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Biomedical subjects

Kevin Morgan

Publications and source records attributed to Kevin Morgan.

At least 19 recordsLinked to original sources
PubMed2007

Parental separation, loss and psychosis in different ethnic groups: a case-control study.

BACKGROUND: Numerous studies have reported high rates of psychosis in the Black Caribbean and Black African populations in the UK. However, few studies have investigated the role of specific risk factors in different ethnic groups. We sought to investigate the relationship between long-term separation from, and death of, a parent before the age of 16 and risk of adult psychosis in different ethnic groups. METHOD: All patients with a first episode of psychosis who made contact with psychiatric services in defined catchment areas in London and Nottingham, UK and a series of community controls were included in the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study. Data relating to clinical and social variables, including parental separation and loss, were collected from patients and controls. RESULTS: Separation from, and death of, a parent before the age of 16 were both strongly associated with a two- to threefold increased risk of psychosis. The strength of these associations were similar for White British and Black Caribbean (but not Black African) subjects. Separation from (but not death of) a parent was more common among Black Caribbean controls than White British controls. CONCLUSIONS: Early separation may have a greater impact in the Black Caribbean population, because it is more common, and may contribute to the excess of psychosis in this population.

Adolescent↗
PubMed2006

Reciprocal cross talk between gonadotropin-releasing hormone (GnRH) and prostaglandin receptors regulates GnRH receptor expression and differential gonadotropin secretion.

The asynchronous secretion of gonadotrope LH and FSH under the control of GnRH is crucial for ovarian cyclicity but the underlying mechanism is not fully resolved. Because prostaglandins (PG) are autocrine regulators in many tissues, we determined whether they have this role in gonadotropes. We first demonstrated that GnRH stimulates PG synthesis by induction of cyclooxygenase-2, via the protein kinase C/c-Src/phosphatidylinositol 3'-kinase/MAPK pathway in the LbetaT2 gonadotrope cell line. We then demonstrated that PGF(2alpha) and PGI2, but not PGE2 inhibited GnRH receptor expression by inhibition of phosphoinositide turnover. PGF(2alpha), but not PGI2 or PGE2, reduced GnRH-induction of LHbeta gene expression, but not the alpha-gonadotropin subunit or the FSHbeta subunit genes. The prostanoid receptors EP1, EP2, FP, and IP were expressed in rat gonadotropes. Incubations of rat pituitaries with PGF(2alpha), but not PGI2 or PGE2, inhibited GnRH-induced LH secretion, whereas the cyclooxygenase inhibitor, indomethacin, stimulated GnRH-induced LH secretion. None of these treatments had any effect on GnRH-induced FSH secretion. The findings have thus elaborated a novel GnRH signaling pathway mediated by PGF(2alpha)-FP and PGI2-IP, which acts through an autocrine/paracrine modality to limit autoregulation of the GnRH receptor and differentially inhibit LH and FSH release. These findings provide a mechanism for asynchronous LH and FSH secretions and suggest the use of combination therapies of GnRH and prostanoid analogs to treat infertility, diseases with unbalanced LH and FSH secretion and in hormone-dependent diseases such as prostatic cancer.

Animals↗
PubMed2006

Incidence of schizophrenia and other psychoses in ethnic minority groups: results from the MRC AESOP Study.

BACKGROUND: The incidence of schizophrenia in the African-Caribbean population in England is reported to be raised. We sought to clarify whether (a) the rates of other psychotic disorders are increased, (b) whether psychosis is increased in other ethnic minority groups, and (c) whether particular age or gender groups are especially at risk. METHOD: We identified all people (n=568) aged 16-64 years presenting to secondary services with their first psychotic symptoms in three well-defined English areas (over a 2-year period in Southeast London and Nottingham and a 9-month period in Bristol). Standardized incidence rates and incidence rate ratios (IRR) for all major psychosis syndromes for all main ethnic groups were calculated. RESULTS: We found remarkably high IRRs for both schizophrenia and manic psychosis in both African-Caribbeans (schizophrenia 9.1, manic psychosis 8.0) and Black Africans (schizophrenia 5.8, manic psychosis 6.2) in men and women. IRRs in other ethnic minority groups were modestly increased as were rates for depressive psychosis and other psychoses in all minority groups. These raised rates were evident in all age groups in our study. CONCLUSIONS: Ethnic minority groups are at increased risk for all psychotic illnesses but African-Caribbeans and Black Africans appear to be at especially high risk for both schizophrenia and mania. These findings suggest that (a) either additional risk factors are operating in African-Caribbeans and Black Africans or that these factors are particularly prevalent in these groups, and that (b) such factors increase risk for schizophrenia and mania in these groups.

