Biomedical subjects

A J Flint

Publications and source records attributed to A J Flint.

At least 19 recordsLinked to original sources

PubMed2001

Nonresponse to first-line pharmacotherapy may predict relapse and recurrence of remitted geriatric depression.

The authors examined whether nonresponse to first-line pharmacotherapy was associated with an increased probability of relapse or recurrence following remission of an episode of geriatric depression. The study group consisted of 74 elderly patients whose index episode of nonpsychotic unipolar major depression had responded to antidepressant pharmacotherapy. In 6 of these patients, the depressive episode had not responded to first-line pharmacotherapy (8 weeks of nortriptyline, including 2 weeks of adjunctive lithium) but it had responded to second-line treatment (phenelzine with or without adjunctive lithium). The 74 patients were maintained on acute doses of the medications that had led to response and were followed for 2 years or until relapse or recurrence, whichever occurred first. The cumulative probability of relapse or recurrence was 67% for patients who responded to second-line treatment compared with 18% for patients who responded to first-line treatment (P = 0.0003). As expected, mean time to response was significantly longer for patients who responded to second-line treatment but this factor did not account for the difference in outcome between the two groups. These findings suggest that pharmacotherapy resistance may constitute a risk factor for relapse or recurrence of remitted geriatric depression, even when patients are maintained on the medication that they eventually respond to.

Aged↗

PubMed2000

Neurohormonal responses to cholecystokinin tetrapeptide: a comparison of younger and older healthy subjects.

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 microg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.

Adrenocorticotropic Hormone↗

PubMed2000

Maintenance treatment for recurrent depression in late life. A four-year outcome study.

The authors examined the 4-year outcome of elderly patients who were given open-label maintenance treatment for recurrent depression. Thirty-eight patients, age 60 years or older, who had recovered from an episode of recurrent nonpsychotic unipolar major depression were maintained on full-dose antidepressant medication and, if necessary, adjunctive lithium. They were followed on a regular basis for 4 years or until recurrence, whichever occurred first. The cumulative probability of remaining well without recurrence was 70%. Longer time to respond to treatment and higher anxiety scores at the time of response predicted shorter time to recurrence.

Aged↗

PubMed1999

Recurrence of first-episode geriatric depression after discontinuation of maintenance antidepressants.

OBJECTIVE: Later age at onset of depression appears to be a risk factor for early recurrence. Therefore, the authors examined the 2-year outcomes of elderly patients with first-episode major depression following discontinuation of their maintenance antidepressant medication. METHOD: The study group consisted of 21 elderly patients who had recovered from a first lifetime episode of major depression. They had taken maintenance antidepressant medication for 2 years and had not had a relapse or recurrence during that time. The antidepressant was then withdrawn, and patients were followed for another 2 years or until recurrence, whichever occurred first. RESULTS: The cumulative probability of suffering a recurrence of major depression was 61%. Eleven of the 12 patients who suffered a recurrence restarted the antidepressant, and 10 responded. CONCLUSIONS: Elderly patients with first-episode major depression were at high risk of recurrence following discontinuation of maintenance antidepressant medication. However, the vast majority of patients who experienced a recurrence responded to reinstated treatment.

Aged↗

PubMed1999

Anxiety disorders in late life.

OBJECTIVE: To review the epidemiology, clinical characteristics, and treatment of anxiety disorders in late life. QUALITY OF EVIDENCE: Epidemiologic and comorbidity data are derived from well designed random-sample community surveys. There are virtually no controlled data specific to treatment of anxiety in the elderly. Guidelines for treating anxiety disorders in late life, therefore, must be extrapolated from results of randomized controlled trials conducted in younger patients. MAIN MESSAGE: Generalized anxiety disorder and agoraphobia account for most cases of anxiety disorder in late life. Late-onset generalized anxiety is usually associated with depressive illness and, in this situation, the primary pharmacologic treatment is antidepressant medication. Most elderly people with agoraphobia do not give a history of panic attacks; exposure therapy is the preferred treatment for agoraphobia without panic. CONCLUSIONS: Physicians need to make more use of antidepressant medication and behavioural therapy and less use of benzodiazepines in treating anxiety disorders in late life.

Agoraphobia↗

PubMed1998

Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by x-ray crystallography.

