Robert Peaston

Androgen supplementation in eugonadal men with osteoporosis: effects of six months' treatment on markers of bone formation and resorption.

There is no established treatment for osteoporosis in men, a common and disabling condition the incidence of which is increasing rapidly. We conducted an open study to investigate the efficacy and mode of action of testosterone therapy in eugonadal men with osteoporotic vertebral crush fracture. Twenty‐one men, aged 34–73 (mean 58), were treated with intramuscular testosterone esters (Sustanon 250®) every 2 weeks for 6 months. Bone mineral density (BMD) measurement by dual‐energy X‐ray absorptiometry was performed at baseline and 6 months. We also measured biochemical markers of bone turnover, testosterone, estradiol, sex hormone binding globulin (SHBG), and gonadotrophins at baseline and after 3 and 6 months of treatment. Treatment was well tolerated, and side effects were uncommon. Lumbar spine BMD increased by 5% from 0.799 to 0.839 g/cm2 (p < 0.001). All bone markers decreased, indicating that treatment suppressed bone turnover. Although serum osteocalcin levels fell only slightly, there were large reductions in urinary deoxypyridinoline and N‐telopeptide (p < 0.05), which were correlated with the increase in spinal BMD. Interpretation of the findings with other markers, such as bone‐specific alkaline phosphatase and pyridinoline, was confounded by the wide scatter of values. Serum testosterone increased by 55%, while SHBG decreased by 20%, leading to a rise in free androgen of 90%. Serum estradiol also increased by 45%. The change in spine BMD was significantly correlated with a change in serum estradiol but not with a change in serum testosterone. We therefore conclude that testosterone is a promising treatment for men with idiopathic osteoporosis, acting to suppress bone resorption by a mechanism that may involve estrogen.

Measurement of catecholamines and their metabolites.

Analysis of the low levels of catecholamines and metabolites in tissue and biological fluids has necessitated the use of highly sensitive analytical techniques. Earlier procedures utilizing radioenzymatic and immunological assays, gas chromatography or fluorimetry have generally been superseded by highly sensitive and selective chromatographic methods utilizing electrochemical or fluorimetric detection. The development of high-performance liquid chromatography (HPLC) methods for the measurement of plasma metadrenalines and the combination of HPLC with tandem mass spectrometry provides additional procedures with minimum interference from drugs and drug metabolites. This review summarizes the methodology currently available for the measurement of catecholamines and metabolites in plasma and urine, the influence of sample collection protocols and the clinical application of the methods for the biochemical detection of catecholamine-secreting tumours.

Biochemical Diagnosis and Localization of Pheochromocytoma Can We Reach a Consensus

Abstract:  Pheochromocytomas can have a highly variable presentation, making diagnosis challenging. To think of the tumor represents the crucial initial step, but establishing the diagnosis requires biochemical evidence of excessive catecholamine production and imaging studies to localize the source. Currently, however, there exist no generally agreed upon guidelines based on which tests and testing algorithms should be used to confirm and locate or exclude a suspected pheochromocytoma. Choice of biochemical tests and imaging studies instead usually depends on institutional experience. At the First International Symposium on Pheochromocytoma (ISP2005), held in Bethesda in October 2005, a panel of experts and patient representatives discussed current problems and available options for tumor diagnosis and localization and formulated recommendations, which were subsequently agreed upon by those in attendance at the meeting. This article summarizes the discussion and recommendations derived from that session.

A randomized controlled trial of calcium with vitamin D, alone or in combination with intravenous pamidronate, for the treatment of low bone mineral density associated with Crohn's disease

Background : Osteoporosis is a common complication of Crohns disease.

How to improve the quality of kidneys from non-heart-beating donors: a randomised controlled trial of thrombolysis in non-heart-beating donors.

