Search PubMed⌕ Search

Biomedical subjects

J A Cooper

Publications and source records attributed to J A Cooper.

At least 235 records · Page 13Linked to original sources
PubMed1992

A component analysis of the generation and release of isometric force in Parkinson's disease.

Paradigms of isometric force control allow study of the generation and release of movement in the absence of complications due to disordered visuomotor coordination. The onset and release of isometric force in Parkinson's disease (PD) was studied, using computerised determinants of latency of response and rate of force generation and release. Components of isometric force control were related to measures of cognitive, affective and clinical motor disability. The effects of treatment were determined by longitudinal study of de novo patients. Patients with PD showed impairment in latency and rate of force change for movement release as well as onset. Rate of force change correlated with depression, clinical motor disability and memory quotient but latency showed no correlation with any of these measures. Treatment improved rate of force release, in concert with clinical motor disability, but not latency. These results suggest dissociations between latency and rate of force change that may be linked to different neurochemical deficits. Further, they demonstrate akinetic deficits in force release that argue against the "neural energy hypothesis" of akinesia.

Bromocriptine↗
PubMed1992

Cognitive components of reaction time in Parkinson's disease.

Studies of reaction time in Parkinson's disease (PD) have suggested a selective deficit in simple reaction time (SRT), compared with choice reaction time (CRT). This finding has been interpreted as a deficit in motor preprogramming but could involve other factors, such as attentional focussing and stimulus predictability. Moreover, not all studies show the same selective deficit, possibly because of differences in patient selection and treatment effects. The neurochemical basis of RT deficits in PD remains unclear. Accordingly, the contribution of cognitive factors to impaired RT was assessed in a large group of PD patients, including early untreated cases, and performance was examined in relation to clinical variables and the effect of treatment in longitudinal study. Motor output was constant in both SRT and CRT tasks. In the SRT task, all stimuli required a response; in the CRT task, subjects were required to respond to only one of the two possible stimuli. Attentional focussing on SRT was examined by variation of the interval between cue and stimulus; effects of stimulus uncertainty were evaluated from a comparison of SRT and CRT; temporal predictability of the stimulus was examined from a comparison of conditions in which the interval between warning signal and imperative stimulus was constant or variable. The PD patients showed similar deficits in SRT and CRT, but normal effects of cue-stimulus interval and temporal predictability. Reaction time correlated with measures of global cognitive capacity and frontal-lobe function, as well as motor disability. Treatment had no effect on SRT or CRT, despite clinical benefit. These findings indicate that RT deficits in PD are not due to impaired attentional focussing or stimulus predictability but are compatible with a deficit in higher-order processes concerned with the orientation of both cognitive and motor responses to a stimulus. These processes are not substantially dopamine-dependent but may be served by non-dopaminergic neurotransmission.

Antiparkinson Agents↗
PubMed1992

Overexpressed Drosophila src 64B is phosphorylated at its carboxy-terminal tyrosine, but is not catalytically repressed, in cultured Drosophila cells.

Little is known about the regulation of non-receptor tyrosine kinases in invertebrates. We have studied the relationship between the phosphorylation state of the Drosophila src 64B (Dsrc) gene product, p62D, and its tyrosine kinase activity in Drosophila Schneider 2 cells, using wild-type and mutated Dsrc constructs that were overexpressed by transient transfection. Phosphopeptide mapping showed that the putative regulatory C-terminal tyrosine (Tyr-547) of p62D was phosphorylated in vivo. In contrast to vertebrate src family kinases overexpressed in fibroblasts, wild-type p62D overexpressed in Schneider 2 cells was phosphorylated at additional tyrosines outside of the C-terminus. These tyrosines corresponded to the major in vitro autophosphorylation sites. Overexpression of wild-type p62D or several catalytically active p62D mutants significantly increased the phosphorylation of numerous Schneider cell proteins on tyrosine, while expression of catalytically inactive mutants of p62D had no such effect. Thus, in contrast to the repression of src family kinase activity in fibroblasts, p62D is catalytically active when overexpressed in Drosophila cells, perhaps because of substoichiometric C-terminal tyrosine phosphorylation. These results raise the possibility that fly development will be sensitive to ectopic expression of p62D.

