Biomedical subjects

Philip Mitchell

Publications and source records attributed to Philip Mitchell.

27 records · Page 2Linked to original sources

PubMed2003

An NMD pathway in yeast involving accelerated deadenylation and exosome-mediated 3'-->5' degradation.

Eukaryotic mRNAs containing premature termination codons are subjected to accelerated turnover, known as nonsense-mediated decay (NMD). Recognition of translation termination events as premature requires a surveillance complex, which includes the RNA helicase Upf1p. In Saccharomyces cerevisiae, NMD provokes rapid decapping followed by 5'-->3' exonucleolytic decay. Here we report an alternative, decapping-independent NMD pathway involving deadenylation and subsequent 3'-->5' exonucleolytic decay. Accelerated turnover via this pathway required Upf1p and was blocked by the translation inhibitor cycloheximide. Degradation of the deadenylated mRNA required the Rrp4p and Ski7p components of the cytoplasmic exosome complex, as well as the putative RNA helicase Ski2p. We conclude that recognition of NMD substrates by the Upf surveillance complex can target mRNAs to rapid deadenylation and exosome-mediated degradation.

3' Untranslated Regions↗

PubMed2003

Valid assessment of the clinical features of depression by relatives appears to slip under the RADAR.

OBJECTIVE: We report on the development of an observational measure designed for completion by relatives, the Recent Appearance of Depression Assessed by Relatives (RADAR), and consider its validity. METHOD: One hundred and one patients with a current major depressive episode had a relative or close friend complete the RADAR, while psychiatrists and research assistants collected extensive data. RESULTS: Correlated against both patient self-report and psychiatrist-rated depression severity measures, RADAR scores evidenced poor validity overall. Recent Appearance of Depression Assessed by Relatives scores also failed to differentiate depressive subtypes, in that scores for patients with melancholic depression were not significantly higher than for those with non-melancholic depression. CONCLUSIONS: Results are consistent with previous findings of poor agreement between clinicians and corroborative witnesses in assessing clinical depressive features, and argue against reliance on corroborative witness reports.

Adult↗

PubMed2003

Schema-focused cognitive therapy for bipolar disorder: reducing vulnerability to relapse through attitudinal change.

OBJECTIVE: Acceptance of, and adaptability to illness, are major determinants of adherence to treatment and functional recovery. This paper addresses the major psychosocial factors associated with bipolar disorder and the role of psychological interventions in symptom management and adaptability to the illness experience. A new model is presented highlighting the role of developmental experiences and temperament in determining reactions to bipolar disorder. The authors propose that by addressing reactions to the illness experiences and effects on self-concept through schema-focused cognitive therapy, functional recovery is more likely to occur among those patients functioning below expectation. METHOD: A systematic review of the current literature including an Index Medicus/MEDLINE search was conducted, focusing on risk factors, cognitive vulnerabilities and triggers associated with bipolar disorder. Psychological treatments available for the treatment of bipolar disorder are reviewed and details of a novel schema-focused cognitive model for this condition are presented. Traditional models of adaptation to chronic illness are outlined and incorporated into the proposed model. Schema-focused cognitive therapy is proposed as an approach to help patients reduce cognitive vulnerability to relapse in addition to adopting effective mood management strategies. RESULTS AND CONCLUSIONS: There is a need for psychological treatments which reduce the risks associated with poor functionality in patients with bipolar disorder. Schema-focused cognitive therapy specifically targets the temperament, developmental experiences and cognitive vulnerabilities that determine adjustment to illness. This proposed treatment, combined with pharmacotherapy, may offer new psychotherapeutic options for the future.

Adaptation, Psychological↗

PubMed2003

Use of antidepressants by general practitioners and psychiatrists in Australia.

