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D A Rees

Publications and source records attributed to D A Rees.

At least 19 recordsLinked to original sources
PubMed2005

Long-term remission following withdrawal of dopamine agonist therapy in subjects with microprolactinomas.

OBJECTIVE: Reports suggest that up to 70% of patients with microprolactinomas treated with dopamine agonist therapy may achieve long-term normoprolactinaemic remission following drug withdrawal. Yet, there is no consensus on the duration of therapy nor is therapeutic interruption universally practised. We have assessed remission rates in a large cohort of treatment-naive subjects with microprolactinomas. Subjects received dopamine agonist (DA) therapy with either cabergoline or bromocriptine for a period of 2 to 3 years in the majority of cases, followed by a trial of treatment withdrawal. DESIGN: Retrospective analysis of clinic records of 89 patients (mean age 32.7 +/- 8.4 years, 84 women and 5 men) who had received either cabergoline (n = 67) (0.5-3 mg weekly) or bromocriptine (n = 22) (2.5-10 mg daily) for a mean duration of 3.1 years. RESULTS: Following withdrawal of therapy, 57 subjects developed recurrence (64%) and the mean time to recurrence was 9.6 months (range 1-44 months), while 32 subjects (36%) remained in remission beyond 1 year (mean 3.6 years, range 1-7 years). There was no difference in remission rates between subjects treated with cabergoline (n = 21) and bromocriptine (n = 11), but a direct relationship between pretreatment prolactin concentration and risk of recurrent symptomatic hyperprolactinaemia was observed. No subjects developed clinical features to suggest tumour expansion following therapeutic discontinuation. CONCLUSIONS: This study confirms that abrupt withdrawal of chronic dopamine agonist therapy, following 2 to 3 years of treatment is safe and associated with long-term remission in 30-40% of subjects with microprolactinomas. This therapeutic strategy is convenient and applicable in clinical practice.

Adolescent↗
PubMed2005

Animal models of diabetes mellitus.

Animal models have been used extensively in diabetes research. Early studies used pancreatectomised dogs to confirm the central role of the pancreas in glucose homeostasis, culminating in the discovery and purification of insulin. Today, animal experimentation is contentious and subject to legal and ethical restrictions that vary throughout the world. Most experiments are carried out on rodents, although some studies are still performed on larger animals. Several toxins, including streptozotocin and alloxan, induce hyperglycaemia in rats and mice. Selective inbreeding has produced several strains of animal that are considered reasonable models of Type 1 diabetes, Type 2 diabetes and related phenotypes such as obesity and insulin resistance. Apart from their use in studying the pathogenesis of the disease and its complications, all new treatments for diabetes, including islet cell transplantation and preventative strategies, are initially investigated in animals. In recent years, molecular biological techniques have produced a large number of new animal models for the study of diabetes, including knock-in, generalized knock-out and tissue-specific knockout mice.

Animals↗
PubMed2003

Transsphenoidal surgery for acromegaly in wales: results based on stringent criteria of remission.

We retrospectively analyzed 90 patients who underwent transsphenoidal surgery (performed by three surgeons) in our center as initial therapy for acromegaly. We used a combination of modern, evidence-based remission criteria including mean day curve GH less than 2.5 micro g/liter (5 mU/liter), a nadir GH less than 1.0 micro g/liter (2 mU/liter) after an oral glucose tolerance test, and normal age-related IGF-I levels (where available). Fifty-seven of 90 (63%) patients remained in remission after surgery. Seventy-nine percent of patients with microadenomas but only 56% of patients with macroadenomas achieved remission (P < 0.001). Eighty-six percent of patients with preoperative GH levels below 10 micro g/liter (day profile or after oral glucose tolerance test) went into remission, compared with 51% of patients with GH levels above 25 micro g/liter at diagnosis (P < 0.002). The remission rate was also related to the period of surgery that was significantly higher in 1998-2001 (76%; P < 0.05) compared with 1990-1997 (54%) and 1980-1989 (63%). There were no recurrences or perioperative deaths. Meningitis occurred in 3% of patients, cerebrospinal fluid rhinorrhea in 7%, and permanent diabetes insipidus in 15%. The proportion of patients who developed new anterior pituitary hormone deficiencies and panhypopituitarism was significantly less in the period 1998-2001 (P < 0.001) when compared with the periods from 1990-1997 and 1980-1989. Transsphenoidal surgery is a safe and effective treatment for acromegaly, and our results compare favorably with those from published series. The presence of an intrasellar lesion and low preoperative GH levels is a good predictor of remission in the long term, but historically in our center this can only be achieved in a significant proportion of patients at the expense of some degree of hypopituitarism. However, surgical outcome in our center, including a reduced frequency of hypopituitarism, has improved significantly over time, coincident with the arrival of a dedicated pituitary neurosurgeon and the use of selective adenomectomy as the preferred surgical approach wherever possible.