Background. The growth in the prevalence of end-stage renal failure has been accompanied with a rise in the waiting list for renal transplantation, which has not been matched by an increase in the kidney donor pool. Non–heart-beating donors (NHBD) offer a potential source of kidneys that are not currently being significantly used. Cardiac arrest for a protracted period of time leads to in situ thrombosis, and, as a consequence, the discard rates for harvested kidneys is higher than brain–stem-dead donors. Methods. A double-blinded, randomised, controlled trial of streptokinase preflush or placebo for NHBD was performed. An initial 30 donors were entered into the study. After routine nephrectomy, NHBD kidneys were machine perfused as part of viability screening before transplantation. Kidneys were then transplanted within 24 hours of cardiac arrest. The primary objectives were the improvements of viability parameters (perfusion, enzyme levels, and histopathology) of the kidneys. The secondary objective was to increase the number of kidneys passing the viability tests and thus transplanted. Results. The two groups of NHBD donors and their kidneys were similar in their descriptive epidemiologic characteristics. The NHBD kidneys from the streptokinase-treated donors had a better appearance at procurement (P <0.001) and performed better during machine preservation (P <0.001). Enzyme biomarkers present in the kidney perfusate were all significantly reduced by the use of streptokinase. These included glutathione S-transferase (P <0.001), fatty acid binding protein (P <0.001), and alanine aminopeptidase (P <0.001). However, although there was a higher proportion of kidneys transplanted through the use of streptokinase (63.6% with streptokinase vs. 42.6% with placebo), this did not achieve significance. There was no difference with respect to postoperative bleeding and transfusion requirements in the recipient whether streptokinase preflush or placebo was used. Conclusion. This study using streptokinase preflush in the NHBD was found to improve the condition of the kidneys retrieved. The improvement in the quality of the donor kidneys was not associated with an increased morbidity in the recipient.

The prevalence of osteoporosis in patients with severe hip and knee osteoarthritis awaiting joint arthroplasty

BACKGROUND the presence of osteoporosis in patients with hip and knee osteoarthritis (OA) has important implications for understanding disease progression and providing optimal surgical and medical management. OBJECTIVE to determine the prevalence of osteoporosis among patients with osteoarthritis awaiting total knee arthroplasty or total hip arthroplasty aged between 65 and 80 years. DESIGN cross-sectional observational study. SETTING tertiary referral centre in Newcastle upon Tyne, UK. SUBJECTS patients with osteoarthritis awaiting total knee hip arthroplasty aged between 65 and 80 years. METHODS lumbar spine, bilateral femoral and forearm bone mineral density (BMD) measurements were obtained using dual-energy X-ray absorptiometry. RESULTS the cohort consisted of 199 patients with a mean age of 72 years (SD 4), and 113 (57%) were women. The overall rate of osteoporosis at any site was 23% (46/199) and a further 43% (85/199) of patients would have been classified as osteopaenic according to World Health Organization criteria. Osteoporosis was more commonly detected in the forearm (14%) than the lumbar spine (8.5%) and proximal femur of the index side (8.2%). CONCLUSIONS in summary, a significant proportion of patients with end-stage OA have osteoporosis but this diagnosis may be missed unless BMD measurements are performed at sites distant from joints affected by OA.

Use of Two Biomarkers of Renal Ischemia to Assess Machine-perfused Non-Heart-beating Donor Kidneys

Renal transplantation is a recognized treatment for end-stage renal failure, offering a better quality of life, independence from dialysis, better survival rates, and decreased cardiovascular complications compared with renal replacement therapy (1). Recently, continued increases in the prevalence of end-stage renal failure and the length of transplantation waiting lists have not been matched by an increased supply of donors from the traditional brainstem dead donors and living donors. Non-heart-beating donor (NHBD) kidneys are regaining importance to substantially increase the kidney donor pool, with estimates indicating a potential increase of 20–40% (2)(3). The use of NHBD kidneys is associated with the development of two adverse conditions, primary nonfunction (PNF) and delayed graft function (DGF), which are caused by the ischemic injury that occurs after cardio-respiratory arrest. Therefore, in centers with NHBD programs, it has become necessary to screen-out damaged kidneys that will never work. Machine preservation using continuous hypothermic pulsatile perfusion has been adopted in NHBD kidney screening initiatives, and perfusion characteristics (flow, pressure, resistance, temperature, weight gain) with enzyme analysis of kidney effluents are used to assess viability. Since its isolation and identification as ligandin, glutathione S -transferase (GST) has evolved as a suitable biomarker in the pretransplantation assessment of machine-perfused NHBD kidneys. Different isoforms have been identified from the distal and proximal renal tubules, and the commonest isoform, α-GST, has previously been used as a biomarker of renal ischemia as assessed by ELISA (4). However, we have previously demonstrated that a spectrophotometric assay for total GST activity (tGST) could reliably be substituted for α-GST (5). Original work by the Maastricht NHBD group has established threshold limits for tGST activity in kidney perfusates for the selection of “viable” kidneys for transplantation (6). This criterion has been introduced in Newcastle, England, where 69 NHBD renal transplants have …