OBJECTIVE: To examine the antidepressant prescribing patterns of psychiatrists and general practitioners (GPs) in Australia, focusing specifically on: the prescribed daily dose, the relative proportions (from subsidized dispensing data) of prescriptions written, and how these proportions change over time for a newly listed antidepressant drug (using paroxetine as an example). METHOD: Retrospective analyses of subsidized claims data (comprising nearly 90% of the community supply of antidepressants) and prescriber surveys. RESULTS: General practitioners prescribe 86% of subsidized antidepressants in Australia. Almost three-quarters of the antidepressant prescriptions prescribed in primary care management are also initiated by a GP. Psychiatrists prescribed higher doses than general practitioners for all the antidepressants examined. For paroxetine, a higher than average proportion of scripts were written by psychiatrists when the drug was initially available and it only reached the GP/psychiatrist split seen with an established drug in the same therapeutic class (fluoxetine) four years after marketing. The most prominent type of depression that GPs believed they were treating was 'chronic mild depression', which contrasts with the subsidized indication for all newer antidepressant classes of 'major depressive disorders'. CONCLUSIONS: General practitioners are the major providers of treatment for depression in Australia. When writing prescriptions for tricyclic antidepressants GPs use doses lower than those recommended for major depression, however, most management in primary care is not for conditions regarded by the GP as major depression. A significant number of prescriptions for the newer antidepressants may not accord with the Pharmaceutical Benefits Scheme (PBS) restrictions for use.

Antidepressive Agents↗

PubMed2003

Neuropsychological performance in patients with depression is associated with clinical, etiological and genetic risk factors.

The present study explores neuropsychological functioning in patients with depression with reference to key clinical, etiological and genetic features. In comparison to healthy volunteers, patients with severe depression demonstrated poorer performance on all neuropsychological tests except for WAIS-R Vocabulary and a 64-item computerized version of the Wisconsin Card Sorting Test. On average, patients exhibited significant impairments (greater than -2 standard deviation units) on tests of simple reaction time, Part B of the Trail Making Test and Raven's Colored Progressive Matrices. When performance decrements were analyzed with reference to key clinical features, patients with melancholia performed more poorly on WAIS-R Vocabulary, semantic fluency and choice reaction time than those with nonmelancholic depression. After controlling for age, those patients with late-onset depression (i.e., age of onset > or =50 years) exhibited poorer performance on a computerized version of the Tower of London test in comparison to those with an early onset. While there was no relationship between neuropsychological test scores and summed vascular risk factors or apolipoprotein E genotypes, presence of the methylenetetrahydrofolate reductase gene mutation was associated with slowed reaction time. The differential relationships between clinical, etiological and genetic risks and neuropsychological performance supports the presence of unique pathophysiological mechanisms in distinct subgroups of patients. These findings underscore the need to consider subtypes when investigating neuropsychological deficits in patients with depression.

Adult↗

PubMed2003

Rrp47p is an exosome-associated protein required for the 3' processing of stable RNAs.

Related exosome complexes of 3'-->5' exonucleases are present in the nucleus and the cytoplasm. Purification of exosome complexes from whole-cell lysates identified a Mg(2+)-labile factor present in substoichiometric amounts. This protein was identified as the nuclear protein Yhr081p, the homologue of human C1D, which we have designated Rrp47p (for rRNA processing). Immunoprecipitation of epitope-tagged Rrp47p confirmed its interaction with the exosome and revealed its association with Rrp6p, a 3'-->5' exonuclease specific to the nuclear exosome fraction. Northern analyses demonstrated that Rrp47p is required for the exosome-dependent processing of rRNA and small nucleolar RNA (snoRNA) precursors. Rrp47p also participates in the 3' processing of U4 and U5 small nuclear RNAs (snRNAs). The defects in the processing of stable RNAs seen in rrp47-Delta strains closely resemble those of strains lacking Rrp6p. In contrast, Rrp47p is not required for the Rrp6p-dependent degradation of 3'-extended nuclear pre-mRNAs or the cytoplasmic 3'-->5' mRNA decay pathway. We propose that Rrp47p functions as a substrate-specific nuclear cofactor for exosome activity in the processing of stable RNAs.

3' Untranslated Regions↗

PubMed2002

Caudate nucleus volumes and genetic determinants of homocysteine metabolism in the prediction of psychomotor speed in older persons with depression.

