A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Dihydropyridine calcium antagonists and renal function in hypertensive kidney transplant recipients.

OBJECTIVE: To investigate whether calcium antagonists are nephroprotective in hypertensive cyclosporine-treated renal allograft recipients. METHODS: We studied 50 hypertensive and 17 normotensive renal transplants (eight females, nine males; 14-54 years, mean age 38.8 +/- 3.5 years). Hypertensive patients were randomized to be treated with (+Ca; 11 females, 13 males; 20-65 years, mean age 43.1 +/- 3 years) or without (-Ca; 15 females, 11 males; 25-60 years, mean age 41.3 +/- 2.5 years) a calcium antagonist (nitrendipine or nifedipine). Additional antihypertensives were given stepwise according to a standardized protocol: beta1-adrenoceptor blocker, diuretic alpha1-adrenoceptor blocker or vasodilator. Data were analysed at 0, 1, 2 and 3 years on an intention-to-treat basis. RESULTS: Hypertensive patients had a higher body mass index at 0/3 years (23.7 +/- 0.6/25.1 +/- 0.6 kg/m2) than normotensive patients (22.2 +/- 0.6/22.1 +/- 0.7 kg/m2). During the study, blood pressure in normotensive transplants was always slightly, but not significantly, lower than that of transplants with treated hypertension. There was no difference between the groups (+Ca) and (-Ca). Cr51-ethylenediaminetetracetic acid (EDTA) clearance (0/2 years) was 58 +/- 4/57 +/- 6 ml/min in normotensives, 52 +/- 4/47 +/- 4 ml/min in hypertensives (+Ca) and 47 +/- 4/49 +/- 6 ml/min in hypertensives (-Ca). Proteinuria (0/3 years) was 0.16 +/- 0.04/0.15 +/- 0.02 g/24 h in normotensive, 0.26 +/- 0.08/0.23 +/- 0.05 g/24 h in hypertensives (+Ca) and 0.26 +/- 0.07/0.22 +/- 0.05 g/24 h in hypertensives (-Ca). CONCLUSIONS: Post-transplant hypertension is associated with higher body mass index and poor renal function. No difference in the course of Cr51-EDTA clearance, serum creatinine, proteinuria or blood pressure was observed between groups treated with or without calcium antagonists. Calcium antagonists and conventional antihypertensive treatment have the same nephroprotective effect in hypertensive renal transplants, when treatment is started 3 months after transplantation.

Bone loss after kidney transplantation: a longitudinal study in 115 graft recipients.

BACKGROUND: Bone loss is an important problem in renal transplant recipients immediately after surgery. No data are available about the bone loss beyond the first post-transplantation year. METHODS: In a longitudinal, uncontrolled observational study bone mineral density (BMD) was measured by dual X-ray absorptiometry in 115 renal graft recipients starting at different times after transplantation (0-20 years after transplantation) with a follow-up time of 12 months. RESULTS: A total of 56 patients showed a reduction of BMD during the observation period. Bone loss depended on the time after transplantation. Mean reduction of BMD at lumbar spine was 7 +/- 10%, 1 +/- 9% during the first and second postoperative year. Beyond the third year bone mineral density did not change or even increased slightly (0 +/- 4% during 3-5th year, 1 +/- 6% during 6-10th year and 2 +/- 4% during 11-20th year after transplantation). Decrease of BMD correlated with a higher mean daily prednisone dosage (P < 0.001), a higher cumulative prednisone dose (P < 0.01), a more frequent and more steroid-resistant rejection (P < 0.001) and a higher initial parathyroid hormone level (P < 0.001). Patients with 25-OH-cholecalciferol therapy (P < 0.05) or more physical activity (P < 0.05) had a smaller bone loss. CONCLUSIONS: Reduction of BMD after transplantation is highest within the first post-transplant year. The effects of acute graft rejection, prednisone dosage and initial parathyroid hormone level are predominant among the multiple factors associated with pronounced bone loss.

Air transporation and the disabled.

Air transportation is becoming increasingly more accessible to the disabled traveller. This is due to many reasons. The disabled themselves are now very much a part of twentieth century society in which air travel plays a large role. To this end, several international organizations representing the disabled have been pressuring for increased accessibility. As well, the airlines have realized that the disabled represent a sizable market potential and thus they have begun accessibility and staff sensitization programs. This article will first provide a summary of the current situation for disabled travellers and will discuss such things as architectural barriers and other limitations both in the airport and on-board the aircraft. The second section will discuss the current research into improving the comsort of the disabled passenger. Topics such as modification of on-board washroom facilities, adapted aids kits and on-board wheelchairs will be presented. Part three will be a short discussion of resources and organizations available to the disabled traveller. It is hoped that occupational therapists will gain a better understanding of the resources and developments in this area.