Acromegaly↗
PubMed2003

Adenosine signalling pathways in the pituitary gland: one ligand, multiple receptors.

Adenosine receptors are widely distributed in most species and mediate a diverse range of physiological and pathological effects. Although adenosine receptors have been identified in the pituitary gland, the distribution of the individual subtypes (A(1), A(2A), A(2B), A(3)) has not been well defined. Furthermore, the effects of adenosine on pituitary trophic activity and function are not well established despite good evidence for growth- and immune-modulating properties of the nucleoside elsewhere. Recent advances have provided a more detailed description of adenosine receptor distribution and function in the anterior pituitary and this commentary reviews these observations and highlights some of the possible implications in relation to the control of the hypothalamic-pituitary-adrenal axis and the regulation of inflammation and pituitary cell growth.

Adenosine↗
PubMed2002

Loss of ACTH expression in cultured human corticotroph macroadenoma cells is consistent with loss of the POMC gene signal sequence.

The proopiomelanocortin (POMC) gene is highly expressed in the pituitary gland where the resulting mRNA of 1200 base pairs (bp) gives rise to a full-length protein sequence. In peripheral tissues however both shorter and longer POMC variants have been described, these include for example placental tissue which contain 800 (truncated at the 5' end) and 1500 as well as the 1200 bp transcripts. The importance of the 800 bp transcript is unclear as the lack of a signal sequence renders the molecule to be non-functional. This transcript has not been previously demonstrated in the pituitary gland. In this report we show evidence of a 5' truncated POMC gene in human pituitary corticotroph macroadenoma cells (JE) maintained in primary culture for >1 year. The original tumour tissue and the derived cells during early passage (up to passage 4-5) immunostained for ACTH and in situ hybridisation confirmed the presence of the POMC gene in the cultured cells. These cells also secreted 15-40 pg/10(5) cells/24 h ACTH. In addition, as expected RT-PCR demonstrated the presence of all three POMC gene exons and is thus indicative of a full-length POMC gene. In late culture passages (passages 8-15) JE cells ceased to express ACTH and cell growth became very slow due presumably to cells reaching their Hayflick limit. ACTH immunostaining in these cells was undetectable and ACTH secretion was also at the detection limits of the assay and no greater than 10 pg/10(5) cells/24 h. ACTH precursor molecules were also undetectable. RT-PCR for the POMC gene in these late passage cells showed that only exon 3 was detectable, in contrast to early passage cells where all three exons were present. In summary we isolated in culture, human pituitary cells that possessed initially all three exons of the POMC gene and immunostained for ACTH. On further passaging these cells showed a loss of exons 1 and 2 in the POMC gene and a loss of ACTH immunostaining and secretion. We would like to suggest that the loss of ACTH peptide expression in these late passage cells is in part due to the loss of the POMC signal sequence. An alternative explanation for our findings is that there were originally two populations of corticotrophs in the cultures, one of which possessed the full-length POMC gene and the other only the 5' truncated POMC transcript and it is these latter cells which survived in culture. In either scenario this is the first report of the 5' truncated POMC gene occurring in pituitary cells.