Adolescent↗
PubMed2006

Bovine and ovine gonadotropin-releasing hormone (GnRH)-II ligand precursors and type II GnRH receptor genes are functionally inactivated.

The decapeptide sequence of GnRH-II is conserved in all jawed vertebrate species studied to date. New data for cattle (Bos taurus) indicates a gene encoding GnRH-II decapeptide possessing arginine (codon: CGG) rather than tryptophan (TGG) at position three in the mature peptide. This substitution is unique. We confirmed the DNA sequence after cloning part of the bovine prepro-GnRH-II gene. Bovine GnRH-II peptide was synthesized and pharmacologically characterized. It did not bind to mammalian GnRH receptors expressed in different types of cell nor did it exhibit agonist or antagonist properties on types I or II GnRH receptors expressed in COS-7 cells. Bovine primers facilitated cloning of ovine GnRH-II DNA. A premature stop codon (TGA) replaces the expected tryptophan codon at position seven of GnRH-II in sheep DNA. Thus, both species possess prepro-GnRH-II genes encoding inactive peptides, as previously described for chimpanzee GnRH-II. The updated bovine type II GnRH receptor gene sequence revealed inactivation by frame shifts, premature stop codons, and nucleotide changes specifying nonconservative replacement of amino acid residues, similar to inactivation of sheep type II GnRH receptor. Spliced RNA transcripts from the disrupted receptor gene were not detected in bovine pituitary. In contrast, bovine prepro-GnRH-I and type I GnRH receptor genes are intact, encoding well-conserved protein sequences. These findings, and previous descriptions of inactivation of the human type II GnRH receptor and deletions of prepro-GnRH-II and type II GnRH receptor in laboratory rodents, suggest the GnRH-II system has been replaced by the GnRH-I system or is redundant in certain mammals.

Amino Acid Sequence↗
PubMed2006

Major carcinogenic pathways identified by gene expression analysis of peritoneal mesotheliomas following chemical treatment in F344 rats.

This study was performed to characterize the gene expression profile and to identify the major carcinogenic pathways involved in rat peritoneal mesothelioma (RPM) formation following treatment of Fischer 344 rats with o-nitrotoluene (o-NT) or bromochloracetic acid (BCA). Oligo arrays, with over 20,000 target genes, were used to evaluate o-NT- and BCA-induced RPMs, when compared to a non-transformed mesothelial cell line (Fred-PE). Analysis using Ingenuity Pathway Analysis software revealed 169 cancer-related genes that were categorized into binding activity, growth and proliferation, cell cycle progression, apoptosis, and invasion and metastasis. The microarray data were validated by positive correlation with quantitative real-time RT-PCR on 16 selected genes including igf1, tgfb3 and nov. Important carcinogenic pathways involved in RPM formation included insulin-like growth factor 1 (IGF-1), p38 MAPkinase, Wnt/beta-catenin and integrin signaling pathways. This study demonstrated that mesotheliomas in rats exposed to o-NT- and BCA were similar to mesotheliomas in humans, at least at the cellular and molecular level.

Acetates↗
PubMed2006

Gray matter abnormalities associated with duration of untreated psychosis.

PURPOSE: A long duration of untreated psychosis (DUP) is associated with relatively poor clinical and social outcomes. In order to identify whether an anatomically mediated mechanism may give rise to poorer outcomes, it is important to identify whether a long DUP is associated with greater brain structural abnormalities. METHOD: 81 patients with first-episode psychosis (schizophrenia, affective, and other psychoses) were scanned using high resolution Magnetic Resonance Imaging. DUP was defined as the number of days between first onset of psychotic symptoms and first contact with mental health services. High-resolution MRI images and voxel-based methods of image analysis were used to investigate brain structure in these patients. RESULTS: Longer DUP was associated with gray matter reductions in left middle and inferior temporal, left occipital and left fusiform cortices, and with gray matter excess of the left basal ganglia. All findings remained significant when co-varying for exposure to antipsychotic treatment. CONCLUSIONS: Temporal gray matter reductions are more marked in patients with a long DUP. This could reflect a progressive pathological process that is active prior to treatment. Alternatively, these abnormalities could be associated with a more insidious onset of illness and a later presentation to services.

