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1.  Influence of the ABCG2 gout risk 141 K allele on urate metabolism during a fructose challenge 
Introduction
Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic response to fructose loading.
Methods
Healthy volunteers (n = 74) provided serum and urine samples immediately before and 30, 60, 120 and 180 minutes after ingesting a 64 g fructose solution. Data were analyzed based on the presence or absence of the ABCG2 141 K gout risk allele.
Results
The 141 K risk allele was present in 23 participants (31%). Overall, serum urate (SU) concentrations during the fructose load were similar in those with and without the 141 K allele (PSNP = 0.15). However, the 141 K allele was associated with a smaller increase in SU following fructose intake (PSNP <0.0001). Those with the 141 K allele also had a smaller increase in serum glucose following the fructose load (PSNP = 0.002). Higher fractional excretion of uric acid (FEUA) at baseline and throughout the fructose load was observed in those with the 141 K risk allele (PSNP <0.0001). However, the change in FEUA in response to fructose was not different in those with and without the 141 K risk allele (PSNP = 0.39). The 141 K allele effects on serum urate and glucose were more pronounced in Polynesian participants and in those with a body mass index ≥25 kg/m2.
Conclusions
In contrast to the predicted responses for a hyperuricemia/gout risk allele, the 141 K allele is associated with smaller increases in SU and higher FEUA following a fructose load. The results suggest that ABCG2 interacts with extra-renal metabolic pathways in a complex manner to regulate SU and gout risk.
Clinical Trials Registration
The study was registered by the Australian Clinical Trials Registry (ACTRN12610001036000).
doi:10.1186/ar4463
PMCID: PMC3978630  PMID: 24476385
2.  Reduced creatinine clearance is associated with early development of subcutaneous tophi in people with gout 
Background
Although typically a late feature of gout, tophi may present early in the course of disease. The aim of this study was to identify factors associated with the presence of early tophaceous disease.
Methods
People with gout for <10 years were prospectively recruited, and had a comprehensive clinical assessment including examination for subcutaneous tophi. The clinical factors independently associated with the presence and number of tophi were analyzed using regression models.
Results
Of the 290 participants, there were 47 (16.2%) with clinically apparent tophi. In univariate analysis, those with tophi were older, were more frequently taking diuretics and colchicine prophylaxis, and had lower creatinine clearance. The association between the presence of tophi and creatinine clearance was strongest in those with creatinine clearance ≤30 ml/min. In logistic regression analysis, creatinine clearance ≤30 ml/min was associated with the presence of tophi, even after adjusting for ethnicity, corticosteroid use, colchicine use and diuretic use (multivariate adjusted odds ratio 7.0, p = 0.005). Participants with tophi reported higher frequency of gout flares, pain scores, patient global assessment scores, and HAQ scores.
Conclusions
The presence of tophi is associated with more symptomatic disease in people with gout for <10 years. Creatinine clearance is independently associated with early presentation of subcutaneous tophi.
doi:10.1186/1471-2474-14-363
PMCID: PMC3878111  PMID: 24359261
Gout; Tophus; Kidney; Creatinine
3.  Randomised controlled trial of vitamin D supplementation in sarcoidosis 
BMJ Open  2013;3(10):e003562.
Objectives
The role vitamin D intake/production plays in sarcoidosis-associated hypercalcaemia is uncertain. However, authoritative reviews have recommended avoiding sunlight exposure and vitamin D supplements, which might lead to adverse skeletal outcomes from vitamin D insufficiency. We investigated the effects of vitamin D supplementation on surrogate measures of skeletal health in patients with sarcoidosis and vitamin D insufficiency.
Design
Randomised, placebo-controlled trial.
Setting
Clinical research centre.
Participants
27 normocalcaemic patients with sarcoidosis and 25-hydroxyvitamin D (25OHD) <50 nmol/L.
Intervention
50 000 IU weekly cholecalciferol for 4 weeks, then 50 000 IU monthly for 11 months or placebo.
Primary and secondary outcome measures
The primary endpoint was the change in serum calcium over 12 months, and secondary endpoints included measurements of calcitropic hormones, bone turnover markers and bone mineral density (BMD).