Protein-tyrosine phosphatases (PTPs) are signal transduction enzymes that catalyze the dephosphorylation of phosphotyrosine residues via the formation of a transient cysteinyl-phosphate intermediate. The mechanism of hydrolysis of this intermediate has been examined by generating a Gln-262 --> Ala mutant of PTP1B, which allows the accumulation and trapping of the intermediate within a PTP1B crystal. The structure of the intermediate at 2.5-A resolution reveals that a conformationally flexible loop (the WPD loop) is closed over the entrance to the catalytic site, sequestering the phosphocysteine intermediate and catalytic site water molecules and preventing nonspecific phosphoryltransfer reactions to extraneous phosphoryl acceptors. One of the catalytic site water molecules, the likely nucleophile, forms a hydrogen bond to the putative catalytic base, Asp-181. In the wild-type enzyme, the nucleophilic water molecule would be coordinated by the side chain of Gln-262. In combination with our previous structural data, we can now visualize each of the reaction steps of the PTP catalytic pathway. The hydrolysis of the cysteinyl-phosphate intermediate of PTPs is reminiscent of GTP hydrolysis by the GTPases, in that both families of enzymes utilize an invariant Gln residue to coordinate the attacking nucleophilic water molecule.

Crystallography, X-Ray↗

PubMed1998

The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval development.

Src homology-2 (SH2) domain-containing protein tyrosine phosphatases (SHPs) have been identified as either positive or negative regulators of signaling events downstream of receptor protein tyrosine kinases (R-PTKs). We describe here our characterization of ptp-2, a Caenorhabditis elegans gene that encodes a 668-amino-acid SHP. We isolated a recessive ptp-2 loss-of-function allele, op194, that lacks the conserved protein tyrosine phosphatase catalytic domain by screening for transposon-mediated deletion mutations. Homozygous ptp-2(op194) hermaphrodites exhibit a completely penetrant zygotic semisterile/maternal effect lethal phenotype, characterized by the presence of abnormally large oocytes in the zygotic semisterile animals. These phenotypes indicate that PTP-2 activity is essential for proper oogenesis. Gain-of-function let-60 ras alleles rescued the defects associated with ptp-2(op194), suggesting that LET-60 Ras acts downstream of, or in parallel to, PTP-2 during oogenesis. Although ptp-2 function is not required for normal vulval development, ptp-2(op194) altered significantly the vulval phenotypes caused by mutations in several genes of the inductive signaling pathway. The penetrance of the multivulva phenotype caused by loss-of-function mutations in lin-15, and gain-of-function mutations in let-23 or let-60 ras, was reduced by ptp-2(op194). Moreover, ptp-2(op194) increased the penetrance of the vulvaless phenotype conferred by a weak loss-of-function sem-5 allele. Taken together, our genetic data positions PTP-2 activity downstream of LET-23 in the vulval induction signaling pathway. Although PTP-2 functions to transmit a requisite signal during oogenesis, PTP-2 function during C. elegans vulval cell differentiation appears to be directed at regulating the overall strength of the inductive signal, which may contribute to the quantitative differences in signaling required for the proper specification of the 1 degrees , 2 degrees , and 3 degrees vulval cell fates.

Alleles↗

PubMed1998

Trends in black/white differences in current smoking among 18- to 24-year-olds in the United States, 1983-1993.

OBJECTIVES: A study was undertaken to analyze the independent relationship between race (black/white) and cigarette smoking among 18- to 24-year-olds in the United States, 1983-1993. METHODS: An 11-year analysis of cross-sectional national surveys was used in the study. Odds ratio for current smoking among black-surveyed subjects (vs. whites) was determined. RESULTS: The multiple logistic regression-derived odds ratio (OR) for current smoking for blacks aged 18 to 24 years, vs. whites, decreased from 0.69 (95% CI 0.53, 0.89) in 1983 to 0.26 (95% CI 0.17, 0.42) in 1993. The combined-years model predicted a decrease in OR for blacks from 0.82 in 1983 to 0.30 in 1993, adjusted for sex, age, education, poverty status, and geographic region. CONCLUSION: From 1983 to 1993, blacks aged 18 to 24 years became decreasingly at risk to be smokers, compared to whites, even after adjustment for confounding factors. Young blacks have been more resistant than young whites to begin smoking in recent years. Understanding reasons behind this widening black/white difference could lead to better prevention strategies.

Adolescent↗

PubMed1998

Protein tyrosine phosphatase 1B antagonizes signalling by oncoprotein tyrosine kinase p210 bcr-abl in vivo.

