Introducing mobile fracture prevention services with DXA in Northern Scotland: a comparative study of three rural communities.

Mobile fracture prevention services, with DXA, significantly improved access to care for those at high risk of fracture living in rural areas. Introduction of mobile services facilitated access to fracture liaison services and development of integrated of care pathways across community- and secondary-based care. INTRODUCTION: The ageing population is growing faster in rural areas, yet most fracture prevention services are located in urban areas. As part of a wider study, evaluating the introduction of mobile fracture prevention services, we focus on whether mobile services improve access to care for those at highest risk of fracture. METHODS: Services outcomes were assessed against the Royal Osteoporosis Society clinical standards for fracture liaison services. This included standardised, age-specific referral rates, FRAX 10-year probability of major osteoporotic and hip fracture of referrals, pre- and post-introduction of the mobile service across two island and one rural mainland sites. This was compared with referrals from a similar rural mainland region with local access to a comprehensive service. RESULTS: Greatest impact occurred in areas with most limited service provision at baseline. Mean age of patients referred increased from 59 to 68 years (CI 6.8-10.1, p < 0.001). Referral rates increased from 2.8 to 5.4 per 1000 population between 2011 and 2018, with a 5-fold rise in those ≥ 75 years (0.4 to 2.0 per 1000). Mean FRAX 10-year risk of major osteoporotic fracture increased from 12.7 to 17.7% (CI 3.2-5.7, p < 0.001). Mean hip fracture risk probability increased from 3.0 to 5.7% (CI 2.0-3.4, p < 0.001). However, referral rates from the mobile sites remained lower than the comparator site. CONCLUSIONS: Mobile fracture prevention services, including DXA, greatly improved uptake amongst high-risk individuals. Mobile services facilitated development of integrated of care pathways, including fracture liaison services, across community- and secondary-based care.

More than a messenger: Alternative splicing as a therapeutic target.

Alternative splicing of pre-mRNA is an essential post- and co-transcriptional mechanism of gene expression regulation that produces multiple mature mRNA transcripts from a single gene. Genetic mutations that affect splicing underlie numerous devastating diseases. The complexity of splicing regulation allows for multiple therapeutic approaches to correct disease-associated mis-splicing events. In this review, we first highlight recent findings from therapeutic strategies that have used splice switching antisense oligonucleotides and small molecules that bind directly to RNA. Second, we summarize different genetic and chemical approaches to target components of the spliceosome to correct splicing defects in pathological conditions. Finally, we present an overview of compounds that target kinases and accessory pathways that intersect with the splicing machinery. Advancements in the understanding of disease-specific defects caused by mis-regulation of alternative splicing will certainly increase the development of therapeutic options for the clinic. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm.

Validation of a short questionnaire for estimating dietary calcium intakes.

UNLABELLED: Concern about calcium supplements, and mainly minor side effects (e.g. constipation) impacting on compliance, means that assessing dietary calcium intake is important. There is no suitable biomarker. Compared to food diaries, a short questionnaire was an efficient way of confirming that patients had adequate calcium intakes (>700 or >1,000 mg) INTRODUCTION: Calcium is usually given alongside treatments for osteoporosis, but recent concerns about potential side effects have led to questioning whether supplements are always necessary. It is difficult to assess calcium intake in a clinical setting and be certain that the patient is getting enough calcium. The aim of this study was to determine whether a short questionnaire for estimating dietary calcium intakes in a clinical setting was fit for purpose. METHODS: We assessed dietary calcium intakes using a short questionnaire (CaQ) in patients attending an osteoporosis clinic (n = 117) and compared them with calcium intakes obtained from a 7-day food diary (n = 72) and a food frequency questionnaire (FFQ) (n = 33). RESULTS: Mean (SD) daily calcium intakes from the CaQ were 836 (348) mg; from the diaries, 949 (384) mg; and from the FFQ, 1,141 (387) mg. The positive predictive value (PPV) was >80% for calcium cut-offs > 700 mg and 70% for cut-offs > 1,000 mg. The calcium intakes for the false positives results were not far below the cut-off. For 1,200 mg, the PPV was 67% or less. CONCLUSION: The CaQ is an adequate tool for assessing whether a patient has daily calcium intakes above 700 or 1,000 mg; if below these cut-offs, it is possible that the patient still has enough calcium in the diet, which could be clarified by questioning the patient further. As there were few patients with calcium intakes above 1,200 mg a day, the CaQ cannot be recommended as a tool for confirming higher dietary calcium intakes.