Adenoma↗
PubMed2002

Mitogen-activated protein kinase mediates epidermal growth factor-induced morphogenesis in pituitary GH3 cells.

Epidermal growth factor (EGF) causes pituitary GH3 cells to change from their normal predominantly rounded morphology to much more elongated cells with extensive filopodia, and this effect is accompanied by a parallel increase in cell volume. In view of this, and because EGF receptor expression is increased in some pituitary tumours, we examined the mechanism of this EGF-induced morphological effect as it may play a role in tumour invasiveness. The effect of treatment of the cells with EGF (1 nm, 4 days) was determined visually (expressed as percent non round cells) and by measuring the cell volume by Coulter Counter analysis. EGF treatment caused the cells to change their morphology with percent non round cells increasing from 37% in control cells to 74% in EGF-treated cultures; this was accompanied by a parallel increase in cell volume. Treatment of the cells with EGF in the presence of the MEK1 inhibitor (PD98059) completely blocked the EGF-induced morphological changes, showing that activation of the mitogen-activated protein kinase (MAPK) pathway is necessary to mediate this effect. Transfection of the cells with a constitutively activated mutant of MEK1 produced a similar morphological change to that produced by EGF treatment, with the proportion of non round cells increasing to 62% with a parallel increase in cell volume compared to cells transfected with the empty vector, demonstrating that direct activation of MAPK pathway is sufficient to mediate the observed morphological effects. The effects produced by activated MEK1 transfection could be blocked by PD98059. EGF had opposing effects on prolactin and growth hormone (GH) secretion by the cells, increasing prolactin release and inhibiting GH release. Transfection of the cells with activated MEK1 produced similar effects on hormone release as EGF treatment. In conclusion, the morphological effects of EGF on GH3 cells are mediated by activation of the MAPK pathway as blockade of this pathway abolished the observed effect, and direct activation of this pathway by transfection with an activated mutant of MEK1 was able to duplicate these effects. This mechanism may contribute to the growth and possibly local invasiveness of some pituitary tumours that express the EGF receptor.

Animals↗
PubMed2002

Long-term follow-up results of transsphenoidal surgery for Cushing's disease in a single centre using strict criteria for remission.

OBJECTIVE: Transsphenoidal selective adenomectomy (TSA) is widely accepted as the treatment of choice for Cushing's disease but not all patients are cured by this procedure. The success of surgery depends on the skill and experience of the surgeon but the criteria used to define remission are highly variable. We have analysed the outcome following surgery in our centre using the stringent requirement of a postoperative serum cortisol of < 50 nmol/l as our definition of remission and assessed whether changes in surgical policy, including a greater emphasis on selective procedures and the move in recent years to a single surgeon undertaking all pituitary surgery, have improved complication and remission rates. PATIENTS AND METHODS: The case notes, histology and pituitary imaging of 54 consecutive patients (42 females, mean age 41 years) with pituitary-dependent Cushing's syndrome who had undergone transsphenoidal surgery between January 1980 and November 2000 were reviewed. Follow-up was for a median of 6 years (range 6 months to 21 years). RESULTS: One patient died within 1 week of surgery (1.9%) and major morbidity occurred in eight patients (15%). Clinical and biochemical remission was achieved in 41 patients (77%) with only two recurrences (5%) to date. Success was related to tumour size with 37 (86%) of 43 intrasellar lesions successfully resected compared with only four (40%) of 10 extrasellar adenomas. Twenty-four (59%) of those in remission developed partial or complete hypopituitarism compared with four (33%) of those not in remission. The extent of surgical exploration predicted the development of hypopituitarism (88% total hypophysectomy, 33% hemihypophysectomy, 14% selective adenomectomy) but not remission (75% total hypophysectomy, 87% hemihypophysectomy, 71% selective adenomectomy). Among complications, an excess of venous thromboembolic disease was noted, with three patients (6%) developing deep venous thrombosis or pulmonary embolism postoperatively. Comparison of the data for individual surgeons revealed an improvement in outcome over time, with 100% remission of microadenomas, 29% hypopituitarism and 12% complications following the move to a single surgeon undertaking all pituitary surgery. CONCLUSION: Transsphenoidal surgery is a safe and effective treatment for Cushing's disease and our results compare favourably with those from published series, the majority of which comprise relatively small numbers. The presence of an intrasellar lesion and postoperative serum cortisol < 50 nmol/l are good predictors of remission in the long term but historically in our centre this can only be achieved in a significant number of patients at the expense of some degree of hypopituitarism. However, the surgical outcome for Cushing's disease, including a reduced frequency of hypopituitarism, can be improved if patients are operated on by a single pituitary surgeon, using selective adenomectomy as the preferred surgical approach wherever possible.