The p210 bcr-abl protein tyrosine kinase (PTK) appears to be directly responsible for the initial manifestations of chronic myelogenous leukemia (CML). In contrast to the extensive characterization of the PTK and its effects on cell function, relatively little is known about the nature of the protein tyrosine phosphatases (PTPs) that may modulate p210 bcr-abl-induced signalling. In this study, we have demonstrated that expression of PTP1B is enhanced specifically in various cells expressing p210 bcr-abl, including a cell line derived from a patient with CML. This effect on expression of PTP1B required the kinase activity of p210 bcr-abl and occurred rapidly, concomitant with maximal activation of a temperature-sensitive mutant of the PTK. The effect is apparently specific for PTP1B since, among several PTPs tested, we detected no change in the levels of TCPTP, the closest relative of PTP1B. We have developed a strategy for identification of physiological substrates of individual PTPs which utilizes substrate-trapping mutant forms of the enzymes that retain the ability to bind to substrate but fail to catalyze efficient dephosphorylation. We have observed association between a substrate-trapping mutant of PTP1B (PTP1B-D181A) and p210 bcr-abl, but not v-Abl, in a cellular context. Consistent with the trapping data, we observed dephosphorylation of p210 bcr-abl, but not v-Abl, by PTP1B in vivo. We have demonstrated that PTP1B inhibited binding of the adapter protein Grb2 to p210 bcr-abl and suppressed p210 bcr-abl-induced transcriptional activation that is dependent on Ras. These results illustrate selectivity in the effects of PTPs in a cellular context and suggest that PTP1B may function as a specific, negative regulator of p210 bcr-abl signalling in vivo.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Two-year outcome of psychotic depression in late life.

OBJECTIVE: The purpose of this study was to determine whether elderly patients with psychotic depression differed in long-term outcome from patients with nonpsychotic depression. METHOD: The study group consisted of 19 patients with psychotic major depression who had responded to ECT (N = 15), nortriptyline and perphenazine (N = 2), or nortriptyline, perphenazine, and adjunctive lithium (N = 2) and 68 nonpsychotic depressed patients who had responded to either nortriptyline alone (N = 61) or nortriptyline and lithium (N = 7). All patients were maintained on regimens of full-dose nortriptyline. When prescribed for the index episode, adjunctive lithium was also maintained, but perphenazine was withdrawn 16 weeks after response. Patients were followed on a monthly basis for 2 years or until relapse or recurrence, whichever occurred first. RESULTS: Patients with psychotic depression had a substantially higher frequency of relapse or recurrence of depression and a shorter time to these events than nonpsychotic depressed patients. At index assessment, patients with psychosis were more severely depressed and had had more prior episodes of depression, but these factors did not account for the difference in outcome between the two groups. Furthermore, before entering the study, none of the psychotic patients had received adequate treatment for the index episode of depression, and so their poor outcome could not be attributed to prior treatment resistance. CONCLUSIONS: Even when they achieved remission and were maintained on a regimen of full-dose antidepressant medication, older patients with psychotic depression were at greater risk of relapse or recurrence than were their nonpsychotic counterparts. In particular, continuation/maintenance treatment with tricyclic monotherapy following response to ECT had limited efficacy in this group of patients. These findings raise important questions about the optimal treatment of psychotic depression in late life.

Age Factors↗

PubMed1998

Effect of aging on cholecystokinin-induced panic.

OBJECTIVE: Epidemiologic surveys have found that the incidence and prevalence of panic disorder decline in later life. The goal of this study was to determine whether aging has an effect on healthy subjects' responses to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). METHOD: The study used a double-blind, placebo-controlled design: 40 subjects 20-35 years old and 40 subjects 65 years old or older were randomly assigned to receive an intravenous bolus of either 50 micrograms of CCK-4 or normal saline. RESULTS: When given CCK-4, older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less of an increase in heart rate than did younger subjects. CONCLUSIONS: This study found an age-related change in responsiveness to CCK-4. Further research to delineate the mechanism of this change is warranted.

Adult↗

PubMed1998

Functional impairment associated with acute poststroke depression: the Stroke Data Bank Study.

To examine the independent association of depression following acute stroke with impairment in activities of daily living (ADL), the authors conducted a cross-sectional analysis of stroke patients enrolled in the Stroke Data Bank (U.S.A.) who had completed the Center for Epidemiological Studies Depression Scale (CES-D). Scores on the Barthel Index, a measure of ADL, were compared between depressed (CES-D > or = 16) and nondepressed patients (CES-D < or = 15) at 7-10 days after stroke. Of the 626 who completed CES-D, 160 were depressed. Depressed stroke patients evidenced greater impairment in ADL than nondepressed patients, independently of all other factors that influenced poststroke physical disabilities. CES-D scores were negatively correlated with Barthel scores in the entire stroke population. Neurological factors, greater age, poor prestroke physical activity, and prestroke disturbances in sexual functioning were also independently associated with limitations in functional status of stroke patients.

