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Richard N. Clayton

Bio: Richard N. Clayton is an academic researcher from Keele University. The author has contributed to research in topics: Loss of heterozygosity & Acromegaly. The author has an hindex of 52, co-authored 116 publications receiving 8544 citations. Previous affiliations of Richard N. Clayton include Diabetes Australia & University Hospitals of North Midlands NHS Trust.


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Journal ArticleDOI
TL;DR: Age at diagnosis, female sex, and above all, craniopharyngioma were significant independent risk factors and specific endocrine-axis deficiency, with the exception of untreated gonadotropin deficiency, does not seem to have a role.

912 citations

Journal ArticleDOI
TL;DR: The data confirmed that mortality in patients with hypopituitarism is significantly increased, and the contribution of vascular disease to this poor prognosis was not as great as previously reported, and overall the results favor a multifactorial explanation of the poor long term outcome.
Abstract: One hundred and seventy-two patients with partial or complete hypopituitarism diagnosed between 1967 and 1994 were studied retrospectively. Those with acromegaly or Cushing's disease were excluded. One hundred and two patients were male (median age at, diagnosis, 53 yr; range, 12-78 yr) and 70 female (median age at diagnosis, 51 yr; range, 1-74 yr). In 131 patients the cause of hypopituitarism was a pituitary tumor or the effects of its treatment, as the majority underwent surgery and/or radiotherapy. In 22, the cause was an extrapituitary tumor, 14 were termed idiopathic, 2 developed hypopituitarism as a result of basal sarcoid, 2 were due to trauma, and 1 was the result of Sheehan's syndrome. The patients were treated with standard replacement therapy. Mortality due to all causes was higher than expected in an age- and sex-matched control population (ratio of observed/expected deaths, 1.73; 95% confidence interval, 1.28-2.28; P < 0.01). Females tended to have a worse prognosis (ratio of observed/expected deaths, 2.29; 95% confidence interval, 1.37-3.58; P < 0.01) than their male counterparts (ratio of observed/expected deaths, 1.50; 95% confidence interval, 1.02-2.13; P < 0.01). There was a small but nonsignificant increase in the number of deaths due to vascular disease (ratio of observed/expected deaths, 1.35; 95% confidence interval, 0.84-2.07; P = 0.11). The only significant independent predictive factors for survival were age at diagnosis and hypogonadism. The majority of the male hypogonadal cohort received replacement therapy (79%), but fewer of the females did so (27%). Hypogonadal patients had a better prognosis than their eugonadal counterparts (log rank, 6.85; P < 0.01). Our data confirmed that mortality in patients with hypopituitarism is significantly increased. However, the contribution of vascular disease to this poor prognosis was not as great as previously reported, and overall, our results favor a multifactorial explanation of the poor long term outcome.

459 citations

Journal ArticleDOI
TL;DR: It is suggested that reduction of GH levels to less than 2 micro g/liter is beneficial in terms of improving long-term outcome and the sole use of IGF-I as a marker for effective treatment of acromegaly is not justified by this data.
Abstract: Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF-I remain uncertain. The West Midlands Pituitary database contains details of 419 patients (241 female) with acromegaly. Serum IGF-I data from the Regional Endocrine Laboratory were available for 360 patients (86%). At diagnosis, mean age was 47 yr (range, 12-84) and mean duration of follow-up was 13 yr (0.5-48). Sixty-one percent were treated by surgery and 39% by nonsurgical means. Radiotherapy was used alone or as adjuvant therapy in 50%. All patients were registered with the Office of National Statistics to obtain information on deaths. At the date of analysis (31 December 2001), 95 of the 419 patients had died (43 males), giving a standardized mortality ratio of 1.26 [confidence interval (CI), 1.03-1.54; P = 0.046]. After controlling for age and sex, data indicated that mortality was increased in subjects with posttreatment GH levels more than 2 micro g/liter, compared with those with levels less than 2 micro g/liter [ratio of mortality rates (RR), 1.55 (range, 0.97-2.50); P = 0.068]. By contrast, a much smaller increase was observed for subjects with elevated posttreatment IGF-I levels compared with those with normal levels [RR, 1.20 (range, 0.71-2.03); P = 0.50]. Treatment with radiotherapy was associated with increased mortality [RR, 1.67 (range, 1.09-2.56); P = 0.018], with cerebrovascular disease the predominant cause of death [standardized mortality ratio, 4.42 (range, 2.71-7.22); P = 0.005]. These results confirm the increased mortality in acromegaly and suggest that reduction of GH levels to less than 2 micro g/liter is beneficial in terms of improving long-term outcome. The sole use of IGF-I as a marker for effective treatment of acromegaly is not justified by this data. This study also highlights the potential deleterious effect of radiotherapy.