Amino Acid Sequence↗
PubMed1992

Developmentally regulated expression of a mitogen-activated protein kinase in Xenopus laevis.

Mitogen-activated protein (MAP) kinases are activated in somatic cells in response to many extracellular stimuli and in oocytes during meiotic maturation. We have examined the tissue specificity of expression of a MAP kinase (Xp42) in adult and larval Xenopus laevis. MAP kinase RNA and protein were abundant in the nervous system and lymphoid tissues and were readily detected in most other organs. A remarkably high level of RNA was detected in ovary. Fractionation of oocytes showed that MAP kinase RNA is expressed at the highest level in small oocytes, suggesting that it is a maternal RNA that is stored for early embryogenesis. The levels of MAP kinase RNA and protein did not change from the time of fertilization through to late blastula. The results are consistent with functions for MAP kinases in signal transduction in embryonic as well as adult cells.

Animals↗
PubMed1992

Phosphorylation and regulatory effects of the carboxy terminus of a Drosophila src homolog.

The kinase activities of the vertebrate src family members are repressed by phosphorylation of a tyrosine residue in the carboxy-terminal 'tail' of these molecules. To explore whether the tail of an invertebrate src homolog might also serve a regulatory function, we examined the ability of the carboxy terminus of a Drosophila src homolog (p62D), which contains a tyrosine homologous to those in the vertebrate src family members, to regulate the following molecules in mammalian fibroblasts: (1) a chimeric protein, p60CD, containing the amino terminus and catalytic domains of chicken p60c-src joined to the C-terminus of p62D; and (2) full-length p62D itself. By a variety of criteria p60CD appears to be a partially, rather than fully, repressed form of p60c-src. Phosphopeptide mapping indicates that partial repression correlates with partial phosphorylation of the tyrosine in the p62D tail of the chimera. Phosphorylation of the tail may also regulate full-length p62D. Expression of p62D in fibroblasts does not affect cell morphology or the overall abundance of tyrosine-phosphorylated proteins. The molecule is phosphorylated at its C-terminal tyrosine (Tyr-547), but not at its in vitro autophosphorylation sites, suggesting that it is catalytically repressed in fibroblasts. Expression of a truncated p62D mutant lacking Tyr-547 is associated with a clear alteration in cellular morphology and a two- to threefold increase in cellular phosphotyrosine levels. These results suggest that phosphorylation of the C-terminal tyrosine of the tail of an invertebrate src-like kinase can repress the activity of adjacent catalytic domains.

Amino Acid Sequence↗
PubMed1992

Effect of patient motion on tomographic myocardial perfusion imaging.

We evaluated the effect of patient motion on inducing false-positive tomographic 201Tl myocardial perfusion studies. The effects of the angle of camera rotation at which movement occurs, the direction of movement and the distance of movement were studied. Movement was stimulated by shifting the raw data from normal motion-free 201Tl tomographic myocardial perfusion studies. The visual detectability of motion artifact was evaluated with receiver-operating characteristic curve analysis. The clinical importance of patient movement was determined by measuring the incidence of quantitative bull's-eye abnormalities induced by motion. Visual artifacts were more detectable and quantitative abnormalities more frequent as the distance of movement increased. Artifacts from 3.25 mm of movement were not visually detectable. Artifacts from 6.5 mm of movement were visually detectable, but were infrequently clinically important. Movement of 13 mm or greater frequently caused quantitative abnormalities. Quantitative abnormalities from axial movement were more frequent than artifacts from lateral movement. Quantitative abnormalities were more frequent when the movement occurred at the beginning or end. We conclude that when patients move during 201Tl tomographic myocardial perfusion imaging, the incidence and character of false-positive results depend on the angle of camera rotation at which the movement occurs, the direction of the movement and distance of the movement.

Artifacts↗
PubMed1992

Diagnosis of sternal wound infection by technetium-99m-leukocyte imaging.