Activities of Daily Living↗

PubMed1998

The pharmacologic treatment of Alzheimer's disease: a guide for the general psychiatrist.

OBJECTIVE: To review the drug treatment of Alzheimer's disease (AD) and to provide guidelines for the physician on how to integrate these treatments into the overall management of this disorder. METHOD: A qualitative review of randomized, double-blind, placebo-controlled trials of medications used to treat cognitive deficits, disease progression, agitation, psychosis, or depression in AD. A computerized search of Medline was used to identify relevant literature published during the period 1968-1998. Key words used in the search were 'randomized controlled trials,' with 'dementia' and with 'Alzheimer's disease'. RESULTS: Agents that are currently available in Canada to treat the cognitive deficits of AD include donepezil, ginkgo biloba, selegiline, and ergoloid mesylates. Donepezil and ginkgo biloba are associated with a statistically significant but clinically modest improvement in cognitive function in a substantial minority of patients with mild to moderate AD. Selegiline may have a mild beneficial effect on cognitive function in some patients with AD, but the data are inconclusive. Ergoloid mesylates have questionable efficacy in AD and can only be recommended as a last line of treatment. The results of a single trial suggest that vitamin E or selegiline (both have antioxidant properties) may slow the progression of AD. Antipsychotic medications can result in clinically significant improvement in agitation and psychosis. Carbamazepine also appears to be an effective treatment for agitation in AD, and there is preliminary evidence that the selective serotonin reuptake inhibitor citalopram reduces irritability in this disorder. There is no evidence that other nonneuroleptic medications are more efficacious than placebo in treating agitation in AD. Limited data indicate that depression in dementia responds to antidepressant medication. CONCLUSION: These data indicate that selected medications can be used to treat cognitive deficits, disease progression, agitation, psychosis, and depression in AD. However, there is considerable heterogeneity in patients' responses to these medications. Pharmacotherapy needs to be considered as a component of a package of care that also includes psychosocial and environmental interventions and support of the caregiver.

Aged↗

PubMed1998

Management of anxiety in late life.

Epidemiologic data are used as a framework to discuss the pharmacologic and cognitive-behavioral management of anxiety disorders in late life. Generalized anxiety disorder (GAD) and phobias account for most cases of anxiety in late life. The high level of comorbidity between GAD and major depression, and the observation that the anxiety usually arises secondarily to the depression, suggests that antidepressant medication should be the primary pharmacologic treatment for many older people with GAD. Most individuals with late-onset agoraphobia do not have a history of panic attacks and the illness often starts after a traumatic event. Exposure therapy is the treatment of choice for agoraphobia without panic. It is uncommon for obsessive-compulsive disorder (OCD) and panic disorder to start for the first time in old age, but these disorders can persist from younger years into late life. Case reports and uncontrolled case series suggest that elderly people with OCD or panic disorder can benefit from pharmacologic and cognitive-behavioral treatments that are known to be effective in younger patients. However, it is not known whether the rate of response among elderly patients is adversely affected by the chronicity of these disorders. The prevalence and incidence of post-traumatic stress disorder in late life are not known. Uncontrolled data support the use of selective serotonin reuptake inhibitors in war veterans with chronic symptoms of post-traumatic stress disorder; other treatments for this condition await evaluation in the elderly.

Aged↗

PubMed1998

Choosing appropriate antidepressant therapy in the elderly. A risk-benefit assessment of available agents.

This article discusses the advantages and disadvantages of tricyclic antidepressants (TCAs), tetracyclic antidepressants (i.e. mianserin), selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), triazolopyridines (i.e. trazodone), phenylpiperazines (i.e. nefazodone), serotonin and noradrenaline (norepinephrine) reuptake inhibitors (i.e. venlafaxine), and aminoketones [i.e. amfebutamone (bupropion)] in the treatment of late-life depression. A limitation of the existing literature is that most data regarding drugs are derived from studies that have involved medically stable outpatients who do not have dementia and who are less than 80 years of age. There is a paucity of data on the use of antidepressants in very elderly individuals, patients who have significant medical comorbity and patients with dementia or other neurological problems. No one class of antidepressant has been found to be more effective than another in the acute treatment of geriatric major depression. However, given design short-comings in many of these studies, the possibility of a real difference in efficacy between drugs (especially in the treatment of severe or melancholic depression) cannot be excluded. With respect to adverse effects, drug interactions, and dosage and administration, each class of antidepressant has its benefits and limitations. There is no one 'first-line' antidepressant for elderly patients with depression. Selection of an antidepressant should be made on a case by case basis, taking into account each patient's characteristics.

