Gastric pacing for diabetic gastroparesis--does it work?

The management of diabetic gastroparesis resistant to medical therapy is very difficult Gastric electrical stimulation (GES) is a relatively new therapeutic modality which has shown some promise in international trials. It has seen use in four patients in Ireland. Our aim was to determine if GES improved patients' outcomes in terms of duration and cost of inpatient stay and glycaemic control. We reviewed the patients' case notes and calculated the number of days spent as an inpatient with symptomatic gastroparesis pre and post pacemaker, the total cost of these admissions, and patients' average HbA1c pre and post GES. Mean length of stay in the year pre GES was 81.75 days and 62.25 days in the year post GES (p=0.89). There was also no improvement in glycaemic control following GES. GES has been ineffective in improving length of inpatient stay and glycaemic control in our small patient cohort.

Isolated acquired ACTH deficiency and primary hypothyroidism: a short series and review.

Idiopathic isolated ACTH deficiency, congenital or acquired, is rare. It may be found in association with primary hypothyroidism. Here we describe four cases of acquired idiopathic isolated ACTH deficiency illustrating its importance and variable presentation. All cases had a structurally normal pituitary gland and persistently normal residual pituitary function. Three cases had co-existing primary hypothyroidism. We discuss the protean presentation of this rare but important condition, its treatment, associations, and possible aetiologies.

Coeliac disease and autoimmune Addison's disease: a clinical pitfall.

BACKGROUND: Coeliac disease has an increased prevalence in a number of autoimmune endocrine conditions. An association between coeliac disease and Addison's disease has been proposed in isolated case reports, but has not been formally studied. AIM: To investigate the extent of this association. DESIGN: Prospective screening of patients with confirmed Addison's disease. METHODS: From central computerized records, we identified all living patients with a diagnosis of autoimmune Addison's disease in the past 30 years and presently attending our affiliated hospitals. After exclusions, 44 were invited to attend for screening. RESULTS: Of 41 patients screened, five (12.2%) had coeliac disease: Three were previously diagnosed coeliacs and this was confirmed on review, including examination of biopsy material. A further two had positive IgA-endomysial antibodies. Histological confirmation was obtained in both cases. Neither had laboratory or clinical evidence of malabsorption. DISCUSSION: In this series of patients with Addison's disease, a higher co-morbidity with coeliac disease was observed than in any previously studied endocrine condition. We recommend that coeliac serology (anti-endomysial and tissue transglutaminase antibody) testing be incorporated routinely into the autoimmune screen for other conditions in patients with Addison's disease.

Fungal infection of the diabetic foot: two distinct syndromes.

AIMS: Fungal infection of diabetic foot ulcers has not been described. We analysed the features of 17 patients with diabetic foot ulcers probably infected with fungi. METHODS: Seventeen patients were identified with clinically infected foot ulcers, (i) which had failed to heal despite prolonged antibiotic therapy and intensive podiatric care, (ii) from which Candida spp. was isolated or hyphae +/- yeasts were visualized in material from ulcers or surrounding skin. RESULTS: Multiple ulcers arising simultaneously were present in 10 patients (59%), preceded by blistering in seven cases. Single ulcers with markedly ulcerated margins were present in seven (41%) patients and were preceded by blisters in two. All 17 cases had neuropathy and 15 (88%) had severe peripheral vascular disease. All ulcers responded to antifungal therapy. CONCLUSIONS: Candida spp. is associated with two distinctive patterns of protracted ulceration in diabetic feet which improve following systemic antifungal therapy. Diabet. Med. 18, 567-572 (2001)

The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia.

Organisms survive by maintaining equilibrium with their environment. The stress system is critical to this homeostasis. Glucocorticoids modulate the stress response at a molecular level by altering gene expression, transcription, and translation, among other pathways. The effect is the inhibition of the functions of inflammatory cells, predominantly mediated through inhibition of cytokines, such as IL-1, IL-6, and TNF-alpha. The central effectors of the stress response are the corticotrophin-releasing hormone (CRH) and locus coeruleus-norepinephrine (LC-NE)/sympathetic systems. The CRH system activates the stress response and is subject to modulation by cytokines, hormones, and neurotransmitters. Glucocorticoids also modulate the growth, reproductive and thyroid axes. Abnormalities of stress system activation have been shown in inflammatory diseases such as rheumatoid arthritis, as well as behavioural syndromes such as melancholic depression. These disorders are comparable to those seen in rats whose CRH system is genetically abnormal. Thus, the stress response is central to resistance to inflammatory and behavioural syndromes. In this review, we describe the response to stress at molecular, cellular, neuroendocrine and behavioural levels, and discuss the disease processes that result from a dysregulation of this response, as well as recent developments in their treatment.

