Biomedical subjects
R Freaney
Publications and source records attributed to R Freaney.
Vitamin D deficiency. Groups at risk need supplementation, and milk could be fortified.
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Bone density, vitamin D status, and disordered bone remodeling in end-stage chronic liver disease.
Hepatic osteodystrophy occurs in up to 50% of patients with chronic liver disease (CLD). The aim of this study was to determine the relative contribution of increased resorption and decreased formation to hepatic osteodystrophy by measuring biochemical markers. Twenty-seven patients with advanced CLD (14 female, 13 male) were enrolled. Bone mineral density (BMD), measured at the lumbar spine, and femoral neck, were measured by dual energy X-ray absorptiometry (DXA); bone turnover was assessed using biochemical markers of bone formation and resorption. Based on WHO criteria, osteoporosis and osteopenia were present in 41% and 18% of patients, respectively. All three markers of bone resorption (free deoxypyridinoline, pyridinoline, and hydroxyproline) were increased significantly in patients with CLD. There was a less marked change in the markers of bone formation (osteocalcin, procollagen type 1 peptide, and bone alkaline phosphatase), resulting in a negative uncoupling index in 23/27 (85%) of the patients. Only two (7%) patients had biochemical changes consistent with osteomalacia. The results suggest that increased bone resorption is the predominant cause of hepatic osteodystrophy and therapeutic strategies should be designed to suppress bone resorption, especially in preparation for liver transplantation. Bone biomarkers may be useful alternatives to bone biopsy in evaluating hepatic osteodystrophy.
Lactate determination in exercise testing using an electrochemical analyser: with or without blood lysis?
The practical use of lactate electrochemical analysers in exercise testing has not been adequately examined. Initial studies have reported differences in lactate concentration between that measured spectrophotometrically and that measured electrochemically. The study described here was undertaken to compare, using the statistical technique of Bland and Altman (1986), two widely available methods of measuring lactate using lysed and non-lysed blood samples and the lactate thresholds derived from the measured lactate values using a log-log transform technique. Thirteen normal, healthy young adults (11 male) undertook progressive exercise tests to exhaustion. Arterialised venous blood samples were taken each minute and the lactate concentration therein was measured both spectrophotometrically and electrochemically and either with or without lysis of the blood samples. The lactate concentrations measured in lysed blood using both methods (182 pairs) were in close agreement. The electrochemical values obtained using non-lysed blood were systematically lower than spectrophotometric values (206 pairs), the difference becoming progressively greater at higher lactate concentrations. Results for the lactate threshold comparisons are given as mean difference (limits of agreement with 95% probability). Lactate thresholds (12 pairs) derived from lysed blood lactate concentrations measured spectrophotometrically and electrochemically were not significantly different -30 (240) ml O2 x min(-1). Lactate thresholds (11 pairs) derived from lysed spectrophotometric and non-lysed electrochemical measurements were also not significantly different + 20 (250) ml O2 x min(-1). Thus, despite the difference in the measured lactate concentrations, the derived lactate thresholds are in agreement and, therefore, electrochemical analysers can be used for lactate threshold determination using the log-log transform technique without sample lysis.
Predicting bone loss following orthotopic liver transplantation.
BACKGROUND: Hepatic osteodystrophy occurs in the majority of patients with advanced chronic liver disease with the abnormalities in bone metabolism accelerating following orthotopic liver transplantation (OLT). AIMS: To examine changes in bone mineral density (BMD) following OLT and to investigate factors that lead to bone loss. METHODS: Twelve patients had BMD (at both the lumbar spine (LS) and femoral neck (FN)) and biochemical markers measured preoperatively and for 24 months following OLT. RESULTS: BMD was low in 75% of patients prior to OLT and decreased significantly from baseline at the LS at three months and the FN at six months. BMD began to increase thereafter at both sites, approaching baseline values at the LS by 12 months. Bone formation markers, osteocalcin and procollagen type I carboxy propeptide, decreased immediately post-OLT, with a concomitant increase seen in the resorption markers pyridinoline and deoxypyridinoline. This resulted in a negative uncoupling index early post-OLT, that rebounded to positive values after six months. There was a significant correlation between the change in the uncoupling index between six and three months which preceded the increase in BMD at 12 months. The decrease in BMD recorded early post-OLT correlated with vitamin D levels at three months. CONCLUSIONS: Results suggest that increased resorption and inadequate formation are the major contributors to additional bone loss following OLT. Non-invasive biochemical markers precede later changes in BMD in this patient group following OLT and may have a role in investigating and planning intervention strategies to prevent bone loss in future studies.
