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D G Lowe

Publications and source records attributed to D G Lowe.

At least 37 records · Page 2Linked to original sources
PubMed1999

Secondary reduction in the apparent diffusion coefficient of water, increase in cerebral blood volume, and delayed neuronal death after middle cerebral artery occlusion and early reperfusion in the rat.

It has been reported recently that very delayed damage can occur as a result of focal cerebral ischemia induced by vascular occlusion of short duration. With use of diffusion-, T2-, and contrast-enhanced dynamic magnetic resonance imaging (MRI) techniques, the occlusion time dependence together with the temporal profile for this delayed response in a rat model of transient focal cortical ischemia have been established. The distal branch of the middle cerebral artery was occluded for 20, 30, 45, or 90 minutes. Twenty minutes of vascular occlusion with reperfusion exhibited no significant mean change in either the apparent diffusion coefficient of water (ADC) or the T2 relaxation time at 6, 24, 48, or 72 hours after reperfusion (P = 0.97 and 0.70, respectively). Ninety minutes of ischemia caused dramatic tissue injury at 6 hours, as indicated by an increase in T2 relaxation times to 135% of the contralateral values (P < 0.01). However, at intermediate periods of ischemia (30 to 45 minutes), complete reversal of the ADC was seen at 6 hours after reperfusion but was followed by a secondary decline over time, such that a 25% reduction in tissue ADC was seen at 24 as compared with 6 hours (P < 0.02). This secondary response was accompanied by an increase in cerebral blood volume (CBV), as shown by contrast-enhanced dynamic MRI (120% of contralateral values; P < 0.001), an increase in T2 relaxation time (132%; P < 0.01), together with clear morphological signs of cell death. By day 18, the mean volume of missing cortical tissue measured with high-resolution MRI in animals occluded for 30 and 45 minutes was 50% smaller than that in 90-minute occluded animals (P < 0.005). These data show that ultimate infarct size is reduced after early reperfusion and is occlusion time dependent. The early tissue recovery that is seen with intermediate occlusion times can be followed by cell death, which has a delayed onset and is accompanied by an increase in CBV.

Animals↗
PubMed1999

Intracellular fragments of the natriuretic peptide receptor-C (NPR-C) attenuate dopamine efflux.

Natriuretic peptides suppress adrenergic neurotransmission by a mechanism apparently involving the natriuretic peptide receptor-C (NPR-C) rather than particulate guanylyl cyclase receptors. The bulk of evidence implicating the NPR-C in neuromodulatory effects relies on the pharmacological specificity of peptides believed to be specific for the NPR-C. This study tests for NPR-C effects on neurotransmitter release by examining fragments of the receptor for biological activity in pheochromocytoma (PC12) cells permeabilized with digitonin. A pentadecapeptide segment of the cytoplasmic portion of the NPR-C mimicked the effect of natriuretic peptides to suppress dopamine efflux evoked by calcium approximately 40%. Furthermore, an antibody generated against the pentadecapeptide fragment abolished the neuromodulatory effect of C-type natriuretic peptide in permeabilized cells. In contrast, the carboxy terminal nonadecapeptide portion of the NPR-C failed to attenuate dopamine efflux. These data are consistent with the proposed role of the NPR-C in transducing the biological activity of natriuretic peptides in adrenergic tissue. The most novel aspect of these observations involves the potency of the small cytosolic region of the NPR-C with the region closest to the membrane accounting for neuromodulatory effects.

Adenylyl Cyclases↗
PubMed1999

Low expression of the cell cycle inhibitor p27Kip1 in normal corticotroph cells, corticotroph tumors, and malignant pituitary tumors.