Type 1 diabetes mellitus, coeliac disease, and lymphoma: a report of four cases.

INTRODUCTION: Patients with Type 1 diabetes mellitus have a high prevalence of coeliac disease, symptoms of which are often mild, atypical, or absent. Untreated coeliac disease is associated with an increased risk of malignancy, particularly of lymphoma. We describe four patients with Type 1 diabetes mellitus and coeliac disease who developed lymphoma. CASE REPORTS: Two patients were male and two female. In three patients, coeliac disease and lymphoma were diagnosed simultaneously. Enteropathy-associated T cell lymphoma occurred in two patients, Hodgkin's disease in one, and B cell lymphoma in one. Response to treatment was in general poor, and three patients died soon after the diagnosis of lymphoma was made. CONCLUSION: As the relative risk of lymphoma is reduced by a gluten-free diet, a high index of suspicion for coeliac disease should exist in all Type 1 diabetic patients with unexplained constitutional or gastrointestinal symptoms.

Novel DAX1 mutations in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism.

OBJECTIVE: Mutations of the DAX1 gene (Dosage-sensitive sex reversal-Adrenal hypoplasia congenita critical region on the X chromosome gene 1), which encodes a novel orphan nuclear receptor, have been identified in patients with X-linked adrenal hypoplasia congenita (AHC) and hypogonadotrophic hypogonadism (HHG). We have investigated two kindreds with AHC and HHG for DAX1 mutations. METHODS: Two kindreds with five affected males, four carrier females and four unaffected males were investigated. The gonadotrophin deficiency in three of the boys was observed to be partial until mid-puberty. DAX1 mutations in the entire 1413 bp coding region were sought by DNA sequence analysis. RESULTS: Two DAX1 mutations, situated within exon 1, were detected. These consisted of an insertional mutation at codon 183 that led to a frameshift and a premature Stop at codon 184, and a missense mutation Leu278Pro that involved a highly conserved leucine residue within the proposed ligand binding domain. Co-segregation of these mutations with the disease in each family, and their absence from 107 alleles in 73 (39 males and 34 females) unrelated control individuals, was demonstrated by allele specific oligonucleotide hybridization (ASO) analysis for the insertional mutation, and by Ban I restriction endonuclease analysis for the missense mutation. CONCLUSIONS: Two novel DAX1 mutations have been detected in two families with adrenal hypoplasia and hypogonadotrophic hypogonadism. The finding of partial gonadotrophin deficiency in the affected males from these families is notable and an early recognition of such a possibility in a patient, which may be facilitated by DAX1 mutational analysis, may help to prevent the sequelae of delayed androgen replacement therapy.

Increased serum lipoprotein(a) concentrations after growth hormone (GH) treatment in patients with isolated GH deficiency.

Fourteen post-pubertal subjects (11 male, 3 female) with isolated growth hormone (GH) deficiency were treated with a low dose (0.125 U/kg for the first 4 weeks and thereafter 0.25 U/kg/week) daily sc GH injection for 1 year. Fasting blood samples were collected at entry into the study and subsequently at 3 monthly intervals for estimation of serum cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol and lipoprotein(a) [Lp(a)]. Serum Lp(a) increased progressively during the treatment period (by analysis of variance) and was 41% higher at 12 months (P < 0.02) despite the fact that five patients showed little or no change. There was no significant change in any of the other lipid fractions. These observations are of concern as Lp(a) is an independent risk factor for cardiovascular disease and should introduce a cautionary note into the enthusiastic efforts to offer GH replacement to all GH deficient adults.

Acromegaly: unravelling a complex disease.

