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The response to glucagon-like peptide 1 receptor agonist treatment may be influenced by endogenous β-cell function. We investigated whether urinary C-peptide creatinine ratio assessed before or during liraglutide treatment was associated with treatment response.A single, outpatient urine sample for urinary C-peptide creatinine ratio was collected 2 h after the largest meal of the day among two separate groups: (1) subjects initiating liraglutide (0.6 → 1.2 mg daily) or (2) subjects already treated with liraglutide for 20-32 weeks. The associations between pretreatment and on-treatment urinary C-peptide creatinine ratio and HbA1c change at 32 weeks were assessed using univariate and multivariate analyses (the ratio was logarithm transformed for multivariate analyses). Changes in HbA1c according to pretreatment urinary C-peptide creatinine ratio quartiles are shown.One hundred and sixteen subjects (70 pretreatment, 46 on treatment) with Type 2 diabetes from 10 diabetes centres were studied. In univariate analyses, neither pretreatment nor on-treatment urinary C-peptide creatinine ratio correlated with HbA1c change (Spearman rank correlation coefficient, r = -0.17, P = 0.17 and r = -0.20, P = 0.19, respectively). In multi-linear regression analyses, entering baseline HbA1c and log urinary C-peptide creatinine ratio, pretreatment and on-treatment log urinary C-peptide creatinine ratio became significantly associated with HbA1c change (P = 0.048 and P = 0.040, respectively). Mean (sd) HbA1c changes from baseline in quartiles 1 to 4 of pretreatment urinary C-peptide creatinine ratio were -3 ± 17 mmol/mol (-0.3 ± 1.6%) (P = 0.52), -12 ± 15 mmol/mol (-1.1 ± 1.4%) (P = 0.003), -11 ± 13 mmol/mol (-1.0 ± 1.2%) (P = 0.002) and -12±17 mmol/mol (-1.1±1.6%) (P=0.016), respectively.Postprandial urinary C-peptide creatinine ratios before and during liraglutide treatment were weakly associated with the glycaemic response to treatment. Low pretreatment urinary C-peptide creatinine ratio may be more useful than higher values by predicting poorer glycaemic response.

In order to predict the fate of biodiversity in a rapidly changing world, we must first understand how species adapt to new environmental conditions. The long-term evolutionary dynamics of species' physiological tolerances to differing climatic regimes remain obscure. Here, we unite palaeontological and neontological data to analyse whether species' environmental tolerances remain stable across 3 Myr of profound climatic changes using 10 phylogenetically, ecologically and developmentally diverse mollusc species from the Atlantic and Gulf Coastal Plains, USA. We additionally investigate whether these species' upper and lower thermal tolerances are constrained across this interval. We find that these species' environmental preferences are stable across the duration of their lifetimes, even when faced with significant environmental perturbations. The results suggest that species will respond to current and future warming either by altering distributions to track suitable habitat or, if the pace of change is too rapid, by going extinct. Our findings also support methods that project species' present-day environmental requirements to future climatic landscapes to assess conservation risks.

The Disk Retention Assay (DRA) is an in vitro method developed to measure the available level of cetylpyridinium chloride (CPC) in mouthwash formulations. This method is based on the binding of the cationic CPC molecule to the anionic surface of a cellulose filter disk. Aqueous CPC solutions demonstrate a linear response (A545) for concentrations up to 0.3%. Higher levels of CPC showed no increased response in the assay. Among common oral product ingredients, at relevant concentrations, surfactants are the primary compounds which inhibit CPC detection and hence, chemical availability. Poloxamer-407 decreased CPC availability to 60% at 0.1%, to 10% at 0.5%, and to 24-33% for 0.2-0.4%. Polysorbate-80 decreased CPC availability to 30% at 0.1% and 6% at 0.25%. A range (4-54%) of available levels of CPC were determined for several commercial products containing 0.045-0.05% nominal levels of CPC indicating significant formulation excipient influence. A plaque glycolysis (PG) assay was used to determine the biological activity of all mouthwash products analyzed by DRA. An experimental series of mouthwash formulations having nominal CPC levels of 0-0.10% demonstrated a good correlation (r2 = 0.955) between the calculated available level of CPC (DRA) and inhibition of plaque glycolysis. The calculated available level of CPC from select commercial mouthwash products, also fit the established correlation with biological activity. The combination of DRA and plaque glycolysis methods are valuable tools which can be used during development to maximize the biological activity of CPC mouthwash formulations prior to clinical evaluation.

