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M Freedman

Publications and source records attributed to M Freedman.

At least 73 records · Page 4Linked to original sources
PubMed1996

A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

Chromosome Mapping↗
PubMed1996

Usefulness of follow-up regional cerebral blood flow measurements by single-photon emission computed tomography in the differential diagnosis of dementia.

The aim of this study was to evaluate whether follow-up measurements of regional cerebral blood flow (rCBF) by single-photon emission computed tomography (SPECT) provide additional information in the differential diagnosis of dementia. Thirty-six patients (70 +/- 14 yr) with suspected dementia who had two technetium 99m-hexamethylpropyleneamineoxime SPECT scans over 18 +/- 7 months were included in this retrospective study. The patients comprised three groups based on the final clinical diagnosis: (1) neurodegenerative disorder (NDD) including Alzheimer's disease (AD) (n = 13), frontotemporal lobe dementia (n = 2), progressive supranuclear palsy (n = 1), and mixed dementia (AD plus multiinfarct dementia [MID]) (n = 3); (2) MID (n = 8); and (3) psychiatric disorders (depression [n = 7], psychosis [n = 1], and anxiety [n = 1]). Blinded to the clinical diagnosis and using visual analysis, the nuclear medicine physicians compared the second scan with the first scan for each patient to characterize temporal changes in rCBF. SPECT findings were categorized into three patterns of rCBF change: worsened, improved, and unchanged. Of the worsened rCBF group, 17 (85%) belonged to the NDD group whereas 2 (10%) and 1 (5%) belonged to the MID and psychiatric disorders groups, respectively. All 5 (100%) of the improved rCBF patients belonged to the psychiatric disorders group. Thus, worsening of rCBF favors the diagnosis of NDD whereas improvement in rCBF may mitigate against the diagnosis of NDD or MID. Follow-up rCBF measurements by SPECT thus provided additional information on the possible cause of dementia. A prospective study to further evaluate the usefulness of follow-up rCBF measurements by SPECT appears warranted.

Aged↗
PubMed1995

Monosomy 7 and activating RAS mutations accompany malignant transformation in patients with congenital neutropenia.

Individuals with severe forms of congenital neutropenia suffer from recurrent infections. The therapeutic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to increase the neutrophil count is associated with fewer infections and an improved quality of life. However, the long-term effects of this new therapy are largely unknown. In particular, it is unclear if myeloid leukemia, a known complication of some forms of congenital neutropenia, will occur with increased frequency among patients who receive long-term treatment with hematopoietic growth factors. We report 13 patients with congenital disorders of myelopoiesis who developed leukemic transformation with either myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) and 1 who acquired a clonal cytogenetic abnormality without evidence of MDS or AML while receiving rhG-CSF. The bone marrows of 10 patients showed monosomy 7 and 5 had activating RAS mutations. These abnormalities were not detected in pretreatment bone marrows and cessation of rhG-CSF was not associated with either clinical improvement or cytogenetic remission. We conclude that patients with severe forms of congenital neutropenia are at relatively high risk of developing MDS and AML. The occurrence of monosomy 7 and RAS mutations in these cases suggests that the myeloid progenitors of some patients are genetically predisposed to malignant transformation. The relationship between therapeutic rhG-CSF and leukemogenesis in patients with severe chronic neutropenia is unclear.

Adolescent↗
PubMed1995

Failure to detect missense mutations in the S182 gene in a series of late-onset Alzheimer's disease cases.

The possibility of an interaction of multiple genes has been speculated in pathogenesis of Alzheimer's disease (AD). Because we have recently cloned a novel gene S182 bearing five different missense mutations which segregate with early-onset familial AD, we sought the frequency of these mutations in familial and sporadic late-onset AD to clarify the incidence of these mutations in the disease. The current study showed lack of these mutations in 118 independent subjects affected with late-onset Alzheimer's disease.

Aged↗
PubMed1995

Digital radiography of the musculoskeletal system: the optimal image.

Digital radiography (DR) is replacing screen-film (SF) radiography for musculoskeletal examinations in our institution. After an iterative process of image quality improvement, our DR images are now preferred to SF images, and we have detailed our current optimized settings for the Fuji 9000 (Fuji Medical Systems, Tokyo, Japan). DR offers the advantages of improved contrast resolution, adjustable image contrast, the ability to reprocess the image, and the ease of transferring the image to an image management and communication system (IMAC).