Acromegaly is a rare endocrine disorder characterized by growth hormone hypersecretion and is usually caused by a pituitary macroadenoma. It is associated with significantly increased patient morbidity and mortality. Molecular biological studies have implicated a causative role for oncogenic mutations (activating Gs alpha mutations and/or chromosomal 11q13 deletions) in less than 50% of cases. The cause(s) in the remaining 50% is speculative. Epidemiological evidence indicates that biochemical cure is achieved when mean GH levels are 5mU/l or less during a day-profile. This GH value correlates well with that required to normalize the serum IGF-1 concentration, a GH-dependent peptide which can be used to monitor the disease activity in acromegaly. Treatment must be carried out under the supervision of a dedicated endocrinologist and tailored to patients needs. The success of any treatment modality (surgery/pituitary irradiation/medical) depends on adenoma size and the extent of pretreatment GH hypersecretion. A combination of therapies is usually required to achieve satisfactory control of adenoma growth and GH hypersecretion. Octreotide, a synthetic analogue of native somatostatin, is particularly effective in controlling GH hypersecretion in this condition and the widespread introduction of a long-acting depot preparation is eagerly awaited. The development of true GH deficiency as a result of treatment is potentially worrying in view of its possible contribution to the increased incidence of cardiovascular mortality associated with hypopituitarism.

Further increase in forearm cortical bone mineral content after discontinuation of growth hormone replacement.

OBJECTIVE: Growth hormone replacement of adults with childhood onset GH deficiency results in an increase in bone mineral density (BMD) after 6-12 months of GH replacement. By measuring BMD 12 months after discontinuation of GH replacement we aimed to investigate whether there is an effect of GH replacement on BMD persisting after GH has been withdrawn. DESIGN: BMD was measured 13 +/- 1 (mean +/- SE, range 11-16) months after discontinuation of GH replacement. PATIENTS: Ten adults, age 23.2 +/- 1.4 (range 18.8-32.4) years, with childhood onset isolated GH deficiency (2 idiopathic, 8 irradiation induced) who had previously completed a study of the effect of 12 months of GH replacement on BMD. MEASUREMENTS: Forearm cortical bone mineral content (BMC) was measured using single-photon absorptiometry at the proximal site of the distal forearm. Forearm integral BMC at the ultradistal site of the forearm and bone width at both proximal and ultradistal sites of the distal forearm were measured by the same technique. Vertebral trabecular BMD was measured using quantitative computed tomography. RESULTS: Forearm cortical BMC was significantly greater than that measured at the time of discontinuation of GH (1.48 +/- 0.04 vs 1.44 +/- 0.05 g/cm). There was no significant change in forearm integral BMC or in vertebral trabecular BMD after discontinuation of GH. There was no significant change in bone width at proximal and ultradistal sites of the distal forearm after discontinuation of GH. CONCLUSION: After discontinuation of GH replacement the further increase in forearm cortical bone mineral content without a significant increase in forearm bone width suggests that the increase in cortical bone mineral content is due to a persisting effect of previous GH replacement, and not to further spontaneous attainment of bone mass before peak bone mass is reached. These findings emphasize the importance of continuing to monitor bone mass after the stimulus to increase bone turnover has been withdrawn.

A family pedigree exhibiting features of both multiple endocrine neoplasia type 1 and McCune-Albright syndromes.

The multiple endocrine neoplasia (MEN) type 1 and McCune-Albright syndromes share many clinical and biochemical characteristics. This report documents for the first time the occurrence and natural history of the McCune-Albright syndrome in a female with a strong family history of MEN type 1. There may be a functional link between both of these conditions, and there is a need to look for G-protein mutations as a mechanism for disease in MEN type 1.

Relationships between insulin-like growth factor-1 levels and growth hormone concentrations during diurnal profiles and following oral glucose in acromegaly.