Aged↗

PubMed1998

The treatment of psychotic depression in later life: a comparison of pharmacotherapy and ECT.

OBJECTIVE: Response to combination pharmacotherapy and to electroconvulsive therapy (ECT) was evaluated in elderly patients with psychotic depression. METHOD: Twenty-five patients, aged 60 years and older, with DSM-III-R unipolar psychotic major depression, were treated in an open, non-randomized fashion with either 6 weeks of nortriptyline and perphenazine (N = 8) or ECT (N = 17). Response was defined as a Hamilton score of < or = 10 and the absence of delusions and hallucinations. Patients who failed to respond to combined antidepressant-antipsychotic medication underwent 2 weeks of lithium augmentation. RESULTS: Two (25.0%) patients responded to the first 6 weeks of pharmacotherapy whereas 15 (88.2%) patients responded to ECT (Fisher's exact test, p = 0.004). Even after lithium augmentation, there was a trend for patients to be less responsive to medication than to ECT (50.0% versus 88.2%, Fisher's exact test, p = 0.059). Survival analysis, based on 8 weeks of observation, demonstrated that patients took longer to respond to pharmacotherapy than to ECT (mean (SE) of 7(0) weeks versus 4(0) weeks; log rank chi2 = 10.43, df = 1, p = 0.001). CONCLUSIONS: We found that elderly patients with psychotic depression had a significantly lower frequency of response to nortriptyline and perphenazine than to ECT. However, patients responded more slowly to pharmacotherapy than to ECT and longer duration of treatment may have improved the outcome of the medication group. These findings suggest the need for a randomized controlled trial comparing the efficacies of drug treatment and ECT in late life psychotic depression.

Age Distribution↗

PubMed1997

Pharmacologic treatment of depression in late life.

A number of age-related factors, including changes in pharmacokinetics and pharmacodynamics, medical comorbidity and an increased risk of drug-drug interaction, can complicate the pharmacologic management of depression in late life. Nevertheless, over 80% of elderly depressed patients will eventually respond to vigorous treatment and, when treated over 2 years, up to 75% of those will not have a relapse or recurrence of depression. This article reviews a number of issues relating to the pharmacotherapy of depression in elderly people. In particular, it discusses the similarities and differences between various antidepressant medications, issues pertaining to dosing and length of treatment, and management of the patient who does not respond to first-line treatment. The author emphasizes that, because of the high risk of relapse and recurrence, a long-term collaboration between the patient and the physician is required to successfully manage depression in late life.

Aged↗

PubMed1997

Association of the T-cell protein tyrosine phosphatase with nuclear import factor p97.

Alternative splicing of the T-cell protein tyrosine phosphatase (TCPTP) transcript generates two forms of the enzyme that differ at their extreme C termini: a 48-kDa endoplasmic reticulum-associated form and a 45-kDa nuclear form. By affinity chromatography, using GST-TCPTP fusion proteins, we have isolated three cytoplasmic proteins of 120, 116, and 97 kDa that interact with TCPTP. The p120 protein associated with residues 377-415 from the C terminus of the 48-kDa form of TCPTP, whereas the recognition site for p97 and p116 was mapped to residues 350-381 encompassing the TCPTP nuclear localization sequence (NLS). The TCPTP NLS was shown to be bipartite, requiring basic residues 350-358 (basic cluster I) and 377-381 (basic cluster II), the sites of interaction with p97 and p116, for efficient nuclear translocation. The interaction between p97, p116, and the TCPTP NLS appeared unique in that these proteins did not form a stable interaction with the classical NLS of SV40 large T antigen or the standard bipartite NLS of nucleoplasmin. Sequence analysis of p97 identified it as the nuclear import factor p97 (importin-beta), which is an essential component of the nuclear import machinery. In assays in vitro in permeabilized cells, p97 was necessary but not sufficient for optimal nuclear import of TCPTP. We found that TCPTP co-immunoprecipitated with the nuclear import factor p97 from cell lysates and that purified recombinant p97 and TCPTP interacted directly in vitro. These results indicate selectivity in the binding of p97 and p116 to the TCPTP NLS and suggest that p97 may mediate events that are distinct from the classical nuclear import process. Moreover, these results demonstrate that the C-terminal segment of TCPTP contains docking sites for interaction with proteins that may function to target the enzyme to defined intracellular locations and in the process regulate TCPTP function.

3T3 Cells↗