Results
The mean age of participants was 57 years and 70% were women. The mean (SD) screening 25OHD was 35 (12) and 38 (9) nmol/L in the treatment and control groups, respectively. Vitamin D supplementation increased 25OHD to 94 nmol/L after 4 weeks, 84 nmol/L at 6 months and 78 nmol/L at 12 months, while levels remained stable in the control group. 1,25-Dihydroxy vitamin D levels were significantly different between the groups at 4 weeks, but not at 6 or 12 months. There were no between-groups differences in albumin-adjusted serum calcium, 24 h urine calcium, markers of bone turnover, parathyroid hormone or BMD over the trial. One participant developed significant hypercalcaemia after 6 weeks (total cholecalciferol dose 250 000 IU).
Conclusions
In patients with sarcoidosis and 25OHD <50 nmol/L, vitamin D supplements did not alter average serum calcium or urine calcium, but had no benefit on surrogate markers of skeletal health and caused one case of significant hypercalcaemia.
Trial registration
This trial is registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). The registration number is ACTRN12607000364471, date of registration 5/7/2007.
doi:10.1136/bmjopen-2013-003562
PMCID: PMC3808783  PMID: 24157819
THORACIC MEDICINE
4.  Lack of change in urate deposition by dual-energy computed tomography among clinically stable patients with long-standing tophaceous gout: a prospective longitudinal study 
Arthritis Research & Therapy  2013;15(5):R160.
Introduction
Dual-energy computed tomography (DECT) has potential for monitoring urate deposition in patients with gout. The aim of this prospective longitudinal study was to analyse measurement error of DECT urate volume measurement in clinically stable patients with tophaceous gout.
Methods
Seventy-three patients with tophaceous gout on stable therapy attended study visits at baseline and twelve months. All patients had a comprehensive clinical assessment including serum urate testing and DECT scanning of both feet. Two readers analysed the DECT scans for the total urate volume in both feet. Analysis included inter-reader intraclass correlation coefficients (ICCs) and limits of agreement, and calculation of the smallest detectable change.
Results
Mean (standard deviation) serum urate concentration over the study period was 0.38 (0.09) mmol/L. Urate-lowering therapy was prescribed in 70 (96%) patients. The median (interquartile range) baseline DECT urate volume was 0.49 (0.16, 2.18) cm3, and change in DECT urate volume was -0.01 (-0.40, 0.28) cm3. Inter-reader ICCs were 1.00 for baseline DECT volumes and 0.93 for change values. Inter-reader bias (standard deviation) for baseline volumes was -0.18 (0.63) cm3 and for change was -0.10 (0.93) cm3. The smallest detectable change was 0.91 cm3. There were 47 (64%) patients with baseline DECT urate volumes <0.91 cm3. Higher serum urate concentrations were observed in patients with increased DECT urate volumes above the smallest detectable change (P = 0.006). However, a relationship between changes in DECT urate volumes and serum urate concentrations was not observed in the entire group.
Conclusions
In patients with tophaceous gout on stable conventional urate-lowering therapy the measurement error for DECT urate volume assessment is substantially greater than the median baseline DECT volume. Analysis of patients commencing or intensifying urate-lowering therapy should clarify the optimal use of DECT as a potential outcome measure in studies of chronic gout.
doi:10.1186/ar4343
PMCID: PMC3978645  PMID: 24286500
5.  Prescription and dosing of urate-lowering therapy, rather than patient behaviours, are the key modifiable factors associated with targeting serum urate in gout 
Background
Long term serum urate (SU) lowering to a target of <0.36 mmol/l (6 mg/dl) is recommended for effective gout management. However, many studies have reported low achievement of SU targets. The aim of this cross-sectional study was to examine the clinical and psychological factors associated with SU targets in patients with gout.
Methods
Patients with gout for <10 years were recruited from primary and secondary care settings. SU target was defined as SU concentration <0.36 mmol/L at the time of the study visit. Both clinical and psychological factors associated with SU target were analysed. The relationship between SU target and measures of gout activity such as flare frequency, tophi, work absences, and Health Assessment Questionnaire-II was also analysed.
Results
Of the 273 patients enrolled into the study, 89 (32.6%) had SU concentration <0.36 mmol/L. Urate-lowering therapy (ULT) use was strongly associated with SU target (p < 0.001). In those patients prescribed ULT (n = 181), allopurinol dose, patient confidence to keep SU under control, female sex, and ethnicity were independently associated with SU target. Other patient psychological measures and health-related behaviours, including adherence scores, were not independently associated with SU target in those taking ULT. Creatinine clearance, diuretic use, age, and body mass index were not associated with SU target. Patients at SU target reported lower gout flare frequency, compared with those not at target (p = 0.03).
