Search PubMed⌕ Search

Biomedical subjects

Kevin Morgan

Publications and source records attributed to Kevin Morgan.

At least 37 records · Page 2Linked to original sources
PubMed2005

Inhibition of human type i gonadotropin-releasing hormone receptor (GnRHR) function by expression of a human type II GnRHR gene fragment.

Humans possess only one functional GnRH receptor, the type I GnRH receptor (GnRHR-I). A type II GnRH receptor (GnRHR-II) gene homolog exists, but it is disrupted by a frame shift and premature stop codon, suggesting that a conventional receptor is not translated from this gene. However, the gene remains transcriptionally active and displays alternative splicing. We identified a putative translational start site 117 bp downstream of the premature stop codon. Use of this start codon encodes a protein (designated as the GnRHR-II-reliquum) corresponding to the domains from the cytoplasmic end of transmembrane domain-5 to the carboxyl terminus of the putative full-length receptor. Immunocytochemistry revealed that GnRHR-II-reliquum expression appeared to be localized throughout the cytoplasm. Transient cotransfection of GnRHR-I and GnRHR-II-reliquum constructs into COS-7 cells resulted in reduced expression of the GnRHR-I at the cell surface and impaired signaling via the GnRHR-I as revealed by reduction of GnRH-induced inositol phosphate accumulation. This inhibitory effect was specific and dependent on the degree of GnRHR-II-reliquum coexpressed. Immunoblot analysis revealed that the total cell GnRHR-I complement, i.e. both cell-surface and nascent intracellular receptors, was markedly reduced by coexpression of the GnRHR-II-reliquum. Treatments with cell-permeable agents that blocked either de novo protein synthesis (cycloheximide) or proteinase-mediated degradation (leupeptin and phenylmethylsulfonyl fluoride) failed to alter the inhibitory effect of GnRHR-II-reliquum coexpression, suggesting that the inhibitory effect is exerted at the nucleus/endoplasmic reticulum or Golgi apparatus level, possibly by perturbing normal processing of GnRHR-I from these sites. We suggest that the GnRHR-II-reliquum plays a modulatory role in GnRHR-I expression.

Amino Acid Sequence↗
PubMed2005

A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer's disease.

Increased levels of alpha-1-antichymotrypsin (ACT), a protease inhibitor and an acute phase protein, have been found in the brain and peripheral blood of patients with Alzheimer's disease (AD). Patients from northern Italy with a clinical diagnosis of probable AD, and patients with early onset AD (EOAD) from UK with AD neuropathological diagnosis were genotyped for a new polymorphism in the promoter region of the ACT gene which has been shown to affect ACT expression. A subset of patients with clinical AD from northern Italy was also followed up for 2 years and monitored for cognitive decline. The ACT TT promoter genotype was associated with an increased risk of EOAD independently from the presence of the apolipoprotein E (APOE) epsilon 4 allele. After manifestation of the disease the ACT TT genotype was also associated with faster cognitive decline in patients with the APOE allele epsilon 4. The ACT gene appears to influence the early clinical development of the disease, and the interaction of the ACT and APOE genes affects clinical progression of AD.

Aged↗
PubMed2005

Incidence of bipolar affective disorder in three UK cities: results from the AESOP study.

BACKGROUND: There has been a relative dearth of epidemiological research into bipolar affective disorder. Furthermore, incidence studies of bipolar disorder have been predominantly retrospective and most only included hospital admission cases. AIMS: To determine the incidence of operationally defined bipolar disorder in three areas of the UK and to investigate any differences in gender and ethnicity. METHOD: All patients who contacted mental health services with first-episode psychosis or non-psychotic mania between September 1997 and August 1999 were identified and diagnosed according to ICD-10 criteria. Incidence rates of bipolar affective disorder were standardised for age and stratified by gender and ethnic group across the three areas. RESULTS: The incidence rate per 100,000 per year in south-east London was over twice that in Nottingham and Bristol. There was no significant difference in the rates of disorder in men and women. Incidence rates of bipolar disorder in the combined Black and minority ethnic groups in all three areas were significantly higher than those of the comparison White groups. CONCLUSIONS: The incidence of bipolar disorder was higher in south-east London than in the other two areas, and was higher among Black and minority ethnic groups than in the White population.

Adolescent↗
PubMed2004

Allele-specific overexpression in astrocytes of an Alzheimer's disease associated alpha-1-antichymotrypsin promoter polymorphism.