OBJECTIVE: The aim of this study was to refine the biochemical definition of disease activity in acromegaly by comparing serum growth hormone (GH) measurements during a 10-hour day profile with serum GH values during an oral glucose tolerance test. DESIGN: Using plasma insulin-like growth factor-1 (IGF-1) levels as a measure of disease activity, serum GH data from a day profile and from an oral glucose tolerance test were compared. PATIENTS: Thirty-five acromegalic patients were studied, 13 of whom had serum GH measured during a day profile and 22 during an oral glucose tolerance test. In addition, basal plasma IGF-1 levels were estimated in all acromegalic patients, and in 24 normal subjects. MEASUREMENTS: Following acid-ethanol extraction of the plasma samples, IGF-1 levels were measured by radioimmunoassay using a polyclonal antibody. In a day profile, six to eight blood samples for serum GH estimation were taken at hourly intervals during the day; during an oral glucose tolerance test samples for serum GH estimation were taken in the fasting state and every 30 minutes for 2 hours and measured by a two-site IRMA for GH. RESULTS: Ninety-four per cent of acromegalic patients with raised plasma IGF-1 levels had serum GH concentrations > 10 mU/l whilst 98% of acromegalic patients with plasma IGF-1 levels in the normal range had serum GH concentrations < 6 mU/l. A highly significant positive correlation was found between the mean serum GH concentrations (r = 0.67), the minimum serum GH concentration (r = 0.65) and the area under the GH curve (r = 0.66) estimated during an oral glucose tolerance test and plasma IGF-1 concentrations. The relations between identical indices of serum GH concentration measured during a day profile and plasma IGF-1 levels, although significant, show a less powerful correlation. The relation between serum GH and plasma IGF-1 levels describes a curvilinear model, plasma IGF-1 levels exhibiting a plateau at serum GH concentrations > 40 mU/l but maintaining a linear relationship with serum GH levels < 20 mU/l. CONCLUSIONS: A highly significant correlation exists between plasma IGF-1 levels and various parameters of serum GH levels in acromegalic patients. Hormonal assessment of disease activity in acromegaly is more accurately reflected by the serum GH concentration during an oral glucose tolerance test rather than by the serum GH level during a day profile. Normalization of plasma IGF-1 levels is rarely achieved unless the mean serum GH level is reduced to < 6 mU/l.

Increased bone density after recombinant human growth hormone (GH) therapy in adults with isolated GH deficiency.

The physiological role of GH in the adult skeleton is unknown. In this study, 12 adults (10 males and 2 females) with isolated GH deficiency were treated with GH as a single daily sc injection (0.125 IU/kg.week for the first 4 weeks and subsequently at 0.25 IU/kg.week) for 1 yr in a double blind, placebo-controlled manner. Bone mineral density of the spine (T12-L3) was measured by quantitative computed tomography, and bone mineral content (BMC) of the forearm by single photon absorptiometry at entry into the study and subsequently at 6 monthly intervals. All baseline bone mineral measurements were reduced compared with those in an age- and sex-matched control population. In the treatment cohort, quantitative computed tomography spinal trabecular bone mineral density increased by 7.8 g/L after 6 months of GH replacement (mean +/- SEM, 151.7 +/- 6.0 vs. 159.5 +/- 5.9 g/L; n = 11; P < 0.01), and this increment was maintained at 1 yr (160.7 +/- 6.3 g/L). Proximal forearm (cortical) BMC showed no change after 6 months of GH replacement, but there was a significant increase of 0.06 g/cm after 12 months of GH replacement (from 1.38 +/- 0.04 to 1.44 +/- 0.04 g/cm; n = 12; P < 0.05). Distal forearm (cortical and trabecular) BMC also increased significantly during the study period from 1.46 +/- 0.04 g/cm to 1.52 +/- 0.05 g/cm; n = 12, P < 0.05. No significant changes occurred in bone mineral measurements during 6 months of placebo therapy. Midthigh muscle and fat cross-sectional area increased and decreased, respectively, during the active treatment phase. These results demonstrate that GH plays an important role in maintaining the integrity of the adult skeleton.

The effects of CV205-502 in patients with hyperprolactinaemia intolerant and/or resistant to bromocriptine.