Adenoma↗
PubMed2002

Adenosine-regulated cell proliferation in pituitary folliculostellate and endocrine cells: differential roles for the A(1) and A(2B) adenosine receptors.

A(1) and A(2) adenosine receptors have been identified in the pituitary gland, but the cell type(s) on which they are located and their effects on pituitary cell growth are not known. Therefore, we analyzed the expression of A(1) and A(2) receptors in primary rat anterior pituitary cells, two pituitary folliculostellate (TtT/GF and Tpit/F1) and two pituitary endocrine (GH(3) and AtT20) cell lines, and compared their effects on cell proliferation. In anterior pituitary and folliculostellate cells, adenosine and adenosine receptor agonists (5'-N-ethylcarboxamidoadenosine, a universal agonist, and CGS 21680, an A(2A) receptor agonist) stimulated cAMP levels with a rank order of potency that indicates the presence of functional A(2B) receptors. This stimulation, however, was not observed in either GH(3) or AtT20 cells, where adenosine and the A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine inhibited VIP/forskolin-stimulated cAMP production. Expression of A(2B) and A(1) receptors in the folliculostellate cells and that of the A(1) receptor in the endocrine cells were confirmed by RT-PCR, immunocytochemistry, and ligand binding. Adenosine and 5'-N-ethylcarboxamidoadenosine dose-dependently (10 nM to 10 microM) stimulated growth in the folliculostellate, but not in the endocrine, cells, whereas in the latter, 100 microM adenosine and 2-chloro-N(6)-cyclopentyladenosine inhibited cell proliferation by slowing cell cycle progression. These data highlight the differential expression of A(1) and A(2B) adenosine receptors in pituitary cells and provide evidence for opposing effects of adenosine on pituitary folliculostellate and endocrine cell growth.

Adenosine↗
PubMed2000

A therapeutic trial of growth hormone in hypopituitary adults and its influence upon continued prescription by general practitioners.

