Search PubMed⌕ Search

Biomedical subjects

A J Flint

Publications and source records attributed to A J Flint.

At least 55 records · Page 3Linked to original sources
PubMed1994

Crystal structure of human protein tyrosine phosphatase 1B.

Protein tyrosine phosphatases (PTPs) constitute a family of receptor-like and cytoplasmic signal transducing enzymes that catalyze the dephosphorylation of phosphotyrosine residues and are characterized by homologous catalytic domains. The crystal structure of a representative member of this family, the 37-kilodalton form (residues 1 to 321) of PTP1B, has been determined at 2.8 A resolution. The enzyme consists of a single domain with the catalytic site located at the base of a shallow cleft. The phosphate recognition site is created from a loop that is located at the amino-terminus of an alpha helix. This site is formed from an 11-residue sequence motif that is diagnostic of PTPs and the dual specificity phosphatases, and that contains the catalytically essential cysteine and arginine residues. The position of the invariant cysteine residue within the phosphate binding site is consistent with its role as a nucleophile in the catalytic reaction. The structure of PTP1B should serve as a model for other members of the PTP family and as a framework for understanding the mechanism of tyrosine dephosphorylation.

Amino Acid Sequence↗
PubMed1994

Epidemiology and comorbidity of anxiety disorders in the elderly.

OBJECTIVE: The author reviewed the epidemiology and comorbidity of anxiety disorders in the elderly. METHOD: Data from 1970 onward were obtained through a computerized literature search, a review of Index Medicus, and the bibliographies of retrieved articles. Eight random-sample community surveys of anxiety disorders in persons 60 years of age or older were identified. Studies relating to the comorbidity of late-life anxiety and depression, dementia, alcoholism, and medical illness were also reviewed. RESULTS: The majority of studies showed that anxiety disorders are less common in the elderly than in younger adults. Generalized anxiety disorder and phobias account for most anxiety in late life; panic disorder is rare. Agoraphobia, and possibly obsessive-compulsive disorder in females, may occur as a primary disorder for the first time in old age, whereas simple phobia, obsessive-compulsive disorder in males, and panic disorder either persist from younger years or arise in the context of another psychiatric or medical disorder. There is considerable comorbidity of geriatric depression and generalized anxiety disorder and phobias, although the depression usually goes untreated or is inappropriately treated with benzodiazepines. The rate of comorbidity of anxiety and medical illness and alcoholism is lower in the elderly than in younger persons. CONCLUSIONS: Epidemiologic data on the prevalence of posttraumatic stress disorder (PTSD) and the first occurrence of generalized anxiety disorder and PTSD in late life are still needed. Further comorbidity studies are needed to determine the extent to which anxiety arises secondary to depression, as well as the optimal treatment and prognosis for this mixed state.

Adult↗
PubMed1994

Recent developments in geriatric psychopharmacotherapy.

This paper highlights recent advances in the pharmacological management of geriatric affective disorders and dementia. The current roles of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) in the treatment of depression in old age are discussed. Recent findings pertaining to continuation and maintenance of antidepressant treatment are also addressed. The treatment of bipolar affective disorder in the elderly has received much less study than has unipolar depression. A number of issues relating to efficacy, side-effects and optimal blood levels of lithium, carbamazepine and valproate in bipolar disorder remain unresolved and await further study. Finally, drug treatment of the cognitive impairment and psychiatric complications of Alzheimer's disease is reviewed.

Aged↗
PubMed1994

A prospective study of lithium augmentation in antidepressant-resistant geriatric depression.

This open, prospective study investigated the efficacy of lithium augmentation in elderly patients who had failed to respond to a 6-week course of antidepressant medication. Twenty-one patients (age range, 64 to 88 years) with DSM-III-R unipolar, nonpsychotic major depression refractory to a 6-week course of nortriptyline, fluoxetine, or phenelzine underwent a minimum of 2 weeks of lithium augmentation. Five patients had a complete response, 3 had a partial response, and 13 did not respond. Half of the patients developed dose-limiting side effects, most commonly neuromuscular or neurologic. Patients developing side effects were significantly older (p = 0.05), and there was a tendency for side effects to occur more frequently in patients treated with fluoxetine. The rate of response to lithium augmentation in this elderly population was lower than that reported for most open and controlled studies in younger patients. Possible reasons for this are discussed.

Aged↗
PubMed1993

Multi-site phosphorylation of the protein tyrosine phosphatase, PTP1B: identification of cell cycle regulated and phorbol ester stimulated sites of phosphorylation.