A parallel group double-blind RCT of vitamin D3 assessing physical function: is the biochemical response to treatment affected by overweight and obesity?

UNLABELLED: Vitamin D may affect skeletal muscle function. In a double-blind, randomised, placebo-controlled trial, we found that vitamin D3 supplementation (400 or 1,000 I.U. vs. placebo daily for 1 year with bimonthly study visits) does not improve grip strength or reduce falls. INTRODUCTION: This study aimed to test the supplementation effects of vitamin D3 on physical function and examine associations between overweight/obesity and the biochemical response to treatment. METHODS: In a parallel group double-blind RCT, healthy postmenopausal women from North East Scotland (latitude-57° N) aged 60-70 years (body mass index (BMI), 18-45 kg/m(2)) were assigned (computer randomisation) to daily vitamin D3 (400 I.U. (n = 102)/1,000 I.U. (n = 101)) or matching placebo (n = 102) (97, 96 and 100 participants analysed for outcomes, respectively) from identical coded containers for 1 year. Grip strength (primary outcome), falls, diet, physical activity and ultraviolet B radiation exposure were measured bimonthly, as were serum 25(OH)D, adjusted calcium (ACa) and phosphate. Fat/lean mass (dual energy X-ray absorptiometry), anthropometry, 1,25-dihydroxyvitamin D and parathyroid hormone were measured at baseline and 12 months. Participants and researchers were blinded throughout intervention and analysis. RESULTS: Treatment had no effect on grip strength (mean change (SD)/year = -0.5 (2.5), -0.9 (2.7) and -0.4 (3.3) kg force for 400/1,000 I.U. vitamin D3 and placebo groups, respectively (P = .10, ANOVA)) or falls (P = .65, chi-squared test). Biochemical responses were similar across BMI categories (<25.25-29.99, ≥30 kg/m(2)) with the exception of a small change at 12-months in serum ACa in overweight compared to non-overweight participants (P = .01, ANOVA; 1,000 I.U. group). In the placebo group, 25(OH)D peak concentration change (winter to summer) was negatively associated with weight (r = -.268), BMI (r = -.198), total (r = -.278) and trunk fat mass (r = -.251), with total and trunk fat mass predictive of winter to summer 25(OH)D change (P = .01/.004 respectively, linear regression). CONCLUSION: We found no evidence of an improvement in physical function following vitamin D3 supplementation for 1 year.

Sunlight and dietary contributions to the seasonal vitamin D status of cohorts of healthy postmenopausal women living at northerly latitudes: a major cause for concern?