Adolescent↗
PubMed2006

Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center AeSOP study.

CONTEXT: Convention suggests uniformity of incidence of schizophrenia and other psychoses; variation would have implications for their causes and biological characteristics. OBJECTIVE: To investigate variability in the incidence of psychotic syndromes in terms of place, ethnicity, age, and sex. DESIGN: Three-center, prospective, comprehensive survey of clinically relevant first-onset psychotic syndromes over a 2-year period (1997-1999). Census data provided the denominator. SETTING: Southeast London, Nottingham, and Bristol, England. PARTICIPANTS: One million six hundred thousand person-years yielded 568 subjects aged 16 to 64 years with clinically relevant psychotic syndromes. MAIN OUTCOME MEASURES: The World Health Organization Psychosis Screen and the Schedules for Clinical Assessment in Neuropsychiatry to classify, blind to ethnicity, all DSM-IV psychotic syndromes and the subclasses of schizophrenia, other nonaffective disorders, affective disorders, and substance-induced psychosis. RESULTS: All syndromes showed a characteristic age distribution. Schizophrenia was significantly more common in men (incidence rate ratio [IRR], 2.3 [95% confidence interval (CI), 1.7-3.1]); affective disorders occurred equally in men and women (IRR, 1.0 [95% CI, 0.7-1.3]). All psychoses were more common in the black and minority ethnic group (crude IRR, 3.6 [95% CI, 3.0-4.2]). Differences in age, sex, and study center accounted for approximately a quarter of this effect (adjusted IRR, 2.9 [95% CI, 2.4-3.5]) in each psychosis outcome. The age-sex standardized incidence rate for all psychoses was higher in Southeast London (IRR, 49.4 [95% CI, 43.6-55.3]) than Nottingham (IRR, 23.9 [95% CI, 20.6-27.2]) or Bristol (IRR, 20.4 [95% CI, 15.1-25.7]). Rates of all outcomes except affective disorders remained significantly higher in Southeast London when the model was expanded to control for ethnicity. CONCLUSIONS: There is significant and independent variation of incidence of schizophrenia and other psychoses in terms of sex, age, ethnicity, and place. This confirms that environmental effects at the individual, and perhaps neighborhood level, may interact together and with genetic factors in the etiology of psychosis.

Adolescent↗
PubMed2006

Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. While cigarette smoking is a major cause of COPD, only 15% of smokers develop the disease, indicating major genetic influences. The most widely recognized candidate gene in COPD is SERPINA1, although it has been suggested that SERPINA3 may also play a role. To detect cryptic genetic variants that might contribute to disease, we identified 15 SNP haplotype tags from high-density SNP maps of the two genes and evaluated these SNPs in the largest case-control genetic study of COPD conducted so far. For SERPINA1, six newly identified haplotypes with a common backbone of five SNPs were found to increase the risk of disease by six- to 50-fold, the highest risk of COPD reported to date. In contrast, no haplotype associations for SERPINA3 were identified.

Aged↗
PubMed2006

Association of improved pulmonary phenotype in Irish cystic fibrosis patients with a 3' enhancer polymorphism in alpha-1-antitrypsin.

Modifier genes other than CFTR are thought to influence lung disease phenotype in cystic fibrosis (CF). In this study, we investigated the relationship between a polymorphism (1237 G --> A) in the 3' enhancer region of the alpha-1-antitrypsin (AAT) gene and pulmonary disease severity in 320 CF patients recruited from two independent adult referral centers in Ireland, and evaluated the in vivo effect of the polymorphism on AAT levels during acute infection. When corrected for confounding variables, the polymorphism was found to make a small but significant contribution to variance in percent predicted forced expired volume in 1 sec (FEV1) (1.1%, P = 0.05), with possession of the A allele being associated with better pulmonary function (AA/AG genotype: percent predicted FEV1, 70.8 +/- 3.9; GG genotype: percent predicted FEV1, 62.0 +/- 1.4). As would be expected of a modifier effect, the influence of the polymorphism was more marked in patient groups traditionally associated with more severe lung disease, contributing 3.2% (P = 0.033) to the variance in percent predicted FEV1 in patients homozygous for DF508, 3.3% (P = 0.007) to those infected with Pseudomonas aeruginosa, and 3% (P = 0.024) in female patients. In each instance, a positive association between possession of the A variant and higher percent predicted FEV1 was observed. We did not, however, find any evidence that possession of the A allele effected upregulation of AAT during acute infection in vivo. This lack of a demonstrable functional effect in vivo suggests that the polymorphism is a marker for a modifying effect on pulmonary phenotype in the Irish CF population by a mechanism that is yet to be explained.