The cell cycle is regulated by a number of inhibitors, including p27Kip1 (p27), which belongs to the kip1 family. By binding to the cyclin/cyclin-dependent kinase complexes, it regulates progression of G1 to S phase in the cell cycle. It has been reported that p27 knockout mice develop multiorgan hyperplasia and intermediate lobe pituitary tumors secreting ACTH. Previously, we and others have been unable to show any consistent change in messenger RNA expression or genomic mutations for p27 in human corticotroph adenomas. However, dysregulation at the protein level has been reported in nonendocrine tumors, and we, therefore, investigated the expression of p27 in a range of benign and metastatic pituitary tumors. We studied a total of 107 pituitaries, including normal pituitary (n = 20), Cushing's disease (n = 21), acromegaly (n = 19), nonfunctioning adenomas (n = 18), prolactinomas (n = 7), TSH-omas (n = 2), FSH-omas (n = 6), aggressive tumors showing invasiveness and recurrence (n = 9), and metastatic pituitary carcinomas (n = 5). Using standard immunohistochemical techniques with a highly specific monoclonal antibody, p27 expression was determined quantitatively as the percentage of cells showing strongly positive, weak, or negative staining. In each sample, approximately 500 cells were analyzed. We also analyzed normal pituitaries using double-labeling for p27 and each of the pituitary hormones to characterize the expression of p27 in each cell type. p27 was expressed in normal pituitary cells; in tumors expressing GH, prolactin, TSH, and FSH; and in aggressive tumors, but markedly reduced expression of p27 was seen in corticotroph tumors and pituitary carcinomas. In the normal pituitary, somatotroph, lactotroph, and thyrotroph cells showed strong p27 staining, whereas normal corticotroph cells showed a much lower level of p27 staining (P < 0.001). Somatotroph, lactotroph, gonadotroph, and thyrotroph adenomas showed a lower level of p27 expression compared with normal somatotrophs (P = 0.02), lactotrophs (P = 0.03), gonadotrophs (P = 0.01), and thyrotrophs, respectively, whereas the lower level of p27 expression present in normal corticotrophs virtually disappeared in corticotroph adenomas (P = 0.001). We conclude that pituitary adenomas show a lower level of p27 protein expression than the normal cells from which they are derived, with malignant transformation leading to complete loss of p27 immunoreactivity. Corticotrophs are quite different to other pituitary cell types in terms of p27 immunoreactivity because both normal and tumorous corticotrophs have low p27 staining, and we speculate that this may relate to their inherent control mechanisms.

Adenoma↗
PubMed1998

Mutation and expression analysis of the p27/kip1 gene in corticotrophin-secreting tumours.

The molecular mechanisms leading to Cushing's disease are unclear. Inhibitors of cyclin-cyclin dependent kinase (CDK) complexes are regulators of the cell cycle and may function as tumour suppressor genes, many of which have been involved in the pathogenesis of several human malignancies. A member of this family, the p27/kip1 gene, maps to chromosome 12p13 and encodes an inhibitor of several cyclin-CDK complexes; these control the progression of the cell cycle from G1 to S-phase. Complete lack of p27/kip1 function, as occurs in the p27/kip1 'knockout' mouse, produces a complex phenotype associated with the development of pituitary tumours, specifically those of the intermediate lobe corticotrophs. We therefore investigated whether structural and functional abnormalities of the p27/kip1 gene and loss at the chromosome 12p13 region were present in human corticotrophin (ACTH)-secreting pituitary tumours. We studied 21 pituitary tumours, of which 20 were ACTH-secreting (two of these had biochemical and histological features of 'intermediate-lobe' tumours and one was malignant) while the remaining tumour was a prolactinoma; three ectopic secretors of ACTH (two bronchial and one thymic carcinoid); and a non-secretory thymic carcinoid. The whole coding region of the p27/ kip1 gene was screened for mutations by PCR-SSCP analysis and/or direct sequencing, while tumour mRNA expression was analysed by means of a semi-quantitative duplex PCR. Three polymorphic microsatellite markers of the 12p13 region were used to assess loss of heterozygosity (LOH) in 12 samples. Finally, tumour p27/kip1 protein expression was assessed by immunohistochemistry using a monoclonal antibody in 12 samples suitable for analysis. No sequence abnormalities were found in any of the samples other than a previously-described polymorphism. No LOH was observed in the tumours analysed. p27/kip1 mRNA expression was similar in tumour samples in comparison with normal pituitaries. Seven of the eight corticotroph tumours analysed by immunohistochemistry stained positive for p27/kip1, including the intermediate lobe. The only malignant pituitary tumour in the original series showed an absence of staining for p27/kip1. In addition, the three carcinoid tumours studied were negative on immunohistochemistry. Of a further three malignant pituitary tumours assessed, two (including a prolactinoma) were essentially negative, while the third was moderately positive. We conclude that mutations of the p27/kip1 gene, deletions of the 12p13 area or changes in expression, are not a general feature of corticotroph tumours, even those with intermediate lobe characteristics. However, other mechanisms of p27/kip1 inactivation, such as an abnormality at the post-translational level, may be related to more aggressive histological subtypes of ACTH-secreting and possibly other pituitary tumours.