Alpha-1-antichymotrypsin (ACT), a serine proteinase inhibitor is synthesised predominantly in the liver and in other tissues including the brain. ACT is a major component of the senile plaques (SP) characteristic of Alzheimer's disease (AD). Increased production locally in the brain may be associated with Alzheimer's disease as ACT acts as a "pathological chaperone", promoting beta-amyloid assembly into neurotoxic fibrils. Recent reports suggest that the T allele of a G/T polymorphism at position -51 of ACT is associated with cognitive decline in AD patients. We demonstrate that the T allele is markedly overexpressed by almost 225% in an astrocytic cell line in response to oncostatin M (OSM) compared with a 35% increase in a mixed population of brain-derived cells. This effect is probably mediated by a higher binding affinity of the transcription initiation complex to the higher expressing allele and overexpression of ACT by astrocytes could thus contribute to increased beta-amyloid fibril formation in AD.

Alleles↗
PubMed2004

Localization and quantification of cyclic changes in the expression of endocrine gland vascular endothelial growth factor in the human corpus luteum.

Angiogenesis is essential for normal growth and function of the corpus luteum. The roles of various angiogenic factors in these events are being elucidated. Endocrine gland vascular endothelial growth factor (EG-VEGF) has recently been described in the human ovary. To define the localization of EG-VEGF mRNA in the corpus luteum and determine changes in its expression, dated human corpora lutea were studied at the early, mid-, and late luteal phases. Quantitative RT-PCR was employed to determine changes in EG-VEGF mRNA and compare expression to its related factor prokineticin-2 and the established angiogenic factor, VEGF. In situ hybridization was used to localize sites of production of EG-VEGF. To investigate whether expression of EG-VEGF was under the influence of LH or progesterone, luteinized granulosa cells were stimulated with human chorionic gonadotropin in the presence or absence of a progesterone synthesis inhibitor. EG-VEGF mRNA increased throughout the luteal phase, whereas there was no change in VEGF mRNA. The relative abundance of RNAs based upon PCR signal intensity showed that VEGF and EG-VEGF were highly expressed, whereas expression of prokineticin-2 was low. EG-VEGF mRNA was localized predominantly to granulosa-derived cells of the corpus luteum. Human chorionic gonadotropin stimulated both VEGF and EG-VEGF mRNA in vitro, but the level of expression was not influenced by progesterone. These results establish that in the human corpus luteum EG-VEGF is principally derived from granulosa lutein cells and that its synthesis is highest during the mid- to late luteal phase.

Adult↗
PubMed2004

Normal cerebral asymmetry in familial and non-familial schizophrenic probands and their unaffected relatives.

Loss of normal fronto-occipital cerebral asymmetry has been reported in patients with schizophrenia and also in their well relatives from multiply affected families, suggesting a relationship with susceptibility genes. We sought to confirm this relationship in a family study of patients with schizophrenia and their unaffected relatives of presumed differing genetic risk. MRI scans were carried out on 25 probands from families multiply affected with the disorder, and 36 of their unaffected relatives, 34 probands from families with no other affected members, 42 of their unaffected relatives, and 76 controls. Volumetric measurements of prefrontal, premotor, sensorimotor and occipitoparietal regions were obtained from which a measure of fronto-occipital torque was derived. There were no significant differences in measurements of fronto-occipital torque between the subject groups. Both schizophrenic probands and their relatives displayed the normal pattern of cerebral asymmetry, with larger right than left frontal regions and a larger left than right occipitoparietal region. Our findings failed to confirm an association between loss of fronto-occipital torque and genetic liability for schizophrenia and also failed to replicate the previously reported association between loss/reversal of fronto-occipital asymmetry and schizophrenia.

Adult↗
PubMed2004

Sheep exhibit novel variations in the organization of the mammalian type II gonadotropin-releasing hormone receptor gene.