Adult↗
PubMed2006

Clinical and social determinants of duration of untreated psychosis in the AESOP first-episode psychosis study.

BACKGROUND: Despite considerable research investigating the relationship between a long duration of untreated psychosis (DUP) and outcomes, there has been much less considering predictors of a long DUP. AIMS: To investigate the clinical and social determinants of DUP in a large sample of patients with a first episode of psychosis. METHOD: All patients with a first episode of psychosis who made contact with psychiatric services over a 2-year period and were living in defined catchment areas in London and Nottingham, UK were included in the AESOP study. Data relating to clinical and social variables and to DUP were collected from patients, relatives and case notes. RESULTS: An insidious mode of onset was associated with a substantially longer DUP compared with an acute onset, independent of other factors. Unemployment had a similar, if less strong, effect. Conversely, family involvement in help-seeking was independently associated with a shorter duration. There was weak evidence that durations were longer in London than in Nottingham. CONCLUSIONS: These findings suggest that DUP is influenced both by aspects of the early clinical course and by the social context.

Adolescent↗
PubMed2006

Impact of cognitive behavior therapy on health-related quality of life among adult hypnotic users with chronic insomnia.

Results were combined from representative surveys of health related quality of life (HRQoL; n=11,877; age range=16-104) with data from a randomized controlled trial of cognitive behavior therapy for chronic insomnia (n=209; age range=31-92). Secondary analyses of scores from the SF-36 measure of HRQoL were conducted in order: (a) to compare the health related quality of life profiles of adult hypnotic users with chronic insomnia with those of population norms, and (b) to assess the impact of cognitive behavior therapy (CBT) for insomnia on HRQoL outcomes over 6 months. Compared with the primary care reference values, HRQoL among the trial participants at baseline was generally poorer. The magnitude of these decrements reduced markedly with advancing age. In the evaluation of the CBT intervention, statistically significant differences in SF-36 scores in favor of the intervention were present for physical functioning, emotional role limitation, and mental health over 6 months. Overall, this study shows that the SF-36 can play an important role in describing HRQoL in this patient group, and in the evaluation of interventions within this group.

Adolescent↗
PubMed2006

First episode psychosis and ethnicity: initial findings from the AESOP study.

In this paper we provide an overview of the design and the initial findings of the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study. The AESOP study is a major multi-centre incidence and case-control study conducted in the UK. Its primary aim is to investigate the high rates of psychosis in African-Caribbean populations from the UK, and from this to shed light on the aetiology of psychosis in general. As the study has progressed, the wealth of data collected has allowed further questions to be addressed: for example, about determinants of duration of untreated psychosis. Initial findings relating to incidence rates and between-case comparisons are presented. Future planned analyses are outlined and details of a follow-up of the AESOP cohort and ongoing international collaborations are provided.

Journal Article↗
PubMed2005

Effects of Alzheimer's peptide and alpha1-antichymotrypsin on astrocyte gene expression.

We employed gene array technology to investigate the effects of alpha1-antichymotrypsin (ACT), soluble or fibrillar Alzheimer's peptide (Abeta(1-42)) alone and the combination of ACT/Abeta(1-42) on human astrocytes. Using a 1.2-fold change as significance threshold, 398 astrocyte genes showed altered expression in response to these treatments compared to controls. Of the 276 genes affected by the ACT/soluble Abeta(1-42) combination, 195 (70.6%) were suppressed. The ACT/fibrillar Abeta(1-42) combination affected expression of 64 genes of which 58 (90.5%) were up-regulated. The most prominent gene expression changes in response to the ACT/soluble Abeta(1-42), were the down-regulation of at least 60 genes involved in transcription, signal transduction, apoptosis and neurogenesis. The ACT/fibril Abeta(1-42) increased the expression of genes involved in transcription regulation and signal transduction. Surprisingly, gene expression of astrocytes exposed to soluble or fibrillar Abeta(1-42) alone was largely unaffected. Thus, the molecular forms generated by the combination of ACT/Abeta(1-42) alter expression of astrocyte genes more profoundly in breadth and magnitude than soluble or fibrillar Abeta(1-42) alone, suggesting that pathogenic effects of Abeta(1-42) may occur as a consequence of its association with other proteins.