UNLABELLED: We assessed sunlight and dietary contributions to vitamin D status in British postmenopausal women. Our true longitudinal 25-hydroxyvitamin D (25(OH)D) measurements varied seasonally, being lower in the north compared to the south and lower in Asian women. Sunlight exposure in summer and spring provided 80% total annual intake of vitamin D. INTRODUCTION: Vitamin D deficiency is highlighted as a potential problem for countries at high latitude, but there are few true longitudinal, seasonal data to allow regional comparisons. We aimed to directly compare seasonal variation in vitamin D status (25(OH)D) in postmenopausal women at two northerly latitudes and to assess the relative contributions of sunlight exposure and diet. METHODS: Vitamin D status was assessed in 518 postmenopausal women (age 55-70 years) in a two-centre cohort study with serum collected at fixed three-monthly intervals from summer 2006 for immunoassay measurement of 25(OH)D and parathyroid hormone. At 57° N (Aberdeen, Scotland, UK), there were 338 Caucasian women; at 51° N (Surrey, South of England, UK), there were 144 Caucasian women and 35 Asian women. UVB exposure (polysulphone film badges) and dietary vitamin D intakes (food diaries) were also estimated. RESULTS: Caucasian women had lower 25(OH)D (p < 0.001) at 57° N compared to 51° N. Median (interquartile range) in nanomoles per litre for summer (June-August) at 57° N was 43.0 (20.9) and at 51° N was 62.5 (26.6) and for winter (December-February) at 57° N was 28.3 (18.9) and at 51° N was 39.9 (24.0). For Asian women at 51° N, median 25(OH)D was 24.0 (15.8) nmol/L in summer and 16.9 (15.9) nmol/L in winter. Median dietary vitamin D intakes were 80-100 IU for Caucasians and 50-65 IU for the Asian women. Sunlight was the main contributor to 25(OH)D with spring and summer providing >80% total annual intake. CONCLUSIONS: These longitudinal data show significant regional and ethnic differences in UVB exposure and vitamin D status for postmenopausal women at northerly latitudes. The numbers of women who are vitamin D deficient is a major concern and public health problem.

Spontaneous resolution of multiple coronary aneurysms complicating drug eluting stent implantation.

Recent reports of coronary aneurysm formation after drug eluting stent implantation have emerged. Although various treatment modalities have been proposed, minimal data is available relating to their natural history and optimal management. We present a case of aneurysm formation in the left anterior descending and right coronary arteries after stenting with paclitaxel-eluting stents. Coronary bypass grafting of the left anterior descending and circumflex coronary arteries was subsequently required. Repeat angiography (16 months later) showed complete resolution of both coronary aneurysms. Spontaneous resolution of potentially drug eluting stent-related coronary aneurysms is documented. This phenomenon may have therapeutic implications.

Predicting erosive disease in rheumatoid arthritis. A longitudinal study of changes in bone density using digital X-ray radiogrammetry: a pilot study.

OBJECTIVE: Periarticular osteoporosis is one of the first radiological signs of rheumatoid arthritis (RA). Osteoporosis is now quantified using dual-energy X-ray absorptiometry (DXA), although it was originally assessed by radiogrammetry. A new updated system of radiogrammetry has been developed: digitized X-ray radiogrammetry (DXR). We used this DXR system to identify whether changes seen in hand X-rays of RA patients can predict those who subsequently develop erosions. METHODS: We enrolled 24 patients with early RA and they attended for hand radiographs at baseline, 12, 24 and 48 months. The hand radiographs were analysed using a Pronosco X-Posure system which measures bone mineral density, and other parameters using DXR. DXA of the hand was also performed to measure bone mineral density. Sharp and Larsen radiographic scores were calculated and other disease activity markers were measured. RESULTS: DXR bone mineral density fell significantly throughout the study. The group of RA subjects were divided according to the change in erosive status. Change in DXR bone mineral density after 1 yr was very specific (100%) and highly sensitive (63%) in predicting those who either became erosive or whose erosions significantly worsened. In contrast, of the other disease activity markers, only baseline ESR (sensitivity 67%, specificity 80%) significantly predicted the erosive status of subjects at 4 yr. CONCLUSION: Computerized radiogrammetry from digitized images can predict at 1 yr those patients with RA who will become erosive at 4 yr. A larger prospective study is required to confirm these findings; however, these results show some promise as a method of targeting those patients who require more aggressive, expensive therapy.

Effect of pregnancy on bone mineral density and biochemical markers of bone turnover in a patient with juvenile idiopathic osteoporosis.