Adrenocorticotropic Hormone↗
PubMed1998

Distinct molecular phenotypes in murine cardiac muscle development, growth, and hypertrophy.

The onset of cardiac hypertrophy is associated with characteristic changes in myocardial gene expression that are thought to recapitulate a developmental gene program. We report here the first gene expression profile of the murine myocardium, using a rapid method of quantitative expression analysis based on real-time analytical RT-PCR. This assay was used to measure expression levels of 29 genes in (1) late stage development as represented by day 1 neonatal ventricles, (2) normal cardiac growth in 3 and 18 month old mice, and (3) cardiac hypertrophy following pressure overload by aortic constriction. For males and females normal growth is not associated with differential expression although there is elevated expression of skeletal and smooth muscle actin mRNA's in males compared to females. Using normal adult ventricles as a reference, there are many qualitative and quantitative differences between the day 1 neonatal myocardium and experimental cardiac hypertrophy. These data suggest that the response to POL involves a subset of re-expressed developmental genes together with altered expression of genes not necessarily associated with cardiac development.

Animals↗
PubMed1998

Receptor-specific ligands distinguish natriuretic peptide receptors-A and -C in primate tissues.

Systemic clearance of atrial natriuretic peptide (ANP) is in part due to neutral endopeptidase (NEP) proteolysis and natriuretic peptide receptor-C (NPR-C) mediated endocytosis. Biological responses to ANP are primarily mediated by the membrane guanylyl cyclase-A/natriuretic peptide receptor-A (NPR-A). Analogs of ANP selective for NPR-A and/or resistant to NEP may have increased activity in those tissues where NPR-C and NEP are coexpressed with NPR-A. The analog of ANP termed vANP; [(R3D, G9T, R11S, M12L, G16R)ANP] is selective for human NPR-A with at least 10,000 fold reduction in affinity for human NPR-C. We report that rat NPR-A is insensitive to 10 nM vANP, demonstrating the limitations of this species in evaluating human therapeutic candidates. As an alternative approach we tested the binding and potency of receptor-selective and NEP-resistant ANP analogs in rhesus monkey tissues. Competition binding studies with a simplified version of vANP, sANP [(G9T, R11S, G16R)rANP], in rhesus monkey kidney and lung membrane preparations shows displacement of 125I-ANP from only a fraction of the total ANP receptor population, 30 and 85%, respectively. The remaining ANP binding sites can be occupied with the NPR-C selective ligand cANP(4-23). These data strongly suggest that only two classes of ANP receptor are present in these membrane preparations, NPR-A and NPR-C. The NEP resistant sANP derivative called sANP(TAPR) was 8 fold more potent (ED50 = 0.6 nM) than rANP (ED50 = 5 nM) in stimulating cGMP production in the lung membrane preparation. Our results demonstrate that the rhesus monkey natriuretic peptide receptors reflect the pharmacology of the human receptors, and that this species may be suitable to determine the role of NPR-C and NEP in peptide clearance and attenuating functional responses.

Amino Acid Sequence↗
PubMed1998

Luteinizing hormone secreting adrenal tumour as a cause of precocious puberty.

A boy aged 6 years presented with genital precocity, enlarged testes and advanced linear growth. An ovoid mass 3-4 cm in diameter was identified by MRI scan in the right adrenal gland. Serum concentrations of LH, testosterone, alpha-subnuit, dehydroepiandrosterone sulphate, androstenedione and oestradiol were persistently elevated. LH was unresponsive to bolus i.v. injection of GnRH or to GnRH analogue therapy. Serum FSH was normal. After removal of the adrenal tumour, serum LH, alpha-subunit, testosterone and adrenal androgen levels fell to normal. In incubation medium of cultured disaggregated tumour cells, LH concentrations were greater than twice the mean serum concentration and 4-5-fold higher than in the medium of cultured non-neoplastic adrenal cells. Specific immunostaining of the tumour was positive for LH and alpha-subunit in many areas and these were not found in the adjacent non-neoplastic adrenal. Testicular biopsy showed almost complete spermatogenesis although germinal cell types were numerically lower than in normal men. These findings are consistent with an adrenocortical adenoma secreting LH being the cause of the patient's precocious puberty.