Macroprolactinemia is a common finding in patients with hyperprolactinemia. There are no published long-term follow-up studies.The aim of this study was to describe findings after prolonged follow-up in a previously published cohort of patients with macroprolactinemia.We studied 51 patients identified as having macroprolactinemia after polyethylene glycol precipitation.Clinical assessment and serum prolactin assay were repeated in 51 patients with macroprolactinemia after a median follow-up of 9.9 yr (range, 9-11 yr).Median age at presentation was 41 yr (range, 18-55 yr). Mean serum prolactin concentration at presentation was 1885 mU/liter, and after follow-up 1370 mU/liter. At follow-up, headache had been experienced in 12 patients (24%) and oligomenorrhea in five (10%). Galactorrhea was present in only two patients (4%). No visual deterioration was noted in 50 patients. One had a transient bitemporal hemianopia. No patients developed an autoimmune condition. Microadenoma had been identified in four patients at presentation with no new pituitary imaging abnormalities identified at follow-up.During prolonged follow-up, no symptomatic progression was noted in any of our patients. This study suggests that patients with macroprolactinemia and normal concentrations of monomeric prolactin can be reassured, and extended endocrine review of such patients is not required.

Somatostatin analogues are an established treatment in acromegaly. This study was designed to evaluate whether the acute serum growth hormone (GH) response to a test dose of octreotide in acromegaly predicts longer-term response to the drug at 3 years.In 23 patients, GH responses across 8 h to a subcutaneous test dose (50 microg) of octreotide were compared with GH levels after 3 years of therapy. The majority had pituitary surgery as primary therapy and at 3 years were receiving at least 600 microg octreotide daily subcutaneously or 20 mg LAR monthly intramuscularly.Seven had a test day GH Nadir of 5 mU/l or less of whom 4 achieved GH5 mU/l at 3 years. Sixteen had a test day nadir GH of 10 mU/l or less and of these 8 achieved GH5 mU/l at 3 years. Seven of the 23 had a GH Nadir10 mU/l and of these 3 had achieved GH5 mU/l at 3 years. However all of these 3 had received external pituitary irradiation within 4 years of the 3 year assessment, as compared with 3 of the5 mU/l nadir group and 5 of the10 mU/l nadir group.In patients on optimal long-term doses of octreotide for acromegaly, absence of a nadir GH10 mU/l in the 8 h after a test dose was associated with failure to achieve GH levels associated with a normal life expectancy (5 mU/l or less) unless adjunctive external pituitary irradiation was given. As well as testing tolerability a test dose of octreotide may help in determining which patients should be offered early external pituitary irradiation or therapy with a GH receptor antagonist if surgery has failed to achieve 'safe' GH levels.

Background Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides. Methods We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant. Results Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L−1] of VIP [patients 27 (2.1–85.5); controls 9.8 (0–34)] and NPY [patients 20 (0–110); controls 12 (5–19)] were higher in patients (P

Pituitary tumours that present with nasal symptoms are uncommon. Management can be difficult due to their aggressive nature, location and extension. We report a series of three cases of prolactinomas that enlarged inferiorly presenting initially as nasal polyps. Recurrence of symptoms (case 1) prompted testing for serum prolactin and examination of histology confirmed the presence of a prolactinoma. In cases 2 and 3, radiological evidence of a pituitary mass prompted testing for a prolactinoma. No patients exhibited clinical signs of hyperprolactinaemia. All three cases have residual tumour at 2–4 years after diagnosis, despite prolactin levels approaching the normal range on dopaminergic therapy. Pituitary tumours that invade the nasal cavity are rare and clinicians should be aware of their existence. A prolactinoma should be considered in the differential diagnosis of nasopharyngeal tumours. Measurement of serum prolactin can expedite a diagnosis and prevent delay of treatment with dopamine agonists.