OBJECTIVES: Adult GH deficiency (GHD) is associated with profound alterations in body composition, lipid profiles and quality of life which frequently improve after GH therapy. However, the beneficial effects of treatment are not derived by all and consequently some scepticism persists with regard to the use of GH therapy in adults. We assessed whether a 3-month therapeutic assessment with GH therapy could be used to determine which GHD adults should be treated over the longer term. We also assessed the continued prescription of GH by general practitioners (GPs) following the initial therapeutic assessment. DESIGN: A three month open therapeutic trial of GH in GHD adults. Patients were treated with GH at an initial dose of 0.01 iU/kg/d, increased after 1 month to 0.015 iU/kg/d for males and 0.02 iU/kg/d for females. After completion of the three months the continued prescription of GH by the GPs was assessed. PATIENTS: All adult GHD patients were considered for GH therapy. Thirty-nine GHD adults wanted GH therapy (group 1) and their baseline characteristics such as age, duration of GHD, and IGF-1 concentration were compared with 24 subjects who declined to receive GH (group 2). MEASUREMENTS: Measurements of body composition using bioelectrical impedance analysis, lipids and quality of life measured using a dedicated questionnaire were made before and after GH therapy. The response of the general practitioners to continued GH therapy after the initial therapeutic assessment was also noted. RESULTS: Compared with subjects who declined GH therapy (group 2), subjects of group 1 were younger (46.4 +/- 14.4 vs. 54.2 +/- 15.7 years, P < 0.05) and had lower peak GH responses to provocative testing (1.4 +/- 2.1 vs. 2.9 +/- 2.7 mU/l, P < 0.001), though there were no differences between IGF-1 concentration (11.7 +/- 6.2 vs. 14. 2 +/- 7.9 nmol/l). Following three months of GH therapy, there were significant improvements in all measured parameters including increased free fat mass (50.2 vs. 52.4 kg, P < 0.005) and total body water (37 vs. 38.7 l, P < 0.005), reduced fat mass (31.6 vs. 29.8 kg, P < 0.005), reduced AGHDA score (7 vs. 4, P < 0.001) and reduced cholesterol (6.3 vs. 5.8 mmol/l, P < 0.001), LDL (4 vs. 3.33 mmol/l, P < 0.001) and cholesterol/HDL ratio (5.57 vs. 4.67, P < 0.001). IGF-1 concentrations were significantly increased following treatment (12 vs. 32.4 nmol/l). Six subjects decided to discontinue GH therapy, 2 before the end of the study due to potential drug-related side-effects and 4 subjects derived no benefit from treatment. Despite the demonstrable benefits of treatment for the remaining 33 GHD adults, 6 GPs refused to continue to prescribe GH therapy for reasons of lack of familiarity with the drug or advice from their health authority. CONCLUSION: Patients who wanted GH therapy were usually younger and more severely GHD than counterparts who elect not to be treated. However, a therapeutic trial of GH therapy is required to distinguish those subjects who derive benefit from treatment. We have shown that three months of low dose GH therapy is a sufficient period to elicit significant beneficial responses in quality of life, body composition parameters and lipids for the majority of patients and appears to be a sufficient period for patients to decide whether they want longer term therapy. The initial therapeutic trial also provides the objective evidence for the general practitioners to decide upon the continued prescription of therapy. Despite the positive evidence provided by this study, a small minority of general practitioners still refuse to prescribe GH therapy.

Adult↗
PubMed1991

Keratinization is associated with the expression of a new protein related to the desmosomal cadherins DGII/III.

Amino acid sequencing of a 48/46 kDa glycoprotein from human plantar callus, recognised by antisera raised against the desmosomal cadherins DGII/III, has revealed N-terminal homology to the DNA-derived sequence of human and bovine DGII/III. However, a tryptic fragment has homology only with a bovine clone. We propose that there are two classes of DGII/III-like molecule, that represented by the bovine cDNA clone and the 48/46 kDa protein, a monoclonal antibody against which stains mainly the suprabasal layers of human epidermis, and that represented by the human cDNA clone, identified by a monoclonal antibody which stains uniformly the living layers of the epidermis.

Amino Acid Sequence↗
PubMed1991

Desmosomal glycoproteins II and III. Cadherin-like junctional molecules generated by alternative splicing.

We have cloned the human genes coding for desmosomal glycoproteins DGII and DGIII, found in desmosomal cell junctions, and sequencing shows that they are related to the cadherin family of cell adhesion molecules. Thus a new super family of cadherin-like molecules exists which also includes the other major desmosomal glycoprotein, DGI (Wheeler, G. N., Parker, A. E., Thomas, C. L., Ataliotis, P., Poynter, D., Arnemann, J., Rutman, A. J., Pidsley, S. C., Watt, F. M., Rees, D. A., Buxton, R. S., and Magee, A. I. (1991) Proc. Natl. Acad. Sci. U.S.A., in press). DGIII differs from DGII by the addition of a 46-base pair exon containing an in-frame stop codon resulting in mature protein molecular weights of 84,633 for DGII and 78,447 for DGIII. The unique carboxyl-terminal region of DGII contains a potential serine phosphorylation site explaining why only DGII is phosphorylated on serine. The cadherin cell adhesion recognition sequence (His-Ala-Val) is replaced by Phe-Ala-Thr, suggesting that DGII/III may be adhesive molecules using a different mechanism.

Amino Acid Sequence↗