336 citations

Journal ArticleDOI
TL;DR: Low-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations.
Abstract: Context: The diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial. Objective: Our objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI. Data Sources: We searched the PubMed database from 1966–2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators. Study Selection: Eligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls. Data Extraction: We constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study siz...

328 citations

Journal ArticleDOI
TL;DR: Overall mortality in CD is double that of the general population, however, patients with CD in remission fare much better than those with persistence of hypercortisolism, and they appear not to have an increased mortality rate.
Abstract: Mortality in Cushing's disease is double that of the general population, but for patients in remission mortality to date is not increased.

307 citations


Cited by
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Journal ArticleDOI
TL;DR: Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes.
Abstract: It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

2,571 citations

Journal ArticleDOI
TL;DR: It is the view of the AES Task Force on the Phenotype of PCOS that there should be acceptance of the original 1990 National Institutes of Health criteria with some modifications, taking into consideration the concerns expressed in the proceedings of the 2003 Rotterdam conference.
Abstract: Objective: The Androgen Excess Society (AES) charged a task force to review all available data and recommend an evidence-based definition for polycystic ovary syndrome (PCOS), whether already in use or not, to guide clinical diagnosis and future research. Participants: Participants included expert investigators in the field. Evidence: Based on a systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, we tried to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. Consensus Process: The task force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the AES Board of Directors. No section was finalized until all members were satisfied with the contents and minority opinions noted. Statements that were not supported by peer-reviewed evidence were not included. Conclusions: Based on the available data, it is the view of the AES Task Force on the Phenotype of PCOS that...

1,877 citations

Journal ArticleDOI
TL;DR: The current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches, and diagnostic algorithms and recommendations for management of Cushing's syndrome are reviewed.

1,465 citations

Journal ArticleDOI
12 Apr 2004-Oncogene
TL;DR: The recent implication of tumor suppressors like Beclin 1, DAP-kinase and PTEN in autophagic pathways indicates a causative role for autophagy deficiencies in cancer formation and underlines the potential utility of its induction as a new cancer treatment modality.
Abstract: Autophagy is characterized by sequestration of bulk cytoplasm and organelles in double or multimembrane autophagic vesicles, and their delivery to and subsequent degradation by the cell's own lysosomal system. Autophagy has multiple physiological functions in multicellular organisms, including protein degradation and organelle turnover. Genes and proteins that constitute the basic machinery of the autophagic process were first identified in the yeast system and some of their mammalian orthologues have been characterized as well. Increasing lines of evidence indicate that these molecular mechanisms may be recruited by an alternative, caspase-independent form of programmed cell death, named autophagic type II cell death. In some settings, autophagy and apoptosis seem to be interconnected positively or negatively, introducing the concept of 'molecular switches' between them. Additionally, mitochondria may be central organelles integrating the two types of cell death. Malignant transformation is frequently associated with suppression of autophagy. The recent implication of tumor suppressors like Beclin 1, DAP-kinase and PTEN in autophagic pathways indicates a causative role for autophagy deficiencies in cancer formation. Autophagic cell death induction by some anticancer agents underlines the potential utility of its induction as a new cancer treatment modality.

1,383 citations