Routine determination of urinary free catecholamines by high-performance liquid chromatography with electrochemical detection

A simple and reliable high-performance liquid chromatographic method is described for the routine determination of the free catecholamines (norepinephrine, epinephrine and dopamine) in urine. The catecholamines are isolated from urine samples using small affinity chromatography columns prepacked with immobilised m-aminophenylboronic acid, separated by ion-pair reversed-phase liquid chromatography and quantified by electrochemical detection. Total analysis, including sample preparation time, is achieved in less than 30 min with analytical recoveries of 92-96% for all three catecholamines. Long-term stability and reproducibility of the liquid chromatographic system is attained by selection of optimised conditions for chromatographic separation with a formate mobile phase and produces detection limits of 1.4, 1.8 and 2.2 nmol/l for norepinephrine, epinephrine and dopamine, respectively, in urine samples and day-to-day coefficients of variation of less than 6%. Furthermore, the affinity isolation gels can be reused a minimum of ten times providing a rapid and cost-effective means of sample preparation.

Biochemical detection of phaeochromocytoma: Why are we continuing to ignore the evidence?

Abstract Phaeochromocytomas are rare tumours that require consideration among large numbers of patients with hypertension. If not diagnosed, the excessive secretion of catecholamines by these tumours can cause considerable morbidity and mortality. With a wide clinical variability in presentation, diagnosis can be difficult and invariably requires the biochemical confirmation of excessive catecholamine production by the tumour. At the First International Symposium on Phaeochromocytoma in October 2005, a panel of experts recommended that initial biochemical testing for phaeochromocytoma should include measurements of plasma and urinary metadrenalines. The accumulated evidence clearly indicates that measurement of fractionated metadrenalines in urine or plasma provides superior diagnostic sensitivity over plasma or urine measurements of catecholamines and metabolites. The low prevalence of phaeochromocytoma and paraganglioma (PGL) emphasizes the need to use biochemical tests of the highest sensitivity. To achieve this, it is recommended that the initial biochemical testing for phaeochromocytoma and secreting PGL should always include the measurements of metadrenalines in plasma or urine or both.

Comparison of perfusate activities of glutathione S-transferase, alanine aminopeptidase and fatty acid binding protein in the assessment of non-heart-beating donor kidneys

Background: With a universal shortage of donor organs, screening and selection of marginal kidneys from non-heart-beating donors (NHBDs) provides a valuable source for transplantation. Pre-transplant viability assessment is based on a combination of flow characteristics and assessment of ischaemic tissue injury during NHBD kidney machine perfusion by measurement of total glutathione S-transferase (GST) activity. Successful viability screening has facilitated 69 renal transplants from 60 NHBDs within our transplant centre since 1998, with a first-year graft survival of 90·5%. Methods: We have investigated alanine aminopeptidase (Ala-AP) and fatty acid binding protein (FABP) as alternative biochemical markers to GST for pre-transplantation viability assessment. They were measured, together with GST, in tissue perfusate samples from machine-perfused kidneys from controlled and uncontrolled NHBDs. Results: During machine perfusion, a parallel response was seen for each of the three markers in the perfusates of controlled and uncontrolled NHBD kidneys over the 4-h perfusion. A highly significant correlation was obtained between GST and Ala-AP activities (P<0·0001) and between GST activity and FABP concentration (P<0·0001) in corresponding samples. Conclusion: In this study, GST, Ala-AP and FABP represent equivalent biochemical markers in terms of their ability to quantitate renal tissue injury in human NHBD kidneys. However, there may be some advantage in using all three analytes to provide complementary information on kidney allograft viability.