The mitochondrial permeability transition pore (mPTP) is widely accepted as an end-effector mechanism of conditioning protection against injurious ischaemia/reperfusion. However, death can be initiated in cells without pre-requisite mPTP opening, implicating alternate targets for ischaemia/reperfusion injury amelioration. Matrix metalloproteinases (MMP) are known to activate extrinsic apoptotic cascades and therefore we hypothesised that MMP activity represents an mPTP-independent target for augmented attenuation of ischaemia/reperfusion injury. In ex vivo and in vivo mouse hearts, we investigated whether the MMP inhibitor, ilomastat (0.25 μmol/l), administered upon reperfusion could engender protection in the absence of cyclophilin-D (CyPD), a modulator of mPTP opening, against injurious ischaemia/reperfusion. Ilomastat attenuated infarct size in wild-type (WT) animals [37 ± 2.8 to 22 ± 4.3 %, equivalent to ischaemic postconditioning (iPostC), used as positive control, 27 ± 2.1 %, p < 0.05]. Control CyPD knockout (KO) hearts had smaller infarcts than control WT (28 ± 4.2 %) and iPostC failed to confer additional protection, yet ilomastat significantly attenuated infarct size in KO hearts (11 ± 3.0 %, p < 0.001), and similar protection was also seen in isolated cardiomyocytes. Moreover, ilomastat, unlike the cyclophilin inhibitor cyclosporine-A, had no impact upon