Bone and Bones↗
PubMed1995

Quality control of storage phosphor digital radiography systems.

Quality control (QC) of storage phosphor devices is important in assuring that the image information entered into an Image management and communication (IMAC) system is sufficient for diagnosis. QC of storage phosphor digital radiography systems is complex because of the self-corrective nature of the image-processing software used in these machines. Currently, one must produce hard copy to perform adequate QC. Inspection of images with reject analysis and inspection of cassettes and imaging plates has helped us in our QC program. For those QC tests using control limits, the appropriate settings for these limits are unknown. Starting approximations are given. Recommended tests are described.

Equipment Failure↗
PubMed1995

Autocrine feedback death and the regulation of mature T lymphocyte antigen responses.

Antigen-induced T cell death is an important regulatory mechanism in the peripheral immune system. Evidence suggests that this process depends on T cell growth-inducing lymphokines such as IL-2 and occurs in proportion to the degree of T cell receptor occupancy. Strong T cell receptor stimulation leads to the synthesis of death molecules such as Fas ligand and tumor necrosis factor that cause T cell suicide. We propose that T cell death under these circumstances is the culmination of a feedback control mechanism termed propriocidal regulation or autocrine feedback death that regulates the expansion of specific T cell clones under conditions of high lymphokine and antigen load. In a quasi-stochastic system such as the antigen receptor repertoire, feedback information may be essential for the appropriate regulation of peripheral immune responses. Our understanding of this feedback mechanism affords a means to manipulate antigen-specific T cell death in vivo. The application of this approach to the therapy of T cell-medicated immunological diseases is discussed.

Animals↗
PubMed1994

Are the associations between Alzheimer's disease and polymorphisms in the apolipoprotein E and the apolipoprotein CII genes due to linkage disequilibrium?

Allele frequencies for polymorphisms in the apolipoprotein E and the apolipoprotein CII genes were determined in subjects of Ashkenazi Jewish origin with late-onset Alzheimer's disease and in unaffected control subjects from the same ethnic group. A significant association was observed between late-onset Alzheimer's disease and the epsilon 4 (112Cys-->Arg) allele of apolipoprotein E; however, no association was detected with apolipoprotein CII. These results suggest that the association with epsilon 4 is probably not due to linkage disequilibrium.

Aged↗
PubMed1994

DNA sequences in the promoter region of the NF1 gene are highly conserved between human and mouse.

The gene for type 1 neurofibromatosis (NF1) is most highly expressed in brain and spinal cord, although low levels of mRNA can be found in nearly all tissues. As a first step in investigating the regulation of NF1 gene expression, we have cloned and sequenced the promoter regions of the human and mouse NF1 genes and mapped the transcriptional start sites in both species. We report here that the 5' ends of the human and murine NF1 genes are highly conserved. While no discernable TATA or CCAAT box sequences are seen, transcription initiates at identical sites in both species, 484 nucleotides upstream of the ATG initiation codon in the human gene. The human and mouse NF1 genes share particularly high sequence homology (95%) between nucleotides -33 and +261 and contain several perfectly conserved transcription factor binding site motifs, including a cAMP response element, several AP2 consensus binding sites, and a serum response element. The high conservation of these sequences indicates that they are likely to be significant in the regulation of NF1 gene expression.

Animals↗
PubMed1994

Frontal and parietal lobe dysfunction in depression: delayed alternation and tactile learning deficits.

To evaluate frontal and parietal lobe involvement in depression, behavioral tests sensitive to damage in these regions were administered to depressed patients over age 50. Delayed alternation (DA), delayed response and object alternation were used to assess dorsolateral frontal and orbitofrontal function. Tactile learning problems (TOL and TRL) assessed parietal lobe integrity. Depressed patients were significantly impaired on DA, TOL and TRL, suggesting spatial memory (DA) and tactile learning deficits. The functional neuroanatomy underlying these deficits may share features with Parkinson's and Alzheimer's diseases.

Aged↗
PubMed1994

SPECT for differential diagnosis of dementia and correlation of rCBF with cognitive impairment.