OBJECTIVE To compare the effects of monthly intramuscular injections of a long acting preparation of octreotide, Sandostatin LAR, with multiple daily subcutaneous injections of octreotide and to study the interrelationships between mean 24 h growth hormone profile, serum total and free IGF-1 levels, 24 h urinary growth hormone levels and serum IGFBP-3. DESIGN Patients were assessed by 24 h GH profile off octreotide or any other GH modifying drug therapy; on subcutaneous octreotide (200–600 μg daily in divided doses for six weeks); and 28 days after the second of two injections of Sandostatin LAR (20 mg by intra-muscular injection) administered 28 days apart. Serum total and free IGF-1, serum IGFBP-3 and 24 h urinary GH were also measured on each occasion. RESULTS Sandostatin LAR was well tolerated. None of the patients reported any adverse effect and all completed the study uneventfully. Mean GH off treatment was 10.1 ± 3.0 μg/l falling equally significantly (P

An association exists between hyperaldosteronism, hypertension and impaired insulin action. Eplerenone is a selective mineralocorticoid receptor antagonist; however, little is known about its effects on insulin action. The aim of this study was to determine the effect of eplerenone on insulin action in hypertensive adults, using the hyperinsulinaemic euglycaemic clamp. A randomised, controlled, double-blind, crossover design was employed. After a 6-week washout period, hypertensive, non-diabetic patients were treated with either eplerenone 25 mg twice daily or doxazosin 2 mg twice daily for 12 weeks. After each treatment period, insulin action was assessed by a hyperinsulinaemic euglycaemic clamp, with isotope dilution methodology. After washout, treatment groups were crossed over. Fifteen patients completed the study. There were no differences in fasting glucose, or fasting insulin between treatment with eplerenone or doxazosin. The measure of overall insulin sensitivity, exogenous glucose infusion rates during the last 30 min of the clamp, was similar with both treatments; 23.4 (3.9) μmol kg(-1) min(-1) after eplerenone and 23.3 (3.6) μmol kg(-1) min(-1) after doxazosin (P=0.83). Isotopically determined fasting endogenous glucose production rates were similar after both treatments (eplerenone 9.4 (0.6) μmol kg(-1) min(-1) vs doxazosin 10.6 (0.7) μmol kg(-1) min(-1)). There was a trend for lower endogenous glucose production rates during hyperinsulinaemia following eplerenone compared with doxazosin (2.0 (0.8) μmol kg(-1) min(-1) vs 4.1 (0.9) μmol kg(-1) min(-1)). There was no difference in insulin stimulated peripheral glucose utilisation rates after treatment with eplerenone or doxazosin (25.4 (3.6) μmol kg(-1) min(-1) vs 27.0 (3.9) μmol kg(-1) min(-1)). This study gives reassuring evidence of the neutral effect of eplerenone on insulin action in hypertensive, non-diabetic patients.

Peripheral circulating levels of atrial natriuretic peptide may exhibit short-term variation compatible with a pulsatile pattern of secretion. We obtained samples every 2 min for 90 min from the antecubital vein of 16 patients with chronic cardiac failure and 13 controls. Overall levels were higher in the patients (median and quartiles 230 (125,325) vs. 26 (16,48) ng l-1; P0.001). In both groups there was considerable variability, with 10 (2-12) peaks, 9 (7-15) troughs (both defined as2 SD from the mean) and 16 (13-18) pulses (defined by computer) during the sampling period in controls, and a similar number in patients. We then carried out simultaneous sampling in the pulmonary artery, femoral artery and peripheral vein in eight subjects with normal cardiac function and six patients with impaired function due to valvular heart disease. The pattern of variability was preserved in all three sites in both groups, suggesting intermittent secretion rather than variable breakdown of the peptide in the lung. No changes in right atrial pressure or heart rate were observed to coincide with the variations, but levels of the peptide in the pulmonary artery correlated with right atrial pressure in patients (r = 0.87; P0.05). The mechanism of such periodicity and its pathophysiological importance remain unknown.

Patients with primary aldosteronism (PA) who are suitable for surgery should undergo adrenal computerised tomography (CT) and adrenal venous sampling (AVS). A retrospective study was performed of 100 patients with PA. We determined the optimal AVS lateralisation ratio for unilateral disease and reviewed adrenalectomy outcomes evaluating which characteristics predicted hypertension cure.AVS was performed in 93 patients. Lateralisation criteria were assessed using ROC curve analysis. The outcome of adrenalectomy was reviewed in 39 patients and predictive factors for cure determined using univariate and multivariate analysis.Of previously published criteria, ROC curve analysis found a cortisol corrected aldosterone affected to unaffected (Aldo/Cort A:U) cut-off of 2·0 was the best predictor of adenoma identifying 80·4% of patients. A novel ratio calculated by dividing the affected to unaffected ratio by the unaffected to peripheral ratio [(Aldo/Cort A:U)/(Aldo/Cort U:IVC)] was successful in identifying 87·0% of patients. Cure rate for blood pressure after adrenalectomy was 38·5% with improvement in 59·0%. On univariate analysis, predictors of post-operative hypertension were increased weight, raised creatinine, left ventricular hypertrophy (LVH) and male sex. On multivariate analysis, male sex and higher pre-operative systolic blood pressure were predictive.Patients with PA should have CT scanning and AVS. Aldo/Cort A:U2·0 is the most accurate of previously published ratios in predicting unilateral disease. When patients were carefully selected for surgery, 97% had cure or improvement in blood pressure control. Further confirmatory work is required on a novel ratio which was even more predictive in our series.

