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Biomedical subjects

J Friedman

Publications and source records attributed to J Friedman.

At least 19 recordsLinked to original sources
PubMed1992

Reproducibility of stress redistribution thallium-201 SPECT quantitative indexes of hypoperfused myocardium secondary to coronary artery disease.

To determine the reproducibility of quantitative indexes of hypoperfused myocardium by exercise thallium-201 single-photon emission computed tomography, duplicate studies were performed in 16 stable patients within 1 month. Twenty-three other patients, with intervals up to 13 months between studies, were retrospectively identified from medical records. Symptoms, weight, heart rate achieved and peak systolic blood pressure during the 2 studies were similar. Maximal counts circumferential profiles' polar maps were generated and divided into 3 vascular territories. The hypoperfused myocardium was defined as the percent stress profile points below the normal level. The observed values were compared between the 2 studies for each patient. Defect size ranged from 0 to 73%. The concordance correlation coefficient (a measure of the closeness of the data points to the line of identity) and mean absolute deviation were 0.94 and 4.5%, respectively, when all patients were considered together, 0.93 and 3.2%, respectively in the reproducibility group, and 0.94 and 5.1%, respectively, in the retrospective group. Inter- and intraobserver reproducibility were also very high. For individual vessels, the concordance correlation coefficients were all > or = 0.89 and the mean absolute deviations between 3.7 and 9%. Thus, in stable patients with repeat thallium studies within a year, the percent hypoperfused myocardium is highly reproducible.

Adult↗
PubMed1992

Quantitative MRI studies for assessment of multiple sclerosis.

Although magnetic resonance imaging (MRI) is a valuable aid in the initial diagnosis of multiple sclerosis (MS), quantitatively MRI has been disappointing in staging and evaluating therapy protocols by means of serial examinations. In this study, image processing algorithms were developed for the global analysis of MR images of the cerebrum. Limited three-dimensional segmentation was achieved through histogram analysis by these algorithms, which are essentially operator independent. The effects of coil response and tip angles, patient positioning, and interslice gap thicknesses were examined for 10 MS patients with repeated examinations for a total of 72 images. Effects of technique and instrumentation errors were approximately 6%, and agreement between two independent operators for measuring the total MR pixel sum from periventricular effusions and intense MS plaques was better than 97% with a standard deviation of 2.9%.

Adipose Tissue↗
PubMed1992

Speech production, syntax comprehension, and cognitive deficits in Parkinson's disease.

Speech samples were obtained that were analyzed for voice onset time (VOT) for 40 nondemented English speaking subjects, 20 with mild and 20 with moderate Parkinson's disease. Syntax comprehension and cognitive tests were administered to these subjects in the same test sessions. VOT disruptions for stop consonants in syllable initial position, similar to those noted for Broca's aphasia, occurred for nine subjects. Longer response times and errors in the comprehension of syntax as measured by the Rhode Island Test of Sentence Comprehension (RITLS) also occurred for these subjects. Anovas indicate that the VOT overlap subjects had significantly higher syntax error rates and longer response times on the RITLS than the VOT nonoverlap subjects--F(1, 70) = 12.38, p less than 0.0008; F(1, 70) = 7.70, p less than 0.007, respectively. The correlation between the number of VOT timing errors and the number of syntax errors was significant. (r = 0.6473, p less than 0.01). VOT overlap subjects also had significantly higher error rates in cognitive tasks involving abstraction and the ability to maintain a mental set. Prefrontal cortex, acting through subcortical basal ganglia pathways, is a component of the neural substrate that regulates human speech production, syntactic ability, and certain aspects of cognition. The deterioration of these subcortical pathways may explain similar phenomena in Broca's aphasia. Results are discussed in relation to "modular" theories.

Adult↗
PubMed1992

A genetic map of the mouse suitable for typing intraspecific crosses.

We report the construction of a genetic linkage map of the mouse, consisting entirely of genetic markers that can be rapidly typed by polymerase chain reaction and that show a high degree of polymorphism among inbred laboratory strains. Specifically, the map contains 317 simple sequence length polymorphisms at an average spacing of 4.3 cM and is detectably linked to approximately 99% of the mouse genome. In typical crosses between inbred laboratory strains, about 50% of the markers are polymorphic, making it straightforward to follow inheritance in almost any cross.