Adenoma↗
PubMed1998

Carcinoid tumours presenting as breast cancer: the utility of radionuclide imaging with 123I-MIBG and 111In-DTPA pentetreotide.

Secondary tumours of any type in the breast are rare. A review of the literature demonstrated only 23 cases of carcinoid tumours with associated breast metastasis, as distinct from primary carcinoid tumours of the breast. Distant metastases from carcinoid tumours are correlated with poor prognosis and survival. Although both primary and metastatic mammary carcinoid tumours are uncommon, the recognition of the true origin of the tumours may be of importance owing to the different clinical management and prognosis of the two conditions. Recently, radionuclide-labelled imaging techniques have been applied to the localization of such lesions, based on isotope uptake by receptors present in these neuroendocrine tumours. We report two new cases of carcinoid tumours with breast metastases, the primaries being in the ileocaecal valve and the bronchus, respectively. The diagnosis of a carcinoid tumour was based on the clinical, biochemical, histopathological and immunostaining features. Furthermore, these patients had both 123I-MIBG and 111In pentetreotide scintigraphy performed. These radionuclides play a useful role in the localization and potentially in the management of carcinoid tumours and their distant metastases.

3-Iodobenzylguanidine↗
PubMed1998

Emergency and prolonged use of intravenous etomidate to control hypercortisolemia in a patient with Cushing's syndrome and peritonitis.

We report the emergency and prolonged use of etomidate to control circulating cortisol levels in a patient with Cushing's syndrome secondary to ectopic ACTH production from a pancreatic islet cell tumor. Duodenal perforation and peritonitis complicated an episode of salmonella septicemia, precluding the use of conventional oral medical adrenolytic therapy. Endogenous cortisol secretion was abolished by parenteral etomidate, allowing serum cortisol levels to be controlled with an iv infusion of hydrocortisone over an 8-week period in intensive care before definitive pancreatic surgery.

Adenoma, Islet Cell↗
PubMed1998

ABS to MRCS at the RCS: philosophy, format and future.

After considering the ABS and CSiG parts of the FRCS examination and the standard for the new MRCS examination, it became important that the MRCS evolved away from the template of multiple true-false questions. Formats other than true-false questions can be used to test mental processes that are not simple factual recall. Formal mathematical tests can be evolved to equate different parts of the examination so that raw marks can be more clearly related to grades. Dispensing with the arbitrary requirement for five items in an MCQ question will enable better questions to be asked. Finally, an examination must be valid in context. With the above advances the examination will be effective, but its goal can be assessed only if the vision of the MRCS learning course is attained. The course aims to prepare surgeons for higher surgical training with a good general knowledge of surgery and an in-depth knowledge of the basic principles of surgery. The surgical trainee who has attained the MRCS should be able to manage a sick patient who suffers from the complications associated with surgery by using the principles of surgical anatomy, physiology and pathology. The trainee should know what to do initially during the 'golden hour' of opportunity, whom to call for help, and when.

Education, Medical, Graduate↗
PubMed1997

Mutations in B-type natriuretic peptide mediating receptor-A selectivity.

Libraries of monovalent display-phage expressing mutant human B-type natriuretic peptide (hBNP) were used to identify variants that preferentially bind natriuretic peptide receptor-A (NPR-A) compared to receptor-C (NPR-C). Position 19 was a significant determinant of receptor specificity for hBNP display phage. The synthetic hBNP variant S19R had a 265-fold improved NPR-A binding over NPR-C, analogous to the atrial natriuretic peptide (ANP) specificity mutation G16R. Mutation of the last three residues of the hBNP disulfide ring, G23F/L24W/G25R, resulted in about 9-fold improved selectivity. The analogous mutations in ANP decreased NPR-A binding, suggesting divergence in the mechanism of NPR-A recognition.