The aim of this study was to use general practice data to estimate the prevalence of diabetic nephropathy within the registered diabetes patients and examine variation in practice prevalence and management performance since introduction of this initiative.Reported quality indicators from the Northern Ireland General Practice Quality and Outcomes Framework were analysed for diabetes and diabetic nephropathy prevalence and management in the period 2004-2008. Variation in prevalence at practice level was assessed using multiple linear regression adjusting for age, practice size, deprivation and glycaemic control.In 2006-2007, 57,454 (4.1%) adult diabetic patients were registered in the denominator population of 1.4 million compared with 51,923 (3.8%) in 2004-2005 (mean practice range 0.5-7.7%). Diabetic nephropathy prevalence was 15.1 and 11.5%, respectively (8688 and 5955 patients). Documented diabetic nephropathy prevalence showed marked variation across practices (range 0-100%) and was significantly negatively correlated with diabetes list size, albumin creatinine ratio testing rates and renin-angiotensin-aldosterone system blockade use and positively correlated with exception reporting rates. Specifically, for every increase in 100 diabetic patients to a register, documented diabetic nephropathy prevalence reduced by 40% (P=0.003). On the positive side, median albumin-creatinine ratio testing rates doubled to 82% compared with figures in the pre-Framework era.Implementation of the Northern Ireland General Practice Quality and Outcomes Framework has positively benefitted testing for diabetic nephropathy and increased numbers of detected patients in a short space of time. Large variation in diabetic nephropathy prevalence remains and is associated with diabetes registry size, screening and treatment practices, suggesting that understanding this variation may help detect and better manage diabetic nephropathy.

The aim of this study is to review the experience of the clonidine suppression test in a regional endocrine centre and to compare the diagnostic sensitivity and specificity using various previous published criteria. The design used is retrospective study. The subjects include 56 patients in whom clonidine suppression tests had been performed from 1995 to 2000: 15 with phaeochromocytoma and 41 patients in whom the diagnosis was excluded using a combination of biochemical testing, abdominal computed tomography scanning and clinical follow-up. Plasma catecholamines were measured by high pressure liquid chromatography on basal samples and at hourly intervals for 3 h after the administration of clonidine 300 μg orally and the following diagnostic criteria were applied: plasma noradrenaline+adrenaline2.96 nmol l(-1) at 3 h post-clonidine or a baseline plasma adrenaline plus noradrenaline11.82 nmol l(-1); plasma noradrenaline2.96 nmol l(-1) at 3 h post-clonidine and plasma noradrenaline2.96 nmol l(-1) and50% fall in noradrenaline at 3 h post-clonidine. The results obtained is that mean plasma noradrenaline plus adrenaline fell across the test in 40/41 patients in the non-phaeochromocytoma patients and was lowest at 3 h (basal 2.28 ± 0.14 vs 1.36 ± 0.11 nmol l(-1), P0.001). In the phaeochromocytoma group, clonidine had a variable effect on adrenaline plus noradrenaline levels with increases in 7/15. Using an abnormal result as a 3 h level of noradrenaline plus adrenaline2.96 mmol l(-1) gave a sensitivity of 93% and specificity of 95%. When a 3 h noradrenaline2.96 mmol l(-1) was used, sensitivity was 87% and specificity 95%. Using the former criteria, noradrenaline plus adrenaline2.96 mmol l(-1), 1/15 in the phaeochromocytoma group had a normal result after clonidine suppression testing. Two of 41 in the non-phaeochromocytoma group had a false-positive result. Under carefully controlled conditions, the clonidine suppression test is well tolerated, safe and accurate for use in the investigation of patients with suspected phaeochromocytoma.