Juvenile idiopathic osteoporosis (JIO) is rare, presenting with vertebral fractures in the immediate prepubertal years; however, recovery is normally observed. We report the case of a 19-year-old pregnant woman previously diagnosed with JIO. She experienced three vertebral fractures in the third trimester of pregnancy. She delivered by caesarean section at 38 weeks gestation. Spinal bone mineral density decreased by 25%, hip bone mineral density by 10%, and forearm bone mineral density by 3% during pregnancy. Bone resorption markers, free pyridinoline and deoxypyridinoline (fPYD and fDPD), were elevated at baseline and markedly increased during pregnancy (fPYD/fDPD at 0, 10, 15, 20, and 28 weeks and immediately postpartum: 36.2/11.5, 52.9/15.8, 54.3/13.3, 51.1/13.3, 90/21.8, and 95.6/22.7 nmol/mmol creatinine, respectively) The bone formation marker, bone-specific alkaline phosphatase (BSAP), was within the reference range at baseline and increased in the third trimester. (BSAP at 0, 10, 15, 20, and 28 weeks and immediately postpartum: 20.5, 18.3, 17.7, 19.8, 26.9, and 30.0 U/liter, respectively). Parathyroid hormone (PTH) was measured by two methods to assess the possible effect of PTH fragments. PTH(1-84) (Roche) showed little change during the pregnancy, whereas the Nichols assay [(1-84) and(7-84) PTH fragment], revealed increases paralleling the changes in bone resorption. This young woman's bone turnover showed an exaggerated response to pregnancy, with bone resorption predominating over formation. PTH fragments may have partially mediated this effect.

Long-term (> or =8 years) outcome after Palmaz-Schatz stent implantation.

The purpose of this single-center study was to evaluate the long-term (> or =8 years) outcome of Palmaz-Schatz intracoronary stenting and to identify independent predictors of outcome. Although short-term results of Palmaz-Schatz intracoronary stenting have been promising, with a reduction in both angiographic restenosis and clinical cardiac events up to 3 years, longer-term follow-up has not been established. We analyzed clinical outcome in 426 consecutive patients at least 8 years after coronary stenting. Demographic, clinical, and procedural predictors of restenosis, survival, and event-free survival, defined as freedom from death, myocardial infarction (MI), and coronary revascularization (target stented site, target vessel, and any revascularization) were analyzed. Before discharge, 28 patients (6.6%) sustained at least 1 major cardiovascular event: 3 deaths (0.7%), 18 MIs (4.2%), and 17 repeat revascularizations. Surviving patients were followed for 8.9 years (interquartile range 8.4 to 9.4). After discharge, 59 patients (13.9%) died, 47 (11.1%) sustained an MI, and 188 (44.4%) underwent coronary revascularization. The 8-year event-free survival (freedom from death, freedom from death/MI/target-stented site revascularization, and freedom from death/MI/any coronary revascularization) was (mean +/- SE) 0.86 +/- 0.01, 0.62 +/- 0.03, and 0.47 +/- 0.02, respectively. Unstable angina, lower left ventricular ejection fraction, and saphenous vein graft stenting were found to be independent predictors of death during follow-up. Hypertension, unstable angina, multivessel disease, and multiple stent implantation were found to be independent predictors of the composite of death/MI/any coronary revascularization during follow-up. This study provided a useful assessment of very long-term outcome in survival, event-free survival, and predictors of major cardiac events 8 to 10 years after Palmaz-Schatz stent implantation.

[Percutaneous angioplasty of unprotected left main coronary disease with implantation of systematic stenting. Immediate and mid-term results]. / Angioplastie percutanée du tronc commun de la coronaire gauche non protégé avec implantation systématique d'une endoprothèse. Résultats immédiats et à moyen terme.