Bone density and vitamin D intoxication.
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Secondary hyperparathyroidism in the elderly: means to defining hypovitaminosis D.
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In vitro optimisation of a microdialysis system with potential for on-line monitoring of lactate and glucose in biological samples.
The optimisation and evaluation of the microdialysis component of a prototype miniaturised total analysis system for application in the continuous monitoring of lactate and glucose is reported. The complete unit comprises a high efficiency microdialysis sampling system, a miniaturised microflow manifold with an integrated biosensor array, together with the hardware and software necessary for controlling the flow parameters and monitoring the sensor signals. Sampling occurs via a microdialysis shunt probe which is perfused continuously with a physiological buffered saline solution. The continuous dialysate outflow is presented to the biosensor array, resulting in the appropriate amperometric signals. Aspects of technological significance addressed here include probe membrane size, perfusate flow rate, sample flow rate, temperature change, probe sterilisation procedures, and heparin content of the physiological saline solution employed.
Novel instrumentation for real-time monitoring using miniaturized flow systems with integrated biosensors.
A prototype miniaturized Total Chemical Analysis System (muTAS) has been developed and applied to on-line monitoring of glucose and lactate in the core blood of anaesthetized dogs. The system consists of a highly efficient microdialysis sampling interface sited in a small-scale extracorporeal shunt circuit ('MiniShunt'), a silicon machined microflow manifold and integrated biosensor array for glucose and lactate detection with associated computer software for analytical process control. During in-vivo testing the device allowed real-time on-screen monitoring of glucose and lactate with system response times of less than 5 min, made possible by the small dead volume of the microflow system. On-line glucose and lactate measurements were made in the basal state as well as during intravenous infusion of glucose or lactate. The prototype muTAS is currently suitable for trend monitoring but refinements are necessary before application of the system for determination of individual lactate values.
Bone remodeling indices and secondary hyperparathyroidism in celiac disease.
OBJECTIVES: To determine the prevalence of hypovitaminosis D and secondary hyperparathyroidism (SHPT) and to assess bone turnover by using markers of bone formation and resorption in celiac disease (CD). METHODS: Forty-three patients with CD were investigated: group 1, newly diagnosed celiacs (n = 19); group 2, treated celiacs responding histologically to a gluten-free diet (n = 16); group 3, refractory celiacs, unresponsive to a gluten-free diet and immunosuppressive therapy (n = 8). Serum was drawn for intact parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], ionized calcium (Cai), total alkaline phosphatase (AP), and biochemical markers of bone formation: procollagen I carboxyterminal propeptide (PICP) and osteocalcin (Oc). Urinary indices of bone resorption, deoxypyridinoline (DPD), pyridinoline (PyD), and hydroxyproline (OHP), were measured in a 2-h fasting urine. In 22 patients, computerized tomographic scan for bone mineral density (BMD) was performed. RESULTS: The prevalence in groups 1, 2, and 3, respectively, of hypovitaminosis D (< 50 nmol/L) was 58%, 25%, and 88%, and the prevalence of SHPT (> 5.4 pmol/L) was 25%, 19%, and 25%. Bone resorption markers were significantly elevated in all groups, and bone formation indices were elevated in the newly diagnosed celiacs compared with a group of healthy adults. Low BMD (T-score greater than -1 SD unit) was found in 68% of patients assessed; 36% of patients had a T-score greater than -2.5 SD units. CONCLUSIONS: Hypovitaminosis D and SHPT are common in newly diagnosed and refractory celiacs but are less common in those who respond to a gluten-free diet. Newly diagnosed patients have a high bone turnover state with elevation of both bone formation and resorption indices. Those with refractory disease demonstrate a remodeling imbalance with high bone resorption.