Amino Acid Sequence↗
PubMed1997

Downregulation of natriuretic peptide C-receptor protein in the hypertrophied ventricle of the aortovenocaval fistula rat.

OBJECTIVES: This study examined the expression of the C-type receptor for the natriuretic peptide family (NPR-C) in the ventricles of normal and aortovenocaval (AV)-fistula rats, the latter a model of cardiac volume overload producing hypertrophy of both ventricles. METHODS: Western blotting with a rabbit anti-NPR-C antibody was used to quantify NPR-C levels in ventricular membranes. NPR-C expression was localised anatomically and measured in frozen sections of cardiac tissue by histochemistry and in vitro autoradiography. RESULTS: Western blot analysis revealed a single band (approximately 120 kDa) in ventricular membranes which was reduced to approximately 60 kDa after treatment with beta-mercaptoethanol. NPR-C immunoreactivity and [125I]rat ANP1-28 binding (displaceable by the NPR-C-specific ligand C-ANP 4-23) were localised to the endocardium. NPR-C protein levels, as measured by all three techniques, were reduced significantly in the hypertrophied ventricles of AV-fistula rats compared to sham-operated animals. CONCLUSIONS: Volume-induced cardiac hypertrophy in the AV-fistula rat is associated with downregulation of endocardial NPR-C. This may be one mechanism by which the endocardium regulates the myocardial response to changes in haemodynamic load.

Animals↗
PubMed1997

Intracardiac metastases from neuroendocrine tumours.

We report three cases of intra-cardiac metastases from neuroendocrine tumours of the carcinoid type. One presented in a manner identical to a left atrial myxoma; in one patient a left atrial mass was noted during investigations for weight loss and a lung mass; and in the third, two right ventricular deposits were detected on echocardiography when a patient with a disseminated GHRH-secreting tumour was investigated for dyspnoea. Although to our knowledge this is only the third report of these lesions, we believe that this represents a form of carcinoid heart disease that is distinct from the valvular abnormalities seen in some patients with carcinoid syndrome. Neuroendocrine metastases should be considered in the differential diagnosis of intra-cardiac tumours.

Adult↗
PubMed1997

Acromegaly, colonic polyps and carcinoma.

OBJECTIVE: It has been suggested that patients with acromegaly may be at risk of developing colorectal carcinoma. In order to clarify this issue, we have evaluated the prevalence of carcinoma, premalignant tubulovillous adenomas and hyperplastic colonic polyps in a large cohort of patients with acromegaly. DESIGN: Prospective colonoscopic examination by a single operator. PATIENTS: One hundred and twenty-nine patients with biochemically proven acromegaly. RESULTS: At least one lesion was visualized in 63 patients. Adenocarcinoma was present in six patients (5%), but only two had symptoms; all lesions were endoscopically obvious. Compared with a normal group, the odds ratio of colorectal cancer is increased at 13.5 (95% confidence intervals (c.i.) 3.1-75). One or more tubulovillous adenoma was found in 34 patients (26%) and this prevalence was age-dependent, occurring in 39% of patients aged 70 years or over. Comparing the prevalence of left-sided colonic adenomas with that in a normal group, there is a higher prevalence among patients over 49 years with an odds ratio of 4.2 (95% c.i. 2.5-6.8). Patients with acromegaly who had an adenoma were significantly older than unaffected patients (61.9 vs 54.1 years; P < 0.001) but had similar GH and IGF-1 levels and duration of disease. CONCLUSIONS: Patients with acromegaly have an increased risk of developing colorectal cancer and a significantly higher prevalence of tubulovillous adenomas compared with normal subjects. Routine surveillance colonoscopy is indicated in this group of patients.

Acromegaly↗
PubMed1997

Metastatic parathyroid carcinoma in the MEN2A syndrome.