An imaging study is needed that can detect sternal wound infections and distinguish between superficial and deep sternal wound infection when a clinical diagnosis is uncertain and a decision regarding surgical intervention must be made. We retrospectively reviewed the 99mTc-leukocyte scans of 29 patients referred to rule out sternal wound infection. The presence or absence of deep or superficial sternal wound infection was determined by microbiology and long-term follow-up. Images obtained 4 and 20 hr after injection were reviewed by two nuclear physicians who were blinded to the clinical history. Findings were categorized as normal or abnormal. Abnormal images were further defined as having intense uptake at 4 and 20 hr, increasing uptake between 4 and 20 hr, or other patterns such as focal cold regions, irregular uptake at 4 and 20 hr or increasing uptake between 4 and 20 hr were 100% sensitive and 89% specific for the detection of deep sternal wound infection. The images were also useful for determining the extent of infection. Superficial sternal wound infection could not be reliably detected. The results indicate that 99mTc-leukocyte imaging is useful for the diagnosis of deep sternal wound infection.

Adult↗
PubMed1991

Regulation of CapZ, an actin capping protein of chicken muscle, by anionic phospholipids.

Chicken muscle CapZ, a member of the capping protein family of actin-binding proteins, binds to the barbed end of actin filaments and nucleates actin polymerization. No regulation of the capping protein family has been described. We report that micelles of phosphatidylinositol 4,5-bisphosphate (PIP2) bind to CapZ and completely inhibit its ability to affect actin polymerization as measured by several independent assays. Higher concentrations of other anionic phospholipids also completely inhibit the activity of CapZ. Neutral phospholipids have no effect. Mixed vesicles of PIP2 with phosphatidylcholine or phosphatidylethanolamine also inhibit CapZ, but addition of Triton X-100 both prevents and reverses PIP2's inhibition of CapZ.

Actin Capping Proteins↗
PubMed1991

Platelet-derived growth factor (PDGF) stimulates PDGF receptor subunit dimerization and intersubunit trans-phosphorylation.

High affinity binding of platelet-derived growth factor (PDGF) has been proposed to involve the interaction of the dimeric PDGF ligand with two receptor subunits, designated alpha and beta. We have cloned and expressed a human PDGF receptor cDNA which differs in sequence from the beta-subunit and which has the PDGF binding properties and monoclonal antibody recognition, predicted for the alpha-subunit. Scatchard analysis indicated that PDGF-AA and PDGF-AB bound to transfected alpha-subunits with affinities of Kd = 0.06 and 0.05 nM, respectively. PDGF-BB bound with a significantly lower affinity (Kd = 0.4 nM). Nevertheless, this affinity is still great enough to mediate substantial PDGF-BB binding at physiological concentrations and would be considered to be "high affinity." We have used wild-type and kinase-inactive human beta-subunits to show that PDGF binding promotes receptor subunit dimerization in intact cells. In addition, we found that PDGF stimulates tyrosine phosphorylation of the kinase-inactive beta-subunit when it is expressed with alpha-subunits. The kinase-inactive beta-subunits were phosphorylated at tyrosine 857 and 751, the major phosphorylation sites of the wild-type beta-subunit, indicating either that intra- and intermolecular phosphorylation occurs on the same sites, or that a significant fraction of receptor tyrosine phosphorylation is intermolecular.

Animals↗
PubMed1991

Cloning of a complementary DNA for a protein-tyrosine kinase that specifically phosphorylates a negative regulatory site of p60c-src.

The protein-tyrosine kinase activity of the proto-oncogene product p60c-src is negatively regulated by the phosphorylation of a tyrosine residue close to the C terminus, tyrosine 527. The phosphorylation might be catalysed by a so-far-unidentified tyrosine kinase, distinct from p60c-src. Recently we purified a protein-tyrosine kinase that specifically phosphorylates tyrosine 527 of p60c-src from neonatal rat brain. We have now confirmed the specificity of this enzyme by using a mutant p60c-src that has a phenylalanine instead of tyrosine 527, and cloned a complementary DNA that encodes the enzyme. The enzyme is similar to kinases of the src family in that it has two conserved regions, Src-homology regions 2 and 3, upstream of a tyrosine kinase domain. The amino-acid identity of each region is no more than 47%, however, and the enzyme lacks phosphorylation sites corresponding to tyrosines 416 and 527 of p60c-src and has no myristylation signal. These results suggest that this protein-tyrosine kinase, which might negatively regulate p60c-src, represents a new type of tyrosine kinase.