An intravascular microdialysis sampling system suitable for application in continuous biochemical monitoring of glucose and lactate.
Direct sensor implantation for continuous biochemical monitoring has proved disappointing, but microdialysis sampling devices can serve as a biocompatible patient-sensor interface. We propose a novel "MiniShunt" extracorporeal microdialysis sampling circuit designed to sample core blood, and report the performance of different microdialysis probe membrane types and sizes with pumped and non-pumped blood flow in anaesthetised dogs. Discrete microdialysate and plasma samples collected during glucose and lactate monitoring were analysed with a YSI analyzer and showed microdialysis efficiency (% relative recovery) in excess of 95% for both analytes using fibres of greater than 70 mm2 internal surface area. Pumped veno-venous extracorporeal blood microdialysis sampling of this type could provide a suitable interface for future multi-analyte on-line biosensor applications in critically ill patients.
Vitamin D supplementation in the elderly: review of safety and effectiveness of different regimes.
Vitamin D deficiency is common in the elderly, especially in countries where effective sunlight or exposure to sunlight is limited. Two regimes for vitamin D supplementation--low-dose daily oral administration and intermittent high-dose administration--were examined with regard to safety and effectiveness. Eleven papers reporting studies in 449 elderly subjects were reviewed. On low-dose continuous supplementation mean concentration of 25 hydroxyvitamin D (25(OH)D) ranged from 57 to 105 nmol/L compared to 55 to 87 nmol/L following high-dose supplementation. These mean values fall within the physiological range for young adults. Hypercalcemia occurred in only 3 subjects and was associated with a predisposing cause in 2 of 3 subjects. We suggest that low dose continuous supplementation (10 to 20 micrograms daily) is the regime of choice but high-dose intermittent supplementation (2.5 mg six monthly) may be suitable where compliance is poor.
Serum neuron-specific enolase and immunohistochemical markers of neuroendocrine differentiation in lung cancer.
An enzyme immunoassay for serum neuron-specific enolase (NSE) was evaluated with respect to analytical performance and clinical utility and compared with immunohistochemical evaluation of neuroendocrine differentiation. Values obtained agreed well with values obtained using a radioimmunoassay method giving a correlation coefficient of 0.934. Analytical performance of the enzyme immunoassay was good but the diagnostic sensitivity of 82% in extensive and 67% in limited disease was insufficient for serum NSE to be of value in the diagnosis of small cell lung cancer (SCLC). Serum NSE decreased significantly in 11 of 15 patients with SCLC following institution of chemotherapy. Classification of lung cancers into SCLC and non small cell lung cancer (NSCLC) types is largely based on tumour morphology. Neuroendocrine differentiation may not be morphologically evident. Immunohistochemical staining of tumour tissue with markers of neuroendocrine differentiation, i.e. NSE (both monoclonal and polyclonal antibodies) Leu 7, Chromogranin A and P G P 9.5 was performed in both patients with SCLC and NSCLC. 38 per cent of patients with NSCLC had both raised serum NSE and positive NSE (polyclonal) immunoperoxidase staining of lung tissue. A further 35 per cent of patients showed a raised serum NSE or positive immunohistochemistry but not both. The presence of two positive immunoperoxidase markers in lung tissue has been suggested as an indicator of responsiveness to chemotherapy in NSCLC patients. A number of factors may affect immunohistochemical positivity in tissue sections and the additional use of a serum marker may better define chemotherapy responsive groups.
Noninvasive testing in the diagnosis of osteomalacia.
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Safety and efficacy of increasing wintertime vitamin D and calcium intake by milk fortification.