Animals↗
PubMed1992

Lymphocyte development from stem cells.

Highly enriched pluripotent and multipotent hematopoietic stem cells (HSCs) are isolated from bone marrow and fetal liver as Thy-1loLin-Sca-1+ cells. Pluripotent HSCs express c-kit receptor on their surface, but the generation and proliferation of early fetal HSCs take place in the absence of steel factor. T precursor cells migrate into the fetal thymus by chemotactic mechanism. CD4lo precursors represent a newly defined phase of T-cell development in the thymus between the bone marrow-derived stem cells and the CD4-8- intrathymic precursors. Only fetal, but not adult, HSCs have the capacity to differentiate into V gamma 3+ and V gamma 4+ T cells under the fetal thymic microenvironment, and HSC themselves may lose some of their developmental potential during ontogeny. It is postulated that HSCs are the locus of a complicated but precise developmental clock that may determine both the time-dependent closure of some gene loci (e.g. V gamma 3 and V gamma 4 T cell receptor, and embryonic and fetal globin) and the activation of others (e.g. the N nucleotide insertion machinery).

Animals↗
PubMed1991

Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA.

We report the cloning and characterization of a new binding protein for the immunosuppressive drug cyclosporin A (CsA). This new cyclophilin, cyclophilin C (cyp C), shows extensive homology with all previously identified cyclophilins. Cyp C mRNA is expressed in a restricted subset of tissues relative to cyclophilins A and B, but is present in those tissues reported to be most affected by CsA therapy. A cyp C fusion protein has peptidyl-prolyl isomerase activity, and CsA inhibits this activity. Using the cyp C fusion protein as an affinity ligand to probe cellular extracts, we find that the cyp C fusion protein binds specifically to a 77 kd protein in the absence of CsA, while in the presence of CsA it instead binds specifically to a 55 kd protein. We propose that the p77 is involved in cyp C native function and that the p55 is involved in signal transduction events blocked by treatment with immunosuppressive levels of CsA.

Amino Acid Isomerases↗
PubMed1991

Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.

Although the immediate receptors (immunophilins) of the immunosuppressants cyclosporin A (CsA) and FK506 are distinct, their similar mechanisms of inhibition of cell signaling suggest that their associated immunophilin complexes interact with a common target. We report here that the complexes cyclophilin-CsA and FKBP-FK506 (but not cyclophilin, FKBP, FKBP-rapamycin, or FKBP-506BD) competitively bind to and inhibit the Ca(2+)- and calmodulin-dependent phosphatase calcineurin, although the binding and inhibition of calcineurin do not require calmodulin. These results suggest that calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that cyclophilin and FKBP mediate the actions of CsA and FK506, respectively, by forming drug-dependent complexes with and altering the activity of calcineurin-calmodulin.

Amino Acid Isomerases↗
PubMed1991

Mouse hematopoietic stem cells and the interaction of c-kit receptor and steel factor.

Hematopoietic stem cells (HSCs) are distinguished from other hematopoietic progenitors in bone marrow by their unique ability to undergo multilineage differentiation and self-renewal. Two mouse mutations, dominant spotting (W) and steel (Sl), have pleiotropic effects on hematopoiesis, gametogenesis, and melanoblast development. These two mutations have been shown to be intrinsic (W) and microenvironmental (Sl) defects. Recently, molecular studies revealed that the W and Sl loci encode the c-kit receptor and steel factor (SLF), respectively. The c-kit receptor is expressed on HSCs and hematopoietic progenitors, while SLF is produced by stromal cells. SLF acts on hematopoietic progenitors synergistically with other growth factors. Here we review the effect of these mutations on mouse hematopoiesis, and show that SLF acts on HSCs and other myeloerythroid progenitors, but that it, in our hands, does not play a critical role in HSC generation or self-renewal. Rather, SLF is the most potent co-mitogen (with IL-1, IL-3, IL-6, G-CSF, GM-CSF, or M-CSF) found that acts on these cells, but the effect of such treatments is the rather specific and massive expansion of myeloerythropoiesis, not lymphopoiesis, and perhaps at the expense of HSC self-renewal.

Animals↗
PubMed1991

Linkage mapping of autosomal dominant retinitis pigmentosa (RP1) to the pericentric region of human chromosome 8.