Amino Acid Sequence↗
PubMed1991

Variant cDNAs encoding proteins similar to the alpha subunit of chicken CapZ.

Chicken adult muscle and liver cDNA libraries were screened with a cDNA, alpha 1, previously isolated from a chicken embryo library by screening with antibodies against the alpha subunit of chicken CapZ. cDNAs with a new coding region, called alpha 2, were found in addition to ones with the alpha 1 coding region. alpha 2 predicts a protein sequence that matches exactly the N-terminal sequence of 5 peptides prepared from CapZ alpha purified from chicken muscle, while the protein sequence predicted by alpha 1 matches the peptides well, but not exactly. The predicted protein sequences of alpha 1 and alpha 2 are very similar to each other, and they are similar to those of the alpha subunit of capping protein from Dictyostelium [Hartmann et al., J. Biol. Chem. 163:5254-5254, 1989] and an actin-binding protein from Xenopus [Ankenbauer et al., Nature 342:822-824, 1989]. Other conserved features of the predicted primary and secondary structures are noted. Chicken alpha 1 and alpha 2 are transcribed in all of 7 adult chicken muscle and non-muscle tissues in comparable amounts by Northern analysis. alpha 2 has four poly(A)+RNA transcripts, one of which is rare in liver. alpha 1 has two transcripts. alpha 1 and alpha 2 are encoded by different single-copy genes by Southern analysis of chicken genomic DNA.

Actin Depolymerizing Factors↗
PubMed1991

Plasma factor VII is activated by postprandial triglyceridaemia, irrespective of dietary fat composition.

Nine adults took two 7-day diets of standardised energy and total fat content, but with a dietary polyunsaturated/saturated fat ratio of less than 0.3 and greater than 3.0 respectively, while adhering to their daily routine. Blood was drawn on 6 occasions between 09.00 and 22.45 h on the final day of each dietary period for factor VII activity (VIIc), factor VII antigen (VIIag) and lipoprotein lipid concentrations. Diurnal variation was described for each variable in terms of its deviation from the individual's daily mean value at each time point across the day. Plasma triglyceride remained low until after the midday meal, whereafter a marked rise was sustained into the later evening. Plasma VIIc declined until early afternoon, but showed a marked rise in the late afternoon. Plasma VIIag showed no significant diurnal variation. Changes in plasma triglyceride concentration during the day were related positively to changes in VIIc about 160 min later, but not to VIIc at other time points. This effect of postprandial triglyceridaemia on VIIc persisted after allowance for the effect of VIIag on VIIc. Dietary fat composition did not influence VIIc or VIIag. The results suggested an acute but evanescent effect of triglyceride-rich lipoproteins on the reactivity of factor VII, irrespective of their lipid core composition.

Antigens↗
PubMed1991

Normal release from proactive interference in untreated patients with Parkinson's disease.

The relationship of release from proactive interference (PI) to set-shifting, explicit free recall and language remains controversial. We tested 56 patients with Parkinson's disease (PD) who had never received medication and 37 matched normal control subjects on a test of PI release based on semantic category. The PD group showed normal PI release but impaired word recall. PI release was independent of impaired Wisconsin card-sorting test performance, language production, explicit memory, overall cognitive status and severity of depression. The results indicate dissociation between ability to benefit from semantic stimulus properties and processes of explicit memory, set-shifting and expressive language.

Attention↗
PubMed1991

Lack of correlation between changes in polyphosphoinositide levels and actin/gelsolin complexes in A431 cells treated with epidermal growth factor.

The polyphosphoinositides, PIP and PIP2, have been proposed to regulate actin polymerization in vivo because they dissociate actin/gelsolin complexes in vitro. We tested this hypothesis by comparing the ability of EGF and bradykinin to affect PI metabolism and the actin cytoskeleton in A431 cells. EGF, but not bradykinin, was found to induce ruffling and dissociation of actin/gelsolin complexes in these cells. However, both EGF and bradykinin stimulated the accumulation of inositol phosphates in [3H]inositol-labeled cells indicating that stimulation of PI turnover is not sufficient for the induction of changes in actin/gelsolin complex levels. EGF stimulated a twofold increase in the level of PIP in A431 cells. Other phosphoinositide levels were not markedly altered. Treatment of the cells with cholera toxin abrogated the EGF-induced rise in PIP levels without altering the dissociation of actin from gelsolin. These data indicate that increases in PIP and/or PIP2 are not necessary for dissociation of actin/gelsolin complexes. Overall, these experiments suggest that in A431 cells, the effects of EGF on the actin cytoskeleton are unlikely to be mediated through changes in PIP or PIP2 levels.