We studied the safety and efficacy of milk fortified with vitamin D3 and calcium. Over the winter, we conducted a double-blind, placebo-controlled trial of fortified milk (12 micrograms vitamin D3 and 1525 mg calcium per litre) compared to unfortified milk (0.3 micrograms vitamin D3 and 1270 mg calcium per litre) in 102 adults (aged 17-54 years). Serum 25-hydroxyvitamin D [25(OH)D], ionized calcium, and creatinine were measured at baseline and after intervention. Fortification reduced the seasonal decline in serum 25(OH)D concentrations by > 50%. In the fortified group, serum 25(OH)D decreased by 15 nmol/l from 77 +/- 35 nmol/l to 62 +/- 26 nmol/l (p < 0.001). In the control group, serum 25(OH)D fell by 31 nmol/l from 85 +/- 38 nmol/l to 54 +/- 25 nmol/l (p < 0.001). We suggest that milk enriched with vitamin D be provided in high-latitude European countries to diminish the wintertime fall in serum 25(OH)D.
Dietary chloride and urinary calcium in stone disease.
We studied six patients with renal stone disease, hypercalciuria, cystinuria and/or hyperuricosuria, during variations in dietary Na and Cl intake. Switching between equimolar NaCl and NaHCO3 intakes reduced urinary Ca (UCa) during the NaHCO3 phase, despite steady-state urinary Na. Switching between equimolar NaCl and KCl did not change UCa, despite a sharp fall in UNa. The results suggest a predominant role for Cl rather than Na ions during sodium-chloride-induced changes in UCa. In stone disease of mixed aetiology, where alkalinization of the urine as well as reduction in UCa may be desirable, treatment with NaHCO3 loading is not accompanied by a rise in UCa, provided that dietary Cl is maintained moderately low at 80-100 mmol/day. The mechanism whereby Cl intake influences UCa remains undefined. Plasma PTH and calcitriol levels showed no significant alteration, and atrial natriuretic peptide levels in one patient remained unchanged.
The prevalence of microalbuminuria and associated risk factors in a population with insulin-dependent diabetes mellitus.
The prevalence of microalbuminuria was studied in a clinic population of patients with insulin-dependent diabetes mellitus [IDDM] with disease duration longer than 5 years. 75 patients were included in the study, 23 patients (30.7%) had microalbuminuria and 2 patients (2.7%) had macroalbuminuria. Comparison of the clinical and laboratory characteristics of patients with microalbuminuria (n = 23) to patients with normoalbuminuria (n = 50) showed no differences with respect to age, duration of diabetes, blood pressure, presence of retinopathy and glycosylated haemoglobin. The mean glomerular filtration rate (GFR) was higher in the microalbuminuric group than in the normoalbuminuric group (125 +/- 45 ml/min compared to 99 +/- 32 ml/min; P < 0.05). In a multiple regression model excluding patients with macroalbuminuria the following predictors of albumin excretion rate (AER) were identified: systolic blood pressure, glycosylated haemoglobin and GFR. Since microalbuminuria is common in Irish patients with IDDM, we suggest that AER should be determined as part of the annual routine screen. Stricter control of blood pressure and glycaemia should be considered.
Secondary hyperparathyroidism in elderly people: combined effect of renal insufficiency and vitamin D deficiency.
The relative effects of renal insufficiency and vitamin D deficiency on parathyroid gland function were assessed in 29 free-living elderly subjects by using a sensitive assay for intact parathyroid hormone (PTH). Serum calcium, phosphate, alkaline phosphatase, creatinine, 25-hydroxyvitamin D [25(OH)D], and PTH were measured after an overnight fast during wintertime, after oral vitamin D therapy (20 micrograms cholecalciferol/d for 4 wk), and at the end of the subsequent summer. Hypovitaminosis D [serum 25(OH)D < 25 nmol/L] was evident in 86% of the subjects during wintertime and 52% had elevated PTH concentrations. Multiple-regression analysis identified serum creatinine as the strongest predictor variable for serum PTH (multiple r = 0.73, P < 0.001). Mean (+/- SD) serum PTH declined from 6.3 +/- 2.8 to 5.0 +/- 2.0 pmol/L (P < 0.001) by the end of the summer season, coincident with an increase in serum 25(OH)D). Secondary hyperparathyroidism is common in elderly people, and in Ireland is the result of both renal insufficiency and hypovitaminosis D.