Linkage mapping in a large, seven-generation family with type 2 autosomal dominant retinitis pigmentosa (ADRP) demonstrates linkage between the disease locus (RP1) and DNA markers on the short arm of human chromosome 8. Five markers were most informative for mapping ADRP in this family using two-point linkage analysis. The markers, their maximum lod scores, and recombination distances were ANK1 (ankyrin)--2.0 at 16%; D8S5 (TL11)--5.3 at 17%; D8S87 [a(CA)n repeat]--7.2 at 14%; LPL (lipoprotein lipase)--1.5 at 26%; and PLAT (plasminigen activator, tissue)--10.6 at 7%. Multipoint linkage analysis, using a simplified pedigree structure for the family (which contains 192 individuals and two inbreeding loops), gave a maximum lod score of 12.2 for RP1 at a distance 8.1 cM proximal to PLAT in the pericentric region of the chromosome. Based on linkage data from the CEPH (Paris) reference families and physical mapping information from a somatic cell hybrid panel of chromosome 8 fragments, the most likely order for four of these five loci and the diseases locus is 8pter-LPL-D8S5-D8S87-PLAT-RP1. (The precise location of ANK1 relative to PLAT in this map is not established). The most likely location for RP1 is in the pericentric region of the chromosome. Recently, several families with ADRP with tight linkage to the rhodopsin locus at 3q21-q24 were reported and a number of specific rhodopsin mutations in families with ADRP have since been reported. In other ADRP families, including the one in this study, linkage to rhodopsin has been excluded. Thus mutations at two different loci, at least, have been shown to cause ADRP. There is no remarkable clinical disparity in the expression of disease caused by these different loci.

Base Sequence↗
PubMed1991

Technetium 99m sestamibi in the assessment of chronic coronary artery disease.

Extensive work has already been performed with regard to both planar and single photon emission computed (SPECT) technetium 99m sestamibi studies. Before widespread application of optimized acquisition and processing methods, clinical results between 99mTc sestamibi and thallium 201 were remarkably similar. It is anticipated that as techniques for 99mTc sestamibi planar and SPECT imaging become optimized, improvements in sensitivity and specificity for detection of coronary artery disease, over those observed with 201TI, might be forthcoming. This expectation is based on the improved image quality inherent in the use of the 99mTc agent with its higher count rate and higher energy. This improvement in image quality may be a principal reason for laboratories to switch from 201TI to 99mTc sestamibi imaging. It is anticipated that, with improved imaging characteristics, it will be easier for the average community hospital to obtain higher quality planar or SPECT imaging using 99mTc sestamibi rather than 201TI. In addition to improved image quality, the characteristics of 99mTc sestamibi allow gated planar or SPECT perfusion images to be obtained. It has been suggested that stress-gated SPECT sestamibi studies may provide all the information contained in a stress-rest nongated 99mTc sestamibi study, thereby potentially increasing patient throughput, a major concern with SPECT. Throughput can also be increased by using dual-isotope approaches with rest 201TI and stress technetium sestamibi acquisitions, employing either separate or simultaneous imaging with which the entire study can be accomplished in less than 2 hours. With simultaneous dual-isotope acquisition, camera time can be reduced by 50%. Finally, 99mTc sestamibi offers the advantage of the ability to perform first-pass exercise ventricular function and SPECT myocardial perfusion studies with a single injection of tracer. Regarding the assessment of myocardial viability, results to date suggest a very high degree of concordance between 201TI and 99mTc sestamibi studies using either planar or SPECT acquisition techniques. Correlative rest studies with both tracers will be of particular interest, as will preoperative and postoperative and position emission tomography correlation studies.

Aged↗
PubMed1991

Detection of aggregated leukocytes in the circulating pool during stress-demargination is not necessarily a result of decreased leukocyte adhesiveness.

