Asthma is a chronic inflammatory condition. Inhibition of the ubiquitin-proteasome system offers promise as a anti-inflammatory strategy, being responsible for the degradation of key proteins involved in crucial cellular functions, including gene expression in inflammation (e.g. inhibitory IkappaB-alpha and the endogenous MAPK deactivator - MKP-1). As MKP-1 inhibits MAPK-mediated pro-remodeling functions in human airway smooth muscle (ASM; a pivotal immunomodulatory cell in asthma) in this study we investigate the effect of the proteasome inhibitor MG-132 on MKP-1 and evaluate the anti-inflammatory effect of MG-132 on cytokine secretion from ASM cells. Examining the time-course of induction of MKP-1 mRNA and protein by MG-132 (10microM) we show that MKP-1 mRNA was first detected at 30min, increased to significant levels by 4h, resulting in a 12.6+/-1.5-fold increase in MKP-1 mRNA expression by 24h (P<0.05). MKP-1 protein levels corroborate the mRNA results. Investigating the effect of MG-132 on secretion of the cytokine IL-6 we show that while short-term pretreatment with MG-132 (30min) partially reduced TNFalpha-induced IL-6 via inhibition of IkappaB-alpha degradation and the NF-kappaB pathway, longer-term proteasome inhibition (up to 24h) robustly upregulated MKP-1 and was temporally correlated with repression of p38-mediated IL-6 secretion from ASM cells. Moreover, utilizing a cytokine array we show that MG-132 represses the secretion of multiple cytokines implicated in asthma. Taken together, our results demonstrate that MG-132 upregulates MKP-1 and represses cytokine secretion from ASM and highlight the potential of the proteasome as a therapeutic target in asthma.

RESULTSTwo hundred twenty-four older adults with T2DM were included. Participant characteristics and a comparison of parameters between the four participant groups according to BMI at the time of the enrollment and at the end of follow-up are shown in Table 1. Statistical analysis of the relationship between BMI and eGFR after adjustment for age, sex, hypertension, eGFR, and albuminuria showed that a high BMI acted as a protective factor (BMI = 30 kg/m 2 , odds ratio = 0.36, 95% confidence interval = 0.04-0.68, P = .001), whereas a low BMI was a risk factor for progression of renal disease. DISCUSSIONThe results suggest that, in elderly adults with T2DM, low BMI is associated with rapid decline of eGFR and that cardiovascular risk remains higher in elderly adults with T2DM with high BMI. No study has precisely investigated the link between BMI and renal progression or between BMI and CVD in elderly adults with T2DM, so any comparison with the current results is impossible. The rapid rate of progression was found in 17.9% of the cases, versus 16% to 25% in a U.S. series. 8 The fastest rate of progression was seen in participants with a BMI <22.5 kg/m 2 . In this group, the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was not optimal because of poor tolerance of these drugs and lack of financial means. A retrospective Chinese study showed that greater total and noncardiovascular mortality was associated with underweight in elderly adults with hypertension. 9 CONCLUSIONCan low BMI be considered as a risk factor for renal progression in elderly adults with diabetes mellitus? How can this link be explained? Is low BMI a parameter that reflects undernourishment, inflammation, or diabetic imbalance? Additional studies with more-rigorous criteria and methodology are needed to support or negate such a hypothesis.

The clinical characteristics and long-term outcomes of patients presenting with acute pulmonary embolism (PE) during treatment with warfarin have not been described. Clinical details of all patients admitted to a tertiary institution from 2000-2007 with acute PE were retrieved retrospectively, baseline warfarin status and the international normalised ratio (INR) were recorded, and their outcomes tracked using a statewide death registry. Of 923 patients with clearly documented warfarin status included in this study, 83 (9%) were taking warfarin. Mean (± standard deviation) day-1 INR of those taking warfarin was 2.3 ± 0.9, with 67% of patients therapeutically anti-coagulated (INR ≥2.0) at presentation (49 patients with INR <2.5 and 34 with INR ≥2.5). Patients taking warfarin on admission were more likely to have heart failure, atrial fibrillation and valvular heart disease, with similar prevalence of malignancy and ischaemic heart disease, compared to patients not on warfarin. Total mortality of the cohort (mean follow-up 4.0 ± 2.5 years) was 31.6% (in-hospital mortality 1.5%), and was similar between warfarin and no warfarin groups. There was however a greater than four-fold increased risk of post-discharge death due to recurrent PE for the patients taking warfarin on admission (hazard ratio [HR] 4.43, 95% confidence interval [CI] 1.36-14.42, p=0.01). Among patients taking warfarin on admission, day-1 INR <2.5 significantly increased long-term all-cause mortality compared to INR ≥2.5 (adjusted HR 2.51, 95% CI 1.08-5.86, p=0.03). In conclusion, patients presenting with PE during treatment with warfarin have an increased risk of death from recurrent PE. Admission INR appears to have independent long-term prognostic importance in these patients.

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