CV205-502 is a new non-ergot dopamine agonist currently being studied for the treatment of hyperprolactinaemia. We have assessed the effects of CV205-502 on prolactin secretion and the clinical consequences of hyperprolactinaemia in 16 patients with hyperprolactinaemia who had previously been unsuccessfully treated with bromocriptine. These patients had been either intolerant of and/or resistant to the effects of bromocriptine. Sixteen patients, all women in an age range between 20 and 49 years (mean 31.5 years), were treated for periods of between 8 and 52 weeks with doses of CV205-502 ranging from 0.075 to 0.3 mg taken once daily at night. Seven out of 10 of the patients, who were intolerant of bromocriptine, tolerated CV205-502 better with fewer side effects although the nature of the side effects was similar to that associated with bromocriptine. Only 1 patient from this group stopped taking CV205-502 due to side effects. Six of 11 patients exhibiting bromocriptine resistance showed a significant reduction in the degree of hyperprolactinaemia but normoprolactinaemia was achieved in only 1. Galactorrhoea ceased in 2 of 6 patients, menstruation resumed in 6 of 11 patients presenting with amenorrhoea, and 2 patients conceived. In patients with bromocriptine intolerance and/or resistance, CV205-502 is useful as a second line treatment.

Identification of bombesin-immunoreactive cells in rat, human, and other mammalian pituitaries, their ontogeny and the effect of endocrine manipulations in the rat.

Bombesin and gastrin-releasing peptide are homologous peptides which have biological activity in mammals. The distribution of bombesin immunoreactivity in rat, guinea pig, cat, dog, pig, cow, monkey, and human pituitaries was investigated using immunocytochemistry with various different antisera. Polyclonal antisera identified bombesin-immunoreactive (IR) cells in the anterior pituitaries of all species except monkey and human, although positive nerves were present in the human posterior lobe. In contrast, a monoclonal antibody demonstrated bombesin-IR cells in anterior and intermediate lobe (or equivalent) of all species. Both types of antibodies identified the anterior pituitary cells as somatotrophs, which may be significant because bombesin and related peptides influence pituitary growth hormone secretion. Differences in bombesin immunoreactivity were seen in male and female rats, with males having more positive cells, and females showing more intense immunoreactivity in those cells which were positive. Ontogenetic studies in rats revealed that bombesin-IR cells were first seen at birth. The effect of estrogen on bombesin-IR cells was studied using ovariectomized and estrogen-treated female rats. Estrogen treatment decreased very significantly the number of bombesin-IR cells, compared with controls, whereas ovariectomy increased significantly the frequency of bombesin-IR cells, so that the staining pattern began to resemble that seen in normal male rats. No bombesin-IR cells were detected in pituitaries from thyroidectomized rats. These results suggest that immunoreactive bombesin/gastrin-releasing peptide in the pituitary is modulated by endocrine status and this peptide may be involved in paracrine interactions in this tissue.

Rat anterior pituitary neuropeptides following chronic prolactin manipulation: a combined radioimmunoassay and mRNA study.

Prolactin secretion is highly regulable, and the possibility exists that there are local intrapituitary factors controlling prolactin secretion. Recently, the neuropeptides vasoactive intestinal peptide (VIP), galanin and substance P (SP) have been co-localized to the lactotroph in the female rat. We investigated the effects of alterations in prolactin status in vivo on pituitary and hypothalamic expression of these peptides by specific radioimmunoassays and mRNA analysis. In the anterior pituitary, following haloperidol treatment, the contents of both VIP and galanin were suppressed to below detectable levels. Similarly, after bromocriptine treatment, the content of VIP was decreased to below the detection limit of the assay while galanin (14.2 +/- 1.3 vs control 21.0 +/- 2.1 fmol/mg, P less than 0.05) also showed a significant reduction. The levels of VIP mRNA and galanin mRNA in these groups showed the same qualitative change as their respective peptides. Concurrent treatment with high-dose oestrogen modified the VIP peptide response to bromocriptine (1368.7 +/- 149.2 vs bromocriptine 843.4 +/- 82.7 fmol/mg, P less than 0.05) but not to haloperidol. Oestrogen-induced decreases in galanin content were not influenced by either treatment. The pituitary content of SP showed a fall after oestrogen treatment (1.1 +/- 0.01 vs control 6.4 +/- 0.8 fmol/mg, P less than 0.05) which was not significantly altered by either bromocriptine or haloperidol. Likewise, SP mRNA levels in the pituitary were decreased by 90% following oestrogen treatment. Hypothalamic expression of these peptides did not change with any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)