Leukocyte endothelial interactions are essential for a normal immune response. It is known that this response is influenced by stress and that the latter induces demargination. We examined the question of whether stress demargination results from a decreased state of leukocyte adhesiveness. Included were various volunteers and patients under different degrees of stress. 66 young athletes before beginning their daily exercises, 67 middle-aged healthy volunteers, 25 patients before ergometry for evaluation of chest pain, 75 patients who were referred to the emergency room with chest pain without ischemia/infarction, 78 patients with ischemia/infarction, 65 patients with minor trauma, 25 with a fracture and 12 with polytrauma. The leukocyte adhesiveness/aggregation (LAA) values were measured with a direct slide test. The respective LAA values were 7.4 +/- 4.7, 6.3 +/- 4.4, 5.8 +/- 3.6, 5.2 +/- 3.5, 10.8 +/- 8.5, 9.1 +/- 5.8, 12.2 +/- 6.6 and 19 +/- 12.6% of aggregated leukocytes. We conclude that an increase in aggregated white blood cells can be detected in the circulating pool during major stress. It is therefore suggested that stress demargination is not necessarily a result of diminished leukocyte adhesiveness.

Adolescent↗
PubMed1991

Impaired DNA repair in patients with end-stage renal disease and its improvement with hemodialysis.

DNA repair following ultraviolet (UV)-induced DNA damage is decreased in some cancer-prone diseases. Cancer frequency in end-stage renal disease patients is higher than in the normal population. Therefore, DNA repair from UV-induced damage in lymphocytes was determined in 11 hemodialysis (HD) patients, 11 patients on continuous ambulatory peritoneal dialysis (CAPD), 10 patients with chronic renal failure (CRF) who had not yet been dialyzed and in 12 controls. UV irradiation at 254 nm was followed by 3H-thymidine incorporation in the presence of hydroxyurea. DNA repair synthesis in CAPD and CRF was significantly reduced to only 69 and 54% of the control, respectively, whereas the repair of HD patients was close to normal (86%, p = n.s.). The impaired ability to correct DNA damage may contribute to the increased cancer incidence in uremic patients.

Adult↗
PubMed1991

Sensitization of adenylyl cyclase by P2 purinergic and M5 muscarinic receptor agonists in L cells.

Many hormones have been shown to activate phospholipase C, which results in the hydrolysis of membrane polyphosphoinositides, such as phosphatidylinositol 4,5-bisphosphate (PIP2). Two second messengers are known to be produced by PIP2 hydrolysis, 1,2-diacylglycerol, an endogenous activator of a family of enzymes called protein kinase C (PKCs), and inositol 1,4,5-trisphosphate, which raises free levels of intracellular Ca2+. Treatment of various cells with 4 beta-phorbol 12-myristate 13-acetate (PMA), a specific exogenous activator of PKCs, causes an enhancement or sensitization of adenylyl cyclase activities. This finding prompted us to examine the effects of direct hormonal activation of PIP2 hydrolysis on the sensitization of adenylyl cyclase. Liao et al. [J. Biol. Chem. 265:11273-11284 (1990)] have shown that P2 purinergic receptor agonists such as ATP and muscarinic receptor agonists such as carbachol stimulate PIP2 hydrolysis in L cells expressing the M5 muscarinic acetylcholine receptor. We investigated the effects of these hormones on adenylyl cyclase and contrasted these effects with the sensitizing effects of PMA. We found that ATP pretreatment of two different types of L cells resulted in a rapid 50-150% sensitization of prostaglandin E1-, epinephrine-, and forskolin-stimulated adenylyl cyclase activity, with an EC50 of 3 microM ATP. This effect was qualitatively similar to that caused by 10 nM PMA. The enhancement of adenylyl cyclase activity was associated with an increase in the Vmax for hormonal stimulation and with a lack of significant effects of ATP on the EC50. The effect was completely eliminated when adenylyl cyclase was assayed in the presence of high free Mg2+ levels (10 mM). Down-regulation of PKCs with long term PMA treatment did not affect the ATP-induced sensitization of adenylyl cyclase, although the PMA-induced sensitization of adenylyl cyclase was eliminated. In contrast to the effects of ATP and PMA, treatment of the cells with carbachol alone had no effect on adenylyl cyclase; however, in combination with nanomolar concentrations of PMA, synergism of the sensitization of adenylyl cyclase was observed. These data indicate that the activation of P2 purinergic receptors by ATP, and possibly activation of M5 muscarinic receptors by carbachol, may be important in the signal transduction pathways leading to the increases in the responsiveness of hormone-stimulated adenylyl cyclase.

Adenosine Triphosphate↗