AD (which temporo-parietal areas are primarily affected) compared with patients with Parkinson-Dementia, Parkinson's disease, and normal controls, using the Posner paradigm. Subjects were instructed to respond by pressing a response key after the appearance of a target at the same location (valid trial) or at the opposite location (invalid trial) indicated by a central cue (arrow). According to the experimental procedure developed by Posner, it has been hypothesized that parietal lobes are involved in "disengagement operation" (when attention has to move from one location to another in the controlateral field). Results showed no differences between AD and the other groups and between left and right hemifield. In conclusion, the authors did not find any sign of difficulty with disengagement, and results are discussed in terms of Kinsbourne's interpretation of a balance between hemispheres.

Aged↗

PubMed1997

Breakdown of cross-modal function in dementia.

To evaluate the possibility that specific language abnormalities in dementia are related to impaired cross-modal ability, the authors studied patients with Alzheimer's disease (which is characterized by a generalized language breakdown or aphasia) and patients with Parkinson's disease and dementia (a disorder associated more with selective deficits in naming than with aphasia). Both groups were initially equated for severity of dementia. Compared with nondemented patients with Parkinson's disease and age-equivalent healthy controls, patients with Alzheimer's disease and Parkinson's disease with dementia showed significant deficits in cross-modal ability. Moreover, the cross-modal deficits were significantly associated with object-naming ability. Results support the concept that language capacity and cross-modal functions are interrelated.

Aged↗

PubMed1997

Building communities that promote successful aging.

Despite the fact that, in a few years, a fifth of the US population will be older than 65 years and people will be living a third of their lives after retirement, we have developed few avenues that would permit older adults to play meaningful roles as they age and few institutions to harness the experience that older adults could contribute to society. In fact, older adults constitute this country's only increasing natural resource--and the least used one. In this article we consider the rationale for developing institutions that harness the abilities and time of older adults, rather than focusing solely on their needs. Such an approach would decrease the structural lag between a social concept of retirement as unproductive leisure and an aging population that is larger, healthier, and with a need for more productive opportunities. Gerontologically designed opportunities for contribution on a large social scale could well provide a national approach to primary prevention to maintain health and function in older adults.

Aged↗

PubMed1996

Qualitative and quantitative contributions of the T cell receptor zeta chain to mature T cell apoptosis.

Engagement of the T cell receptor (TCR) of mature T lymphocytes can lead either to activation/proliferation responses or programmed cell death. To understand the molecular regulation of these two fundamentally different outcomes of TCR signaling, we investigated the participation of various components of the TCR-CD3 complex. We found that the TCR-zeta chain, while not absolutely required, was especially effective at promoting mature T cell apoptosis compared with the CD3 epsilon, gamma, or delta chains. We also carried out mutagenesis to address the role of the immunoreceptor tyrosine-based activation motifs (ITAMs) that are the principal signaling components found three times in the TCR-zeta chain and once in each of the CD3 epsilon, gamma, or delta chains. We found that the ability of the TCR-zeta chain to promote apoptosis results both from a quantitative effect of the presence of multiple ITAMs as well as qualitatively different contributions made by individual ITAMs. Apoptosis induced by single chain chimeras revealed that the first zeta ITAM stimulated greater apoptosis than the third zeta ITAM, and the second zeta ITAM was unable to trigger apoptosis. Because microheterogeneity in the amino acid sequence of the various ITAM motifs found in the TCR-zeta and CD3 chains predicts interactions with distinct src-homology-2-domain signaling proteins, our results suggest the possibility that individual ITAM motifs might play unique roles in TCR responses by engaging specific signaling pathways.

Amino Acid Sequence↗

PubMed1996

Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor.

Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemotherapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage. Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor cells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth. Here we show that leukaemic cells from patients in relapse have constitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.

Animals↗

PubMed1996

Subcortical dementia: a neurobehavioral approach.

The subcortical dementias are a heterogeneous group of disorders in which the predominant pathological lesions occur in subcortical structures such as basal ganglia, brainstem nuclei, and the cerebellum. When the cerebral cortex is involved, the lesions are most often in the frontal lobes. These pathologic lesions are associated with cognitive changes that include bradyphrenia, personality change (apathy, depression, irritability), memory impairment, and impaired manipulation of acquired knowledge (calculation, abstraction). Aphasia, apraxia, and agnosia are commonly seen in the cortical dementias, but are absent in the subcortical dementias. Progress in research on the anatomy and connectivity of cortical-subcortical structures has led to refinement in our understanding of the cortical dementias. Despite the connectivity between the cortical and subcortical structures, patterns of cognitive impairment in subcortical dementias remain distinct.

Aphasia↗