Conclusions
ULT prescription and dosing are key modifiable factors associated with achieving SU target. These data support interventions focusing on improved use of ULT to optimise outcomes in patients with gout.
doi:10.1186/1471-2474-13-174
PMCID: PMC3493372  PMID: 22978848
Gout; Urate; Target; Allopurinol
6.  Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial 
BMJ : British Medical Journal  2008;336(7638):262-266.
Objective To determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women.
Design Randomised, placebo controlled trial.
Setting Academic medical centre in an urban setting in New Zealand.
Participants 1471 postmenopausal women (mean age 74): 732 were randomised to calcium supplementation and 739 to placebo.
Main outcome measures Adverse cardiovascular events over five years: death, sudden death, myocardial infarction, angina, other chest pain, stroke, transient ischaemic attack, and a composite end point of myocardial infarction, stroke, or sudden death.
Results Myocardial infarction was more commonly reported in the calcium group than in the placebo group (45 events in 31 women v 19 events in 14 women, P=0.01). The composite end point of myocardial infarction, stroke, or sudden death was also more common in the calcium group (101 events in 69 women v 54 events in 42 women, P=0.008). After adjudication myocardial infarction remained more common in the calcium group (24 events in 21 women v 10 events in 10 women, relative risk 2.12, 95% confidence interval 1.01 to 4.47). For the composite end point 61 events were verified in 51 women in the calcium group and 36 events in 35 women in the placebo group (relative risk 1.47, 0.97 to 2.23). When unreported events were added from the national database of hospital admissions in New Zealand the relative risk of myocardial infarction was 1.49 (0.86 to 2.57) and that of the composite end point was 1.21 (0.84 to 1.74). The respective rate ratios were 1.67 (95% confidence intervals 0.98 to 2.87) and 1.43 (1.01 to 2.04); event rates: placebo 16.3/1000 person years, calcium 23.3/1000 person years. For stroke (including unreported events) the relative risk was 1.37 (0.83 to 2.28) and the rate ratio was 1.45 (0.88 to 2.49).
Conclusion Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular event rates. This potentially detrimental effect should be balanced against the likely benefits of calcium on bone.
Trial registration Australian Clinical Trials Registry ACTRN 012605000242628.
doi:10.1136/bmj.39440.525752.BE
PMCID: PMC2222999  PMID: 18198394
7.  Osteomalacia in an HIV-infected man receiving rifabutin, a cytochrome P450 enzyme inducer: a case report 
Introduction
People infected with human immunodeficiency virus are frequently treated with medications that can induce or inhibit cytochrome P450 enzymes.
Case presentation
A 59 year old man treated with zidovudine, lamivudine, indinavir, and ritonavir for infection with human immunodeficiency virus volunteered to take part in a study of bone loss. He was found to have vitamin D insufficiency with secondary hyperparathyroidism and received vitamin D and calcium supplementation. He suffered a recurrence of infection with Mycobacterium avium intracellulare for which he received treatment with ciprofloxacin, rifabutin, and ethambutol. Subsequently, he developed worsening vitamin D deficiency with hypocalcaemia, secondary hyperparathyroidism and elevated markers of bone turnover culminating in an osteomalacic vertebral fracture. Correction of the vitamin D deficiency required 100,000 IU of cholecalciferol monthly.
Rifabutin is a cytochrome P450 inducer, and vitamin D and its metabolites are catabolised by cytochrome P450 enzymes. We therefore propose that treatment with rifabutin led to the induction of cytochrome P450 enzymes catabolising vitamin D, thereby causing vitamin D deficiency and osteomalacia. This process might be mediated through the steroid and xenobiotic receptor (SXR).
Conclusion
Treatment with rifabutin induces the cytochrome P450 enzymes that metabolise vitamin D and patients treated with rifabutin might be at increased risk of vitamin D deficiency. In complex medication regimens involving agents that induce or inhibit cytochrome P450 enzmyes, consultation with a clinical pharmacist or pharmacologist may be helpful in predicting and/or preventing potentially harmful interactions.
doi:10.1186/1476-0711-7-3
PMCID: PMC2253556  PMID: 18226256

Results 1-7 (7)