99mTc-HM-PAO single photon emission computed tomography (SPECT) was used to image 30 patients referred for the assessment of dementia. SPECT images revealed various patterns of regional cerebral perfusion (rCBF) in the subgroups of patients with the clinical diagnoses of Alzheimer's disease (AD, n = 14), Pick's disease (n = 1), and multi-infarct dementia (n = 7). In three patients, SPECT clarified the clinical differential diagnostic possibilities. Using a relative rCBF quantification technique, the relationship between specific cognitive impairments and rCBF in the AD patients was determined. There was a significant correlation between language impairment and left hemisphere hypoperfusion, whereas, apraxia correlated with hypoperfusion in the left parietal region. Thus, HM-PAO SPECT is useful as an aid in the differential diagnosis of dementia and the technique of relative rCBF quantification with SPECT may contribute to the understanding of the clinico-anatomical relations of cognitive deficits in dementia.

Aged↗
PubMed1994

Neuropsychological test performance in patients with dominantly inherited spinocerebellar ataxia: relationship to ataxia severity.

To determine whether the cognitive status of patients with dominantly inherited spinocerebellar ataxia (DSCA) might be related to neurologic severity, we administered a comprehensive neuropsychological test battery to 43 patients with DSCA, ranging in ataxia severity from mild to end-stage. As compared with the controls, the mildly ataxic patients scored normally or close to normal as a group on all of the neuropsychological tests. In contrast, approximately one-half of the moderately and all of the severely ataxic patients showed poor performance, independent of age, Hamilton Rating Scale for Depression score, or education, on the Wisconsin Card Sorting Test, suggesting impaired executive system function. In addition, a subgroup of these patients had a neuropsychological profile suggestive of mild generalized cognitive impairment. We conclude that DSCA is not a homogeneous group of disorders with respect to cognitive status and that the neurologic severity of the disorder is a major factor. Impaired executive system function could be explained by damage to olivopontocerebellar system control over cerebral cortical function or to damage to other neuronal systems (especially cholinergic) that degenerate in parallel with the olivopontocerebellar system.

Adult↗
PubMed1994

Helping home bound elderly clients understand and use advance directives.

The Patient Self-Determination Act passed by the United States Congress in December 1991 is usually defined in terms of the responsibility of health care institutions to inform patients about their rights and privileges in connection with life support measures. Social workers as well as other providers are aware that the time of admission is neither the auspicious time nor is the hospital the place of choice for conveying that information. The intent will be better fulfilled when patients arrive at the hospital with these decisions made and the documents in hand. This article presents the process of presenting the options of living wills and health care proxies to patients who receive home care services. With the cooperation and support of her team, the social worker informed these patients about these documents in their own homes and helped them with decisions required. The problems encountered, how help was given, and what was learned that can be used by other social workers in both practice and planning are covered.

Advance Directives↗
PubMed1993

Regulatory effect of interferon-gamma and phorbol esters on the surface expression and biosynthesis of MHC class I antigens by human leukemia cells.

We have used cell surface radioiodination, biosynthetic incorporation of [35S]methionine, and flow cytometry to analyze the effects of interferon gamma (IFN-gamma) and/or phorbol esters (PMA) on the turnover and expression of class I antigens of a human leukemia B cell line. Our results demonstrated that although both IFN-gamma and PMA enhance HLA expression, they act synergistically to increase by eightfold the amount of HLA polypeptides synthesized by the acute lymphoblastic leukemia cells and acted additively to augment the cell surface expression of HLA as quantified by flow cytometry. We observed a cyclic increase or decrease in the expression of class I antigens as a function of time in cell culture. IFN-gamma and/or PMA modulated this effect inducing more cells to express HLA maximally. These results suggest that there is a physiologic limit for the expression of major histocompatibility complex class I antigens.

B-Lymphocytes↗
PubMed1993

Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia.

The pericentric inversion of chromosome 16 [inv(16)(p13q22)] is a characteristic karyotypic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. The 16p and 16q breakpoints were pinpointed by yeast artificial chromosome and cosmid cloning, and the two genes involved in this inversion were identified. On 16q the inversion occurred near the end of the coding region for CBF beta, also known as PEBP2 beta, a subunit of a heterodimeric transcription factor regulating genes expressed in T cells; on 16p a smooth muscle myosin heavy chain (SMMHC) gene (MYH11) was interrupted. In six of six inv(16) patient samples tested, an in-frame fusion messenger RNA was demonstrated that connected the first 165 amino acids of CBF beta with the tail region of SMMHC. The repeated coiled coil of SMMHC may result in dimerization of the CBF beta fusion protein, which in turn would lead to alterations in transcriptional regulation and contribute to leukemic transformation.

Amino Acid Sequence↗