The authors report the immediate and medium term results of percutaneous angioplasty of unprotected left main coronary disease with systematic stenting. Between March 1994 and December 1998, out of 6,006 patients undergoing coronary angioplasty, 92 had significant unprotected left main stem disease. The majority of patients was male (74 men, 80%) with an average age of 74.3 +/- 8.1 years. Between March 1994 and October 1996, only patients with a surgical contraindication were treated by angioplasty (n = 39). After October 1996, the indications were extended to patients who did not have surgical contraindications (n = 53). During the hospital phase, 4 patients (4%) died (ventricular arrhythmia: 1, cardiogenic shock: 2, gastro-intestinal haemorrhage: 1). No non-fatal infarction with or without Q waves were observed, and no emergency coronary bypass surgical procedures were required. The angiographic success rate was 100%. During follow-up (7.3 +/- 5.8 months), 6 other patients died, 13 required a repeat coronary angioplasty, 4 for restenosis of the left main coronary artery, and 2 underwent coronary bypass surgery. The actuarial survival rate was 89 +/- 5% at 1 year and 85 +/- 17% at 3 years. Percutaneous angioplasty for unprotected left main coronary disease with systematic stenting was performed with acceptable hospital and medium term results.

Bone mineral density in osteoarthritis.

The inverse relation between osteoporosis and osteoarthritis has long been considered in the literature. This review looks at current evidence to support this relation, concentrating on studies published since 1998. The review also summarizes previous large studies investigating this relation. Recent studies indicate higher bone mineral density as measured by dual energy x-ray absorptiometry in subjects with osteoarthritis at a distant site, but suggest less association with hand osteoarthritis. Genetic work has sought to explain this association and this too is discussed. There is some indication that a higher bone density may not protect against fracture in these subjects, due to the increased risk of falls.

Long-term clinical outcome after endoluminal reconstruction of diffusely degenerated saphenous vein grafts with less-shortening wallstents.

OBJECTIVES: This study was designed to evaluate the immediate and long-term clinical results of patients undergoing endoluminal reconstruction in diffusely degenerated saphenous vein grafts (SVGs) with elective implantation of one or more less-shortening Wallstents. BACKGROUND: The optimal treatment strategy for patients with diffusely degenerated SVGs is controversial. Endoluminal reconstruction by stent implantation is one proposed strategy; however, there are few data regarding long-term clinical outcome. METHODS: Between May 1995 and September 1998, 6,534 consecutive patients underwent angioplasty in our institution, including 440 who were treated for SVG lesions. Of these, 126 (115 men, 11 women, median age 69.5 years, range: 33-86 years) with old SVGs (mean age: 13+/-5 years) diffusely degenerated stenosed or occluded (mean lesion length: 27+/-12 mm) were treated electively with implantation of one or multiple (total 197) less-shortening Wallstents. RESULTS: Before discharge, 13 patients (10.3%) sustained at least one major cardiovascular event, including 4 deaths (3.2%), 11 myocardial infarctions (MI) (8.7%), and 3 repeat revascularizations (target vessel = 1, nontarget vessel = 2, 2.4%). Surviving patients were followed for 22+/-11 months: 13 patients (11.1%) died, 11 (9.4%) sustained an MI, 37 underwent angioplasty (31.6%), and 4 (3.4%) underwent bypass surgery. The estimated three-year event-free survival rates (freedom from death, and freedom from death/MI/target vessel revascularization) were (mean +/- SE) 81.1+/-7.8% and 43.2+/-18.5%, respectively. CONCLUSIONS: The long-term clinical outcome of patients undergoing endoluminal reconstruction in diffusely degenerated SVG is relatively poor, mainly because of a high incidence of death or MI and the frequent need for repeat angioplasty. It is unlikely that percutaneous intervention alone will provide a satisfactory or definitive solution for these patients.

[Percutaneous coronary angioplasty via the radial artery. Feasibility and safety]. / Angioplastie coronaire percutanée par voie radiale. Faisabilité et innocuité.