Prior to establishing a specialist diabetic renal clinic in our unit, we studied across 12 months all 1845 patients attending one of our diabetes clinics with a serum creatinine150 μmol/l. Diabetic control was examined along with renal function and cardiovascular risk using current audit standards. 74 such patients were identified (male:female 54:20 mean HbA1c 7.8% (sd ± 1.45) and age 64.2 years (± 12.8). 30 patients had creatinine200 μmol/l and 15250 μmol/l. Using the chronic kidney disease classification, 33, 28 and 6 patients were in groups III, IV and V with 7 patients undergoing renal replacement therapy. 65% of patients met JBS2 audit standards of blood pressure using a mean of 2.93 agents (sd ± 1.43). Ace-inhibitors or angiotensin receptor blockers were used in 81% and 81% were on regular antiplatelet or anticoagulant therapy. Audit standard for total cholesterol and LDL were met in 89% and 97% of patients respectively. All patients identified in our study were in CKD class III-V and therefore we considered also alternative inclusion criteria. 136 patients had a urinary ACR ≥ 30 mg/mmol. Using this and/or the serum creatinine level above identified 197 patients from the clinic. This study shows that measurement of serum creatinine alone is not sufficiently sensitive but extended criteria identified a 10% subgroup who will now be offered detailed assessments and intensified therapies at a subspecialty in-house renal clinic. eGFR has recently been added to our computerised proforma and will enable us to further refine inclusion criteria.

These lifestyle changes are ultimately the responsibility of the individual and can be difÞcult to achieve andmaintain. The National Service Framework for Diabetes published by the UK Department of Health in 2001 states that individuals withdiabetes should have information and education to help them self-care

Defects in a triad of organelles (melanosomes, platelet granules, and lysosomes) result in albinism, prolonged bleeding, and lysosome abnormalities in Hermansky-Pudlak syndrome (HPS). Defects in HPS1, a protein of unknown function, and in components of the AP-3 complex cause some, but not all, cases of HPS in humans. There have been 15 inherited models of HPS described in the mouse, underscoring its marked genetic heterogeneity. Here we characterize a new spontaneous mutation in the mouse, cappuccino (cno), that maps to mouse chromosome 5 in a region conserved with human 4p15-p16. Melanosomes of cno/cno mice are immature and dramatically decreased in number in the eye and skin, resulting in severe oculocutaneous albinism. Platelet dense body contents (adenosine triphosphate, serotonin) are markedly deficient, leading to defective aggregation and prolonged bleeding. Lysosomal enzyme concentrations are significantly elevated in the kidney and liver. Genetic, immunofluorescence microscopy, and lysosomal protein trafficking studies indicate that the AP-3 complex is intact in cno/cno mice. It was concluded that the cappuccino gene encodes a product involved in an AP-3-independent mechanism critical to the biogenesis of lysosome-related organelles. (Blood. 2000;96:4227-4235)

Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides.We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant.Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L-1] of VIP [patients 27 (2.1-85.5); controls 9.8 (0-34)] and NPY [patients 20 (0-110); controls 12 (5-19)] were higher in patients (P0.05). Circulating plasma levels of ET-1 and CGRP were about the same in both groups [ET-1: patients 18 (2-84); controls 18 (0-48); CGRP: patients 4 (1-18.5), controls 5.5 (1-15); P = NS]. Levels of CGRP, VIP and ET-1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery.The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10-15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.

The mechanism of hypertension in Cushing's syndrome remains undetermined. Some studies have demonstrated an increased sensitivity to pressor agents but it is not clear if patients with Cushing's syndrome of different aetiologies demonstrate this finding. We have examined pressor sensitivity in a group of patients with Cushing's disease (pituitary dependent hypercortisolism) by measuring blood pressure during incrementally increasing infusions of noradrenaline.Eight subjects (7 female, 1 male), aged 42.2 +/- 4.5 years (mean +/- SEM) with Cushing's disease were studied. Eight age- and sex-matched control subjects were also studied. Four of the eight controls and five patients with Cushing's disease had elevated blood pressure. All medication for this had been stopped at least seven days prior to the study. After subjects ate a light breakfast, ECG leads and a sphygmomanometer were attached, an intravenous cannula was inserted and all subjects then rested quietly for 60 minutes. Noradrenaline was then infused intravenously for 10-minute periods at concentrations of 0.01, 0.03, 0.07, 0.11 and 0.18 microg/kg/minute.On the day of the study the baseline blood pressures and pulse rates in the patients with Cushing's disease (blood pressure; 138/87 +/- 6/3 mmHg, pulse 76.5 +/- 4.8 beats/minute) and controls (blood pressure; 126/86 +/- 6/6 mmHg, pulse 71.2 +/- 3.7 beats/minute) were not significantly different. The mean change in diastolic blood pressure from baseline at the time of the peak increase or when the test was stopped was 21. 5 +/- 4.7 mmHg in Cushing's disease compared to 7.0 +/- 2.5 mmHg in controls (P = 0.03). The mean change in mean arterial pressure from baseline at the time of the peak increase or when the test was stopped was 22.0 +/- 4.0 mmHg in Cushing's disease compared to 13.0 +/- 2.4 mmHg in controls (P = 0.03). No significant difference in mean change of systolic pressure (26.0 +/- 4.6 vs. 25 +/- 4.0 mmHg) or pulse rates (- 11.1 +/- 1.8 vs. - 4.7 +/- 2.6) was seen in the group with Cushing's disease as compared to the control group.We conclude that patients with pituitary-dependent Cushing's syndrome have enhanced pressor diastolic and mean arterial responses to noradrenaline and this may be an important underlying mechanism for the hypertension seen in this particular group of Cushing's syndrome patients.