Actins↗
PubMed1991

Functions of the major tyrosine phosphorylation site of the PDGF receptor beta subunit.

Two tyrosine phosphorylation sites in the human platelet-derived growth factor receptor (PDGFR) beta subunit have been mapped previously to tyrosine (Y)751, in the kinase insert, and Y857, in the kinase domain. Y857 is the major site of tyrosine phosphorylation in PDGF-stimulated cells. To evaluate the importance of these phosphorylations, we have characterized the wild-type (WT) and mutant human PDGF receptor beta subunits in dog kidney epithelial cells. Replacement of either Y751 or Y857 with phenylalanine (F) reduced PDGF-stimulated DNA synthesis to approximately 50% of the WT level. A mutant receptor with both tyrosines mutated was unable to initiate DNA synthesis, as was a kinase-inactive mutant receptor. Transmodulation of the epidermal growth factor receptor required Y857 but not Y751. We also tested the effects of phosphorylation site mutations on PDGF-stimulated receptor kinase activity. PDGF-induced tyrosine phosphorylation of two cellular proteins, phospholipase C gamma 1 (PLC gamma 1) and the GTPase activating protein of Ras (GAP), was assayed in epithelial cells expressing each of the mutant receptors. Tyrosine phosphorylation of GAP and PLC gamma 1 was reduced markedly by the F857 mutation but not significantly by the F751 mutation. Reduced kinase activity of F857 receptors was also evident in vitro. Immunoprecipitated WT receptors showed a two- to fourfold increase in specific kinase activity if immunoprecipitated from PDGF-stimulated cells. The F751 receptors showed a similar increase in activity, but F857 receptors did not. Our data suggest that phosphorylation of Y857 may be important for stimulation of kinase activity of the receptors and for downstream actions such as epidermal growth factor receptor transmodulation and mitogenesis.

Animals↗
PubMed1991

Cognitive impairment in early, untreated Parkinson's disease and its relationship to motor disability.

Current knowledge of cognitive dysfunction in Parkinson's disease (PD) has largely been obtained from studies of chronically treated patients in whom effects of disease chronicity, treatment, depression and dementia are confounding factors. Studies of untreated patients have examined few cognitive domains and relationships between cognition, depression and motor disability have been incompletely explored. Accordingly, we studied 60 consecutive patients with newly diagnosed, untreated, idiopathic PD and 37 matched, healthy control subjects; no subject had clinical dementia or depression. All subjects received tests of specific processes of memory and cognition, including working memory, verbal and non-verbal short- and long-term memory, language, visuospatial capacity, set-formation and shifting and sequencing. Patients also received quantitative global clinical measures of severity of dementia, depression and motor disability. The PD group as a whole showed deficits in immediate recall of verbal material, language production and semantic fluency, set-formation, cognitive sequencing and working memory and visuomotor construction. However, this group was unimpaired in immediate memory span, long-term forgetting, naming, comprehension and visual perception. Language deficits and more severe frontal lobe impairments were confined to those PD patients scoring abnormally on a Mini Mental State examination. Motor disability correlated strongly with severity of depression but weakly with cognitive impairment. Cognitive sequencing, set-formation and set-shifting deficits tended to associate with depression, but otherwise there was no association between cognition and depression. The results indicate dissociation of cognition and motor control in early PD which suggests that cognitive dysfunction is largely independent of frontostriatal dopamine deficiency underlying motor disability. Some, but not all, of the frontal lobe deficits of chronic disease are detectable in early, untreated PD. The pathogenesis of the cognitive deficits shown here appears to involve extrastriatal dopamine systems or non-dopaminergic pathology. Longitudinal study is necessary to determine whether increasing disease duration exacerbates the early cognitive deficits and affects new cognitive domains, in addition to producing increasing motor disability.

Adult↗