Species-specific differences in genes encoding type II GnRH receptor indicate that a functional hepta-helical receptor is produced in monkeys but not in rodents, cows, chimpanzees, or humans. To further investigate the extent of evolutionary differences, we sequenced the type II GnRH receptor gene from wild-type Soay sheep. The gene was isolated by long-distance PCR using primers to PEX11beta and RBM8A genes known to flank type II GnRH receptor gene homologues. The gene spans 5.7-kb DNA and was sequenced after shot-gun subcloning. Its novel features include absence of a Pit-1 transcription factor binding site, a premature stop codon (TAG) in exon 1, an in-frame deletion of 51 bp (17 codons) in exon 2, and several nonconservative codon changes. Sheep breed variation in the gene was assessed using genomic DNA in PCR-restriction digest assays for the premature stop codon and in a PCR assay for the deletion. Both characteristics were present in all 15 breeds tested. Receptor gene expression was investigated using poly-A(+) RNA Northern analysis, RT-PCR, and in situ hybridization. An oligonucleotide probe to exon 1 revealed an alternative transcript in testis but not in pituitary gland. No transcripts in testis or pituitary were detectable using an exon 2-3 probe. All tissues examined including multiple brain areas and gonadotrope-enriched cell cultures were negative for type II GnRH receptor in RT-PCR. Testis and pituitary sections were negative with exon 1 riboprobes and exon 1 or 2-3 oligonucleotide probes in in situ hybridization. A hepta-helical type II GnRH receptor is therefore not expressed from this sheep gene.

Alternative Splicing↗
PubMed2004

Haplotypes of the alpha-1 antitrypsin gene in healthy controls and Z deficiency patients.

Alpha-1 antitrypsin (AAT; HUGO symbol, SERPINA1) is one of the major serine protease inhibitors (serpins) in human plasma. Deficiency of AAT is a recognised risk factor for chronic obstructive pulmonary disease (COPD), attributed to uninhibited neutrophil elastase released into the lung tissue during inflammatory states. In this study we used sequencing to screen the exonic regions, 5' and 3' flanking sequence of the AAT gene in order to generate a high density map of single nucleotide polymorphisms (SNPs). 16 SNPs were identified throughout AAT. Haplotypes based on SNPs with a minor allele frequency of > or =5% were estimated using genotypic information from 225 healthy control individuals and 41 AAT deficient Pi-ZZ individuals. AAT shows a large amount of variation in the control population, with 17 haplotypes accounting for 88% of the observed variation. The haplotype distribution of the common deficiency Pi-Z variant of AAT was significantly different when compared to the normal variants. In addition to the haplotype information, we present evidence for a functional effect of a SNP in intron 1.

Cell Line↗
PubMed2004

Neutrophil counts, monocyte counts and cardiovascular disease in the elderly.

BACKGROUND: Previous studies have reported on the association between white blood cell counts, in particular monocytes, and cardiovascular disease, but have predominantly been conducted on middle-aged men. We examined whether this association is sustained in an elderly population-based sample. METHODS: Two samples of individuals aged 65 years and older living in Cambridge and Nottingham were recruited from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Venepuncture was undertaken in 1046 individuals, excluding only those who had probable dementia or were physically frail. Monocyte, neutrophil, lymphocyte, eosinophil and basophil counts were analysed for possible associations with history of cardiovascular disease. RESULTS: We found that monocyte and neutrophil counts were both significantly associated with history of cardiovascular disease, with respective odds ratios of 1.48 (95% CI 1.22-1.79) and of 1.44 (95% CI 1.19-1.75) per count tertile. These relationships remained significant on adjusting for age, sex, smoking and body mass index. We found no evidence of association between lymphocyte, eosinophil or basophil counts and history of cardiovascular disease. CONCLUSIONS: Monocyte and neutrophil counts are both associated with cardiovascular disease in a relatively healthy elderly population.

Aged↗
PubMed2004

Evolution of GnRH ligand precursors and GnRH receptors in protochordate and vertebrate species.

Primary structure relationships between GnRH precursors or GnRH receptors have received significant attention recently due to rapid DNA sequence determination of gene fragments and cDNAs from diverse species. Concepts concerning the evolutionary history of the GnRH system and its function in mammals, including humans, are likely to be modified as more complete sequence information becomes available. Current evidence suggests occurrence of fewer GnRH ligand and GnRH receptor genes in mammals compared to protochordates, fish and amphibians. Whilst several sequence-related GnRH decapeptide precursors and 2 or 3 separate GnRH receptors are encoded within the genomes of protochordates, fish and amphibians, only two types of GnRH (GnRH-I and GnRH-II) and two GnRH receptors occur in mammals. In addition, fish and mammalian genomes both retain inactive remnants of GnRH ligand or GnRH receptor genes. The number of distinct GnRH receptor genes in teleosts (at least five complete genes in pufferfish and three in zebrafish) partly reflects whole genome duplication during the evolution of this order of animals. Three GnRH receptor genes occur in certain frog species, consistent with the occurrence of up to three types of prepro-GnRH in amphibians. In contrast, only one functional GnRH receptor gene (the type I GnRH receptor) has been identified in humans and chimpanzees and a gene encoding a second receptor, homologous to a functional monkey receptor (the type II GnRH receptor), is either partially or completely silenced in a range of mammalian species (human, chimpanzee, sheep, cow, rat, and mouse). Further work is required to determine the significance of species-specific differences in the GnRH system to reproductive biology. For instance, recent data show that even species as closely related as humans and chimpanzees exhibit important organisational changes in the genes comprising the GnRH system.