The authors report the results of percutaneous coronary angioplasty using the radial approach with respect to feasibility and safety. Between February 1994 and December 1998, out of a total of 9,070 coronary angioplasties performed in our Institute, the radial arterial approach was chosen in 5,354 cases (59%). During this period, the proportion of procedures performed via the radial artery progressively increased to 78% of cases in 1998. Cannulation of the radial artery was successful in 5,244 cases (98%). Rotatory atherectomy was used in 96 cases (2%), the excimer laser in 38 cases (1%) and stenting was performed in 3,350 cases (64%). Angiographic success was obtained in 5,224 patients (99%). Serious cardiac complications occurred in 82 patients (1.5%), including 17 deaths (0.3%), 22 Q wave myocardial infarctions (0.4%), 28 non-Q wave infarcts (0.5%), 5 coronary bypass procedures (0.1%) and 10 sub-acute occlusions (0.2%). The vascular complications included 1 death due to an ischaemic cerebrovascular accident, 25 haematomas at the puncture site (0.5%) and 3 surgical arterial repairs. The radial pulse disappeared after the procedure in 4% of cases, all asymptomatic. Angioplasty by the radial artery in the hands of trained operators is feasible and associated with a relatively low rate of cardiac and vascular complications.

In-stent restenosis: long-term outcome and predictors of subsequent target lesion revascularization after repeat balloon angioplasty.

OBJECTIVES: We sought to evaluate the long-term clinical outcome of patients undergoing successful balloon angioplasty for in-stent restenosis, and to determine correlates of the need for subsequent target lesion revascularization (TLR). BACKGROUND: In-stent restenosis can be safely treated by repeat percutaneous intervention. Reported subsequent TLR rates have varied from 20% to 80% and seem related to the type of restenotic lesion. METHODS: The study population comprised 234 patients with follow-up data who were successfully treated with repeat balloon angioplasty for in-stent restenosis in 257 lesions between May 1995 and January 1998 at our institution. RESULTS: Clinical follow-up was available at 459 (286 to 693) days after the repeat procedure. Event-free survival was 78.5% and 74.6% at 12 and 24 months, respectively. Recurrent events occurred in 58 patients (24.8%), including 6 deaths (2.6%), 4 myocardial infarction (1.7%) and repeat target vessel revascularization in 50 patients (21.4%). Independent predictors of repeat TLR were time to in-stent restenosis <90 days (Hazard ratio 4.67, p < 0.001), minimal luminal diameter after repeat procedure (Hazard ratio 0.38, p = 0.034) and the angiographic pattern of in-stent restenosis (Hazard ratio 1.65, p = 0.036). CONCLUSIONS: Balloon angioplasty is an effective means of treating in-stent restenosis. The long-term results are acceptable particularly for focal restenotic lesions. Further restenosis is more common in patients with early initial recurrence, more proliferative lesions and a poorer angiographic result from repeat angioplasty.

A detailed assessment of alterations in bone turnover, calcium homeostasis, and bone density in normal pregnancy.