OBJECTIVE: The authors sought to determine whether caudate nucleus volumes or specific genotypes predict psychomotor slowing in older persons with depression. METHOD: Forty-seven persons with depression (mean age=51.8 years, SD=12.4) and 20 healthy volunteers (mean age=56.1 years, SD=9.8) underwent clinical assessments, a neuropsychological test of psychomotor speed (part A of the Trail Making Test), high-resolution magnetic resonance imaging scans, and genotyping for the apolipoprotein E epsilon4 allele and a mutation of the methylenetetrahydrofolate reductase enzyme. RESULTS: Multivariate analyses revealed that psychomotor speed was uniquely predicted by age, a diagnosis of depression, right caudate nucleus volume, and mutation of the methylenetetrahydrofolate reductase enzyme. CONCLUSIONS: Psychomotor slowing, a key clinical and cognitive phenomenon in older persons with depression, is predicted by reduced caudate nucleus volumes and genetic determinants of homocysteine metabolism.

Adult↗

PubMed2002

Atypical depression: a reappraisal.

OBJECTIVE: The study evaluated the DSM-IV definition of the atypical features specifier for a major depressive episode in major depressive disorder. METHOD: Nonpsychotic patients with major depressive disorder were assessed to determine if the DSM-IV model and decision rules for the atypical features specifier for a major depressive episode could be supported. RESULTS: The five clinical features of the DSM-IV atypical features specifier for a major depressive episode showed weak internal consistency, and the mandatory criterion A feature of mood reactivity did not show specificity in relation to any of the four criterion B accessory symptoms. The more severe the depression, the less likely the patient was to report criterion A and hence to meet criteria for the atypical features specifier. Remodeling the five features favored the personality style descriptor of interpersonal rejection sensitivity as an alternate primary feature. A reformulated model also suggested lifetime panic disorder and social phobia as higher-order determinants of atypical features in major depressive disorder. Additional analyses of criteria suggested that interpersonal rejection sensitivity and leaden paralysis had a phenomenological base in anxiety, that mood reactivity was linked with irritability, and that neither weight gain nor hypersomnia were clearly aligned with anxiety or depression, raising questions about their status as symptoms. CONCLUSIONS: The current definition and modeling of the DSM-IV atypical features specifier for a major depressive episode in major depressive disorder appears problematic. As suggested by earlier descriptions of atypical depression, certain expressions of anxiety may have primacy, and some clinical features associated with the DSM-IV model may be adaptive homeostatic responses rather than pathological symptoms.

Antidepressive Agents, Tricyclic↗

PubMed2001

Familial idiopathic basal ganglia calcification (Fahr's disease) without neurological, cognitive and psychiatric symptoms is not linked to the IBGC1 locus on chromosome 14q.

Idiopathic basal ganglia calcification (IBGC) is characterised by radiological, neurological, cognitive and psychiatric abnormalities. The associations between these abnormal phenotypes and abnormal genes remain unclear despite the recent mapping to chromosome 14q of a susceptibility locus for IBGC ( IBGC1). We identified two siblings, from a large multigenerational pedigree, who had both been diagnosed with radiological IBGC, dementia, bipolar affective disorder and Parkinsonism. We assessed (1) other family members to determine whether these four phenotypes were co-segregating as symptoms of IBGC, and (2) possible IBGC linkage to the IBGC1 locus on chromosome 14q or to any known or potential dementia genes. Nine second-generation and 21 third-generation members received radiological, neurological, neuropsychological and psychiatric assessments. We genotyped all family members for microsatellite markers at the IBGC1 locus and polymorphisms of the ApoE, VLDL, alpha1-ACT, BChE-K, APP, PS1, PS2 and tau genes and tested these for linkage to IBGC, dementia and bipolar disorder. Of the ten family members with radiological intracranial calcification, all except the two index cases were normal. There was no significant association between IBGC status and severe cognitive impairment or dementia ( P=0.335) or bipolar affective disorder or Parkinsonism ( P=1.0). Linkage to the IBGC1 locus was excluded. Of the eight dementia gene markers tested, the only positive LOD score was for the ApoE epsilon4 polymorphism and dementia/severe cognitive impairment. We have identified a form of IBGC in which calcification is inherited independently of neurological, cognitive and psychiatric symptoms. This may represent a second locus for this disorder.

Basal Ganglia Diseases↗