Animals↗
PubMed2004

Gonadotropin-releasing hormone receptors.

GnRH and its analogs are used extensively for the treatment of hormone-dependent diseases and assisted reproductive techniques. They also have potential as novel contraceptives in men and women. A thorough delineation of the molecular mechanisms involved in ligand binding, receptor activation, and intracellular signal transduction is kernel to understanding disease processes and the development of specific interventions. Twenty-three structural variants of GnRH have been identified in protochordates and vertebrates. In many vertebrates, three GnRHs and three cognate receptors have been identified with distinct distributions and functions. In man, the hypothalamic GnRH regulates gonadotropin secretion through the pituitary GnRH type I receptor via activation of G(q). In-depth studies have identified amino acid residues in both the ligand and receptor involved in binding, receptor activation, and translation into intracellular signal transduction. Although the predominant coupling of the type I GnRH receptor in the gonadotrope is through productive G(q) stimulation, signal transduction can occur via other G proteins and potentially by G protein-independent means. The eventual selection of intracellular signaling may be specifically directed by variations in ligand structure. A second form of GnRH, GnRH II, conserved in all higher vertebrates, including man, is present in extrahypothalamic brain and many reproductive tissues. Its cognate receptor has been cloned from various vertebrate species, including New and Old World primates. The human gene homolog of this receptor, however, has a frame-shift and stop codon, and it appears that GnRH II signaling occurs through the type I GnRH receptor. There has been considerable plasticity in the use of different GnRHs, receptors, and signaling pathways for diverse functions. Delineation of the structural elements in GnRH and the receptor, which facilitate differential signaling, will contribute to the development of novel interventive GnRH analogs.

Amino Acid Sequence↗
PubMed2003

Differential regulation of secretory leukocyte protease inhibitor and elafin by progesterone.

Elafin and secretory leukocyte protease inhibitor (SLPI) are anti-protease and anti-microbial molecules present at mucosal surfaces. Both molecules are expressed in the female reproductive tract where they may be involved in innate immune defence. This study examines the role of progesterone in the regulation of SLPI and elafin. Progesterone treatment increases expression of SLPI mRNA and protein in the T47D breast epithelial cell line and this upregulation is attenuated in the presence of the anti-gestogens, RU486 and ZK98734, confirming the involvement of the nuclear progesterone receptor. A putative progesterone response element has been identified in the SLPI promoter. Progesterone also acts in synergy with the proinflammatory cytokines, IL-1beta and TNFalpha, to increase SLPI. In contrast, progesterone treatment has no direct effect on elafin mRNA expression. In summary, progesterone has a differential effect on SLPI and elafin expression and although both vary within the uterus throughout the menstrual cycle, progesterone is likely to contribute to the direct regulation of SLPI in the female reproductive tract even in the presence of inflammatory agents.

Base Sequence↗
PubMed2003

Predicting longer-term outcomes following psychological treatment for hypnotic-dependent chronic insomnia.

OBJECTIVES: To identify predictors of treatment adherence, patient dropout, and treatment response among long-term hypnotic users recruited into a randomized controlled trial of psychological treatment for insomnia. METHODS: Of 108 treatment and 101 control patients initially recruited, 37 treatment group patients (34.3%) failed to complete all 6 sessions (i.e., were nonadherent), while across both groups 61 (29.2%) patients failed to return postal assessments at 3-month follow-up (i.e., dropped out). Relationships between baseline characteristics and adherence (adherent vs. nonadherent) and attrition (dropout vs. nondropout) were examined in discriminant models. Relationships between baseline characteristics and treatment response (sleep quality, sleep latency, sleep efficiency, and hypnotic drug use) were examined in a series of multiple regression models. RESULTS: Adherent patients showed a significantly greater severity of pretreatment sleep disturbance, as measured by the Pittsburgh Sleep Quality Index (PSQI). Dropout at 3 months was associated with significantly lower perceived health status at baseline. In the regression models, lower Cure/Control subscale scores from the Illness Perception Questionnaire (IPQ) predicted greater posttreatment improvements in sleep efficiency and PSQI scores, while lower baseline anxiety scores predicted a posttreatment increase in hypnotic-free nights/week. CONCLUSION: In routine clinical practice settings, higher anxiety and a less positive attitude towards symptom control were associated with poorer treatment response. Adherence and attrition show a different pattern of associations, with greater need (as indexed by insomnia severity) predicting higher levels of service uptake and poorer general health predicting a higher likelihood of dropout.