The effects of pregnancy on bone turnover and the potential risk of developing an osteoporotic fracture in pregnancy are controversial. Utilizing biochemical markers of bone formation and resorption and dual-energy X-ray absorptiometry (DEXA), bone turnover before, during, and after pregnancy was studied in detail. Ten women (mean age 30 years; range 23-40) were recruited. Prepregnancy data were obtained and then a review was performed at 2-week intervals , once pregnancy was confirmed, until 14 weeks of gestation and thereafter monthly until term. Bone mineral density (BMD) was estimated by DEXA scanning of hip, spine, and forearm preconception and postpartum. In addition, BMD of the forearm at 14 weeks and 28 weeks gestation was obtained. All pregnancies had a successful outcome. Urinary free pyridinium cross-links, free pyridinoline (fPyr) and free deoxypyridinoline (fDPyr), were normal prepregnancy (mean [+/-SD]) 14.6 nmol/mmol (1.8) and 5.0 nmol/mmol (1.0) creat, respectively. By 14 weeks, they had increased to 20.8 nmol/mmol (4.3) and 6.1 nmol mmol (1.4) (both p < 0.02) and by 28 weeks to 26.3 nmol/mmol (5.6) and 7.4 nmol/mmol (1.6) (both p < 0.01). The ratio of fPyr to fDPyr remained constant. A similar significant increase was observed in N-telopeptide (NTx). Bone formation was assessed by measurement of carboxyterminal propeptide of type 1 collagen (P1CP) and bone-specific alkaline phosphatase (BSAP). Neither were altered significantly before 28 weeks, but subsequently mean P1CP increased from 110 microg/liter (23) to 235 microg/liter (84) at 38 weeks and mean BSAP increased from 11.1 U/liter (5.0) to 28.6 U/liter (11.1) (p < 0.01 for both variables). Lumbar spine (L1-L4) BMD decreased from a prepregnancy mean of 1.075 g/cm (0.115) to 1.054 g/cm2 (0.150) postpartum (p < 0.05). Total hip BMD decreased from a prepregnancy mean of 0.976 g/cm2 (0.089) to 0.941 g/cm2 (0.097) (p < 0.05). Forearm BMD at midradius, one-third distal and ultradistal decreased but did not reach statistical significance. As assessed by these bone markers, in the first 2 trimesters of pregnancy, bone remodeling is uncoupled with a marked increase in bone resorption. A corresponding increase in formation markers is not observed until the third trimester. Spinal BMD exhibits a significant decrease from prepregnancy to the immediate postpartum period with a mean reduction in BMD of 3.5 % in 9 months.

Sleep of the great.

Both Lewis Carroll and William Shakespeare appear to have made clinical observations of sleep apnea syndromes long before they were discovered by medical science, and to have understood something about their physiological mechanisms. The somnolent dormouse in Alice in Wonderland indicates that his problem is one of sleep and breathing and is subject to modern treatment for obstructive apnea. Shakespeare in Henry IV presents a case of obstructive apnea along with a case of Cheyne-Stokes breathing and uses the plot of these history plays to explain by analogy the theoretical basis for periodic breathing.

Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine.

BACKGROUND: Substantial hematologic toxicity limits the use of azathioprine. OBJECTIVE: To evaluate 1) polymorphic inactivation of azathioprine by thiopurine methyltransferase and 2) clinical toxicity. DESIGN: Prospective cohort study. SETTING: Two rheumatology units. PATIENTS: 67 patients for whom azathioprine was prescribed as second-line therapy for rheumatic disease. MEASUREMENTS: Polymerase chain reaction-based assays were used to detect mutations in thiopurine methyltransferase. The primary end point was discontinuation of azathioprine therapy because of toxicity. RESULTS: Six of 67 patients (9%) were heterozygous for mutant thiopurine methyltransferase alleles. Five of the 6 patients discontinued therapy within 1 month of starting treatment because of low leukocyte counts. The sixth patient did not adhere to treatment. Patients with wild-type thiopurine methyltransferase alleles received therapy longer than did patients with mutant alleles (median duration of therapy, 39 weeks [range, 6 to 180 weeks] and 2 weeks [range, 2 to 4 weeks], respectively; P = 0.018). CONCLUSION: Analysis of thiopurine methyltransferase genotype is a quick way to identify patients at risk for acute toxicity from azathioprine.

Osteoporosis in pregnancy: more than postural backache.

Though uncommon, osteoporosis can occur in pregnancy or shortly after delivery. The most common feature is back pain, often severely disabling. Suspect osteoporosis if pain of sudden onset in the upper lumbar or thoracic spine is not relieved by simple analgesia, or if there is a noticeable loss of height. X-rays reveal low bone density and fractures of the vertebrae. 70% of cases occur in first pregnancies. Recurrence is unusual. Most cases resolve spontaneously; a minority cause disability lasting months or years. If osteoporosis is diagnosed, breast feeding should be discouraged because of its effect on bone mineral density. Anyone who has had osteoporosis of pregnancy is at risk of postmenopausal osteoporosis and should take medical advice.