To compare the effects of monthly intra-muscular injections of a long acting preparation of octreotide, Sandostatin LAR, with multiple daily subcutaneous injections of octreotide and to study the interrelationships between mean 24 h growth hormone profile, serum total and free IGF-1 levels, 24 h urinary growth hormone levels and serum IGFBP-3.Patients were assessed by 24 h GH profile off octreotide or any other GH modifying drug therapy; on subcutaneous octreotide (200-600 micrograms daily in divided doses for six weeks); and 28 days after the second of two injections of Sandostatin LAR (20 mg by intra-muscular injection) administered 28 days apart. Serum total and free IGF-1, serum IGFBP-3 and 24 h urinary GH were also measured on each occasion.Sandostatin LAR was well tolerated. None of the patients reported any adverse effect and all completed the study uneventfully. Mean GH off treatment was 10.1 +/- 3.0 micrograms/l falling equally significantly (P0.05) during therapy with subcutaneous octreotide to 3.0 +/- 0.7 micrograms/l and Sandostatin LAR to 2.8 +/- 0.7 micrograms/l. Fasting 0900 h GH was significantly reduced (P0.05) on Sandostatin LAR (3.0 +/- 0.7 micrograms/l) compared with subcutaneous octreotide (5.1 +/- 1.2 micrograms/l). Mean total IGF-1 off treatment was 658.6 +/- 56.1 micrograms/l and was reduced to a comparable extent with subcutaneous octreotide and Sandostatin LAR (466.0 +/- 59.7 and 448.6 +/- 59.5 micrograms/l respectively; both P0.05). Free IGF-1 off treatment was 3.1 +/- 0.6 micrograms/l and was reduced equally by subcutaneous octreotide and Sandostatin LAR (1.2 +/- 0.2 and 1.2 +/- 0.2 micrograms/l; both P0.05). IGFBP-3 was reduced to a greater extent during Sandostatin LAR than during subcutaneous octreotide (4518.2 +/- 247.3 vs 5132.8 +/- 280.7 micrograms/l; P0.05). Twenty-four hour urinary GH excretion was reduced to a comparable extent with both therapies. Highly significant positive correlations were found between mean 24 h GH levels and free IGF-1 (r = 0.66, P0.0001) and 24 h urinary GH excretion (r = 0.94, P0.0001). The relationships between mean 24 h GH levels and total IGF-1 and IGFBP-3 although significant showed less powerful correlations.These results suggest that Sandostatin LAR is well tolerated and as effective as subcutaneous octreotide. In addition, urinary growth hormone and serum free IGF-1 may prove valuable for outpatient follow-up of acromegalic patients, as both correlate well with mean 24 h serum growth hormone levels.

The presence of spectrin was demonstrated in chick osteoclasts by Western blotting and light and electron microscopic immunolocalization. Additionally, screening of a chick osteoclast cDNA library revealed the presence of alpha-spectrin. Light microscope level immunocytochemical staining of osteoclasts in situ revealed spectrin staining throughout the cytoplasm with heavier staining found at the marrow-facing cell margin and around the nuclei. Confocal microscopy of isolated osteoclasts plated onto a glass substrate showed that spectrin encircled the organelle-rich cell center. Nuclei and cytoplasmic inclusions were also stained and the plasma membrane was stained in a nonuniform, patchy distribution corresponding to regions of apparent membrane ruffling. Ultracytochemical localization showed spectrin to be found at the plasma membrane and distributed throughout the cytoplasm with especially intense staining of the nuclear membrane and filaments within the nuclear compartment.