Amyloid beta-Peptides↗
PubMed2005

Duration of untreated psychosis and ethnicity in the AESOP first-onset psychosis study.

BACKGROUND: There is a common assumption that Black patients with a psychotic mental illness experience longer treatment delays during a first episode. We sought to investigate this issue in a large cohort of patients with a first episode of psychosis. METHOD: All patients with a first episode of psychosis presenting to secondary mental health services within tightly defined catchment areas in south-east London and Nottingham over a 2-year period were included in the study. Data relating to duration of untreated psychosis (DUP) and clinical and sociodemographic characteristics were collected from patients, relatives and case-notes. RESULTS: There was no evidence that African-Caribbean or Black African patients experienced longer periods of untreated psychosis than White British patients prior to first contact with services. There was evidence that Black African patients experienced shorter periods of untreated psychosis than White British patients. CONCLUSIONS: Contrary to what is commonly assumed, our study suggests that Black patients with a psychotic mental illness do not experience longer treatment delays prior to first contact with services than White British patients. This suggests that strategies to reduce treatment delays targeted specifically at Black patients will be of limited value.

Adolescent↗
PubMed2005

Cystic fibrosis, disease severity, and a macrophage migration inhibitory factor polymorphism.

RATIONALE: Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. It contributes toward an exaggerated gram-negative inflammatory response via its ability to induce Toll-like receptor-4 expression. Studies have shown that MIF knockout mice have less aggressive Pseudomonas infection (compared with wild-type). OBJECTIVES: To assess whether a novel functional MIF polymorphism was associated with clinical prognosis in a patient cohort with chronic gram-negative infection, namely cystic fibrosis (CF). METHODS: Collected genomic DNA was analyzed via polymerase chain reaction amplification for the polymorphic region for the CATT repeat polymorphism. Individuals may have a 5-, 6-, 7-, or 8-CATT tetranucleotide repeat unit on each allele. The 5-CATT repeat allele exhibits the lowest MIF promoter activity. MEASUREMENTS AND MAIN RESULTS: Patients with stable CF (n = 167) and a matched control group (n = 166) were enrolled. In patients with CF, the MIF5(+) group had a decreased incidence of Pseudomonas aeruginosa colonization (odds ratio, 0.25; 95% confidence interval, 0.09-0.65; p = 0.004) and a significant reduction in the risk of pancreatic insufficiency (odds ratio, 0.27; 95% confidence interval, 0.07-1.0; p = 0.05). A trend toward milder disease activity in the MIF5(+) group was seen with all other parameters. CONCLUSIONS: The results support the concept of a regulatory role for MIF in CF.

Adolescent↗
PubMed2005

Evolution of constrained gonadotropin-releasing hormone ligand conformation and receptor selectivity.

Gonadotropin-releasing hormone (GnRH) is the central regulator of reproduction in vertebrates. GnRHs have recently been identified in protochordates and retain the conserved N- and C-terminal domains involved in receptor binding and activation. GnRHs of the jawed vertebrates have a central achiral amino acid (glycine) that favors a type II' beta-turn such that the N- and C-terminal domains are closely apposed in binding the GnRH receptor. However, protochordate GnRHs have a chiral amino acid in this position, suggesting that they bind their receptors in a more extended form. We demonstrate here that a protochordate GnRH receptor does not distinguish GnRHs with achiral or chiral amino acids, whereas GnRH receptors of jawed vertebrates are highly selective for GnRHs with the central achiral glycine. The poor activity of the protochordate GnRH was increased >10-fold at vertebrate receptors by replacement of the chiral amino acid with glycine or a d-amino acid, which favor the type II' beta-turn. Structural analysis of the GnRHs using ion mobility-mass spectrometry and molecular modeling showed a greater propensity for a type II' beta-turn in GnRHs with glycine or a d-amino acid, which correlates with binding affinity at vertebrate receptors. These findings indicate that the substitution of glycine for a chiral amino acid in GnRH during evolution allows a more constrained conformation for receptor binding and that this subtle single amino acid substitution in a site remote from the ligand functional domains has marked effects on its structure and activity.

Amino Acid Sequence↗