We report a patient with a metastatic parathyroid carcinoma and medullary carcinoma of the thyroid. This patient represents a variation of the multiple endocrine neoplasia syndrome (MEN) type 2A. There was no evidence of a phaeochromocytoma. The case illustrates the difficulties that may be encountered in localising the source of PTH secretion; the patient underwent four unsuccessful exploratory operations of the neck and mediastinum before further investigations revealed a single metastatic deposit of parathyroid carcinoma involving the first thoracic vertebra. PCR amplification and sequencing of the RET oncogene from the metastatic parathyroid carcinoma and genomic DNA revealed a heterozygous mutation (Cys634Tyr) in exon 11, as has previously been described to occur in MEN 2A. In addition, loss of tumour heterozygosity was demonstrated at loci from chromosomes 1, 2, 3p, 13q and 16p. This represents the first report of a parathyroid carcinoma in a MEN2A patient, in which the multiple allelic deletions are consistent with the generalised losses observed in aggressive tumours.

Carcinoma↗
PubMed1997

Basal cell carcinoma of the vulva: a clinicopathologic study of 45 cases.

Basal cell carcinoma (BCC) of the vulva is rare, accounting for 4.9% of primary vulvar cancers in our material. We present a study of 45 of these cases. Patients' age at presentation ranged from 60 to 92 years (mean 76 years). Symptoms were not specific, the most common being vulvar pruritus, and no specific etiological factors were apparent. Delayed treatment was frequent. The gross appearance was of a nodule or polyp, ulcer, or area of pigmentation or depigmentation; few were diagnosed as BCC before microscopic examination. Histologically, almost half were of infiltrative type, none was of morpheic type, and six contained areas of adenoid BCC. There were lymph node metastases from one large, deeply invasive BCC. After follow-up of 1 to 112 months (mean 59 months), four (9%) tumors recurred, three of which had been incompletely excised. The metastasizing tumor recurred locally after 23 months, despite apparent complete excision, and resulted in the only death from disease. Unrelated disease killed 19 patients, and 25 were alive at last follow-up. Our findings indicate that vulvar BCC usually behaves in a benign fashion, but is potentially fatal.

Aged↗
PubMed1997

Clinical, radiological and pathological features of patients with Rathke's cleft cysts: tumors that may recur.

Rathke's cleft cysts are cystic sellar and suprasellar lesions, characteristically lined by a single layer of ciliated cuboidal or columnar epithelium. In contrast, craniopharyngiomass, which are also cystic sellar and suprasellar lesions, are characteristically lined by stratified squamous epithelium with keratinization on a layer of connective tissue. The usual management recommended for Rathke's cleft cysts is simple surgical drainage with partial excision of the cyst wall. Recurrences of these cysts reportedly have been very rare. This retrospective study presents the details of 12 patients (6 females; median age 30 yr, range 21-58 yr) with Rathke's cleft cyst, referred to our department over a 15-yr period (1981-1996), an unusual feature being the recurrence of 4 (33%) of these lesions. Clinical, endocrine, radiological, surgical (10 transsphenoidal; 2 transcranial), and pathological details were recorded. Nine out of 12 patients (75%) were symptomatic; visual symptoms were the commonest, and 8 had visual field defects. The median duration of symptoms was 12 months (range 3-24 months). Three patients (25%) had panhypopituitarism, 2 of whom also had diabetes insipidus (17%). The cysts varied in size from 6 mm to 50 mm, 1 being entirely suprasellar. There were no pathognomonic clinical or radiological features to differentiate them from other pituitary lesions, although the presence of diabetes insipidus in 2 patients suggested that the lesion was not a pituitary adenoma. A definite histological diagnosis was possible in 8 patients; in 4, the diagnosis was presumptive. The median duration of follow-up was 30 months (1-168 months). Four patients (33%) showed reexpansion at 3, 6, 48, and 48 months after initial surgery, 3 of whom were symptomatic and required repeat surgery. Two of these patients were given postoperative external beam pituitary radiotherapy. Apparent recurrence of Rathke's cleft cysts after initially successful surgery in our series was higher than suggested by previous reports, and thus, long-term follow-up with pituitary imaging and neuroophthalmological assessment is essential. There are no specific characteristics of the cyst that predict recurrence. Ideal management of these cysts is unclear, but aspiration, followed by extensive excision of the cyst wall when possible, seems to be the best initial option. For recurrent symptomatic tumors, surgical resection is the treatment of choice. Considering the high recurrence rate with residual structural and functional dysfunction, the role of radiotherapy in preventing recurrence of these cysts needs careful evaluation with a larger study with a longer follow-up period.

Adult↗