Adult↗
PubMed2003

Survival in a population sample is predicted by proportions of lymphocyte subsets.

Comparisons of lymphocyte subsets show that the ratio of CD4 to CD8 is usually greater than one. Inversion of this ratio was found to predict survival in a Swedish octogenarian sample (n=27 deaths), although individual lymphocyte subsets did not predict survival. We have examined these relationships in a larger sample (n=153 deaths). Inversion of the CD4 to CD8 ratio was present in 16% of the sample and predicted survival when adjusted for age but not when adjusted for sex. For individual lymphocyte subsets, higher CD4 and CD19 percentages were associated with better survival, but only the CD19 percentage remained significant when adjusted for age and sex.

Aged↗
PubMed2003

Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease.

The processing of amyloid precursor protein (APP) generates amyloid-beta (Abeta) peptides 1-40 and 1-42. The latter is neurotoxic and its accumulation results in amyloid fibril formation and the generation of senile plaques, the hallmark of Alzheimer's disease (AD). Whilst there has been considerable progress made in understanding the generation of Abeta by alpha-, beta- and gamma-secretase activity on APP, recently enzymes involved in the degradation of Abeta have been identified including neprilysin and insulin-degrading enzyme (IDE). We review the pathways involved in proteolytic processing of APP and discuss the potential implications of aberrant proteolysis on neurodegeneration. It is conceivable that single nucleotide polymorphisms (SNPs) in the regulatory regions of genes in these proteolytic cascades, which alter their expression, could contribute to some of the age-related changes seen in AD.

Alzheimer Disease↗
PubMed2003

Serpins: structure, function and molecular evolution.

The superfamily of serine proteinase inhibitors (serpins) are involved in a number of fundamental biological processes such as blood coagulation, complement activation, fibrinolysis, angiogenesis, inflammation and tumor suppression and are expressed in a cell-specific manner. The average protein size of a serpin family member is 350-400 amino acids, but gene structure varies in terms of number and size of exons and introns. Previous studies of all known serpins identified 16 clades and 10 orphan sequences. Vertebrate serpins can be conveniently classified into six sub-groups. We provide additional data that updates the phylogenetic analysis in the context of structural and functional properties of the proteins. From these, we can conclude that the functional classification of serpins relies on their protein structure and not on sequence similarity.

Animals↗
PubMed2003

Daytime activity and risk factors for late-life insomnia.

Laboratory evidence linking exercise with improved sleep quality raises the possibility that the lower levels of physical activity characteristic of older age groups may contribute to late-life insomnia. While support for this hypothesis appears to come from epidemiological surveys, few such studies have distinguished satisfactorily between social and physical activities which differ widely in terms of energy cost and theoretical significance. The present analyses were, therefore, designed to assess the independent influence of physical and social activity levels on the prevalence and natural history of late-life insomnia. Survivors from a nationally representative UK sample (n = 1042) of elderly people originally interviewed in 1985 were reassessed in 1989 (n = 690) and 1993 (n = 410). Detailed assessments of physical and social activities, mental and physical health status, and sleep quality were made at each survey wave. Logistic regression models, adjusted for age, sex and health status, were used to assess relationships between activity levels and the prevalence, remission/persistence, and incidence of late-life insomnia. Lower physical health, depressed mood and lower physical (but not social) activity levels consistently emerged as significant risk factors for prevalent, persistent and incident insomnia. Age was unrelated to insomnia variables in all the cross-sectional models, but did emerge as a significant risk for cumulative 4-8-year insomnia incidence. These findings suggest that, independent of those activities more closely associated with social engagement, higher levels of customary physical activity per se appear to be protective against incident and chronic late-life insomnia.

Aged↗