The non-transmembrane protein tyrosine phosphatase, PTP1B, comprises 435 amino acids, of which the C-terminal 114 residues have been implicated in controlling both localization and function of this enzyme. Inspection of the sequence of the C-terminal segment reveals a number of potential sites of phosphorylation. We show that PTP1B is phosphorylated on seryl residues in vivo. Increased phosphorylation of PTP1B is seen to accompany the transition from G2 to M phase of the cell cycle. Two major tryptic phosphopeptides appear in two-dimensional maps of PTP1B from mitotic cells. One of these comigrates with the peptide generated following phosphorylation of PTP1B in vitro at Ser386 by the mitotic protein Ser/Thr kinase p34cdc2:cyclin B. The site of phosphorylation that is responsible for the pronounced retardation in the electrophoretic mobility of PTP1B from mitotic cells has been identified by site directed mutagenesis as Ser352. The identify of the kinase responsible for this modification is presently unknown. We also show that stimulation of HeLa cells with the phorbol ester TPA enhances phosphorylation of PTP1B. Two dimensional phosphopeptide mapping reveals that the bulk of the phosphate is in a single tryptic peptide. The site, identified as Ser378, is also the site of phosphorylation by protein kinase C (PKC) in vitro. Thus the TPA-stimulated phosphorylation of PTP1B in vivo appears to result directly from phosphorylation by PKC. The effect of phosphorylation on the activity of PTP1B has been examined in immunoprecipitates from TPA-treated and nocodazole-arrested cells. TPA treatment does not appear to affect activity directly, whereas the activity of PTP1B from nocodazole-arrested cells is only 70% of that from asynchronous populations.

Alanine↗
PubMed1993

Homophilic binding of PTP mu, a receptor-type protein tyrosine phosphatase, can mediate cell-cell aggregation.

The receptor-like protein tyrosine phosphatase, PTPmu, displays structural similarity to cell-cell adhesion molecules of the immunoglobulin superfamily. We have investigated the ability of human PTPmu to function in such a capacity. Expression of PTPmu, with or without the PTPase domains, by recombinant baculovirus infection of Sf9 cells induced their aggregation. However, neither a chimeric form of PTPmu, containing the extracellular and transmembrane segments of the EGF receptor and the intracellular segment of PTPmu, nor the intracellular segment of PTPmu expressed as a soluble protein induced aggregation. PTPmu mediates aggregation via a homophilic mechanism, as judged by lack of incorporation of uninfected Sf9 cells into aggregates of PTPmu-expressing cells. Homophilic binding has been demonstrated between PTPmu-coated fluorescent beads (Covaspheres) and endogenously expressed PTPmu on MvLu cells. Additionally the PTPmu-coated beads specifically bound to a bacterially expressed glutathione-S-transferase fusion protein containing the extracellular segment of PTPmu (GST/PTPmu) adsorbed to petri dishes. Covaspheres coated with the GST/PTPmu fusion protein aggregated in vitro and also bound to PTPmu expressed endogenously on MvLu cells. These results suggest that the ligand for this transmembrane PTPase is another PTPmu molecule on an adjacent cell. Thus homophilic binding interactions may be an important component of the function of PTPmu in vivo.

Animals↗
PubMed1993

New onset rapid cycling bipolar disorder in an 87 year old woman.

New onset rapid cycling bipolar disorder is rare in late life. The authors report the case of an 87 year old woman who first developed this disorder at age 82 and was successfully treated with valproate and L-thyroxine. The contribution of aging, hypothyroidism and stroke to the etiology of this woman's disorder is discussed. The pharmacological management of rapid cycling bipolar disorder in the elderly is also reviewed.

Aged↗
PubMed1992

Acoustic analysis in the differentiation of Parkinson's disease and major depression.

In its early stages, Parkinson's disease (P.D.) may be difficult to distinguish from major depression (M.D.) leading to inappropriate management. Both illnesses are characterized by psychomotor retardation. The neurovegetative symptoms used to diagnose M.D. are not specific and in P.D. may be due to the physical illness itself. Currently, differentiation of the two disorders relies on subjective clinical observation. Improved diagnostic accuracy based on more objective data is needed. To this end, this study used computerized acoustic analysis to contrast speech patterns in P.D. and M.D. The sample consisted of 30 P.D. patients without depression or dementia, 30 patients with uncomplicated M.D., and 31 normal controls, each 60 years of age or over. Of the acoustic variables studied, M.D. patients had significantly reduced rates of speech compared with P.D. patients. The data suggest that this temporal measure of speech may be useful in the differentiation of P.D. and M.D.

Aged↗
PubMed1992

Behavioural disturbances in the demented elderly: phenomenology, pharmacotherapy and behavioural management.

Behavioural disturbances in the demented elderly cause a significant amount of distress both to the patients and their caregivers. This article first summarizes the phenomenology associated with these disturbances. It then deals with the pharmacological methods of reducing these disturbances. Finally, it deals with some of the more recent advances in combining the insights of behavioural modification with those of neuropsychology in finding non pharmacological methods of reducing problematic behaviours. It is stressed that a combination of the two approaches is most likely to be required, and most likely to be successful, in the individual case.

Aged↗
PubMed1991

Delusions in dementia: a review.

A number of psychiatric phenomena complicate dementia. The author suggests that if we are to understand and manage these noncognitive, neuropsychiatric manifestations, they need to be studied individually rather than in a global fashion. As one example of these phenomena, delusions complicating dementia are reviewed. Nosology, phenomenology, epidemiology, clinical characteristics, treatment, and course are discussed. Ideas for future research are suggested.

Alzheimer Disease↗
PubMed1990

Autophosphorylation of protein kinase C at three separated regions of its primary sequence.

The major autophosphorylation sites of the rat beta II isozyme of protein kinase C were identified. The modified threonine and serine residues were found in the amino-terminal peptide, the carboxyl-terminal tail, and the hinge region between the regulatory lipid-binding domain and the catalytic kinase domain. Because this autophosphorylation follows an intrapeptide mechanism, extraordinary flexibility of the protein is necessary to phosphorylate the three regions. Comparison of the sequences surrounding the modified residues showed no obvious recognition motif nor any similarity to substrate phosphorylation sites, suggesting that proximity to the active site may be the primary criterion for their phosphorylation.

Amino Acid Sequence↗
PubMed1988

Frontal lobe syndrome and depression in old age.

Frontal systems disorder can easily be misdiagnosed as depression, since patients may present with similar symptoms. Two cases are reported that illustrate the confusing features of the two disorders. Characteristics that help differentiate frontal systems disorder from depression include: patients are apathetic rather than deeply depressed; personality changes are more dramatic than those that occur in depression; and insight and judgement are usually impaired.

Aged↗
PubMed1987

Compensatory regulation in metabolic pathways--responses to increases and decreases in citrate synthase levels.

The level of citrate synthase was varied in Escherichia coli by recombinant DNA methods to elucidate regulatory interactions between the individual steps of the citric acid cycle. The effects of overproduction and underproduction of citrate synthase were assessed by measuring metabolite levels, rates of carbon flow, the phosphorylation state of isocitrate dehydrogenase, and the growth rate of the culture. This analysis revealed that the levels of citrate synthase and isocitrate dehydrogenase activity are co-ordinated for efficient growth on acetate. When citrate synthase was overproduced the isocitrate dehydrogenase reaction became rate limiting and prevented large increases in the flux through the citric acid cycle. Furthermore, changes in the level of citrate synthase were found to modulate the phosphorylation state of isocitrate dehydrogenase which regulates the distribution of carbon flow between the citric acid cycle and the glycoxylate shunt. These adjustments allowed the organism to maintain a relatively constant metabolic state despite changes in the level of a central metabolic enzyme. The interplay between citrate synthase and isocitrate dehydrogenase illustrates how living systems can compensate for variations in their internal environment.

Acetates↗
PubMed1985

Concomitant purification of three porcine heart mitochondrial enzymes: citrate synthase, aspartate aminotransferase, and malate dehydrogenase.

The mitochondrial enzymes citrate synthase, malate dehydrogenase, and aspartate aminotransferase were purified to homogeneity from porcine hearts by use of Bio-Rex 70, carboxymethylcellulose CM32, and Affi-Gel blue chromatography. This procedure provides relatively rapid, large-scale preparation of the three enzymes based on their differential binding to commercially available cation-exchange resins followed by a final affinity chromatography step.

Ammonium Sulfate↗
PubMedDate not supplied

Black-white differences in cigarette smoking uptake: progression from adolescent experimentation to regular use.

BACKGROUND: More U.S. adolescents and young adults have initiated cigarette smoking in recent years. Blacks have been less likely than whites to start smoking, and the gap has widened recently. Reasons accounting for this large black-white difference remain unclear. METHODS: A multiple logistic regression analysis was performed using a cohort of 2,467 adolescent smoking experimenters ages 11-18, within the 1989-1993 Teenage Attitudes and Practices Survey, a nationally representative survey. RESULTS: Among experimenters (1989), 25.7% of whites and 10.3% of blacks had progressed to current smoking (1993). The unadjusted odds ratio (OR) of progression for blacks (vs whites) was 0.33 [95% confidence interval (CI) 0.23, 0.48]. Adjustment for factors significantly predictive of progression (most parsimonious model) modified the black-white OR to 0.36 (CI 0.24, 0.55), while the full model yielded a black-white OR of 0.39 (CI 0.24, 0.66). CONCLUSIONS: The observed black-white difference in smoking progression was only partly explained by the factors evaluated, and some additional factor(s) must be important. Understanding the black-white difference in the progression from experimentation to current smoking may help prevent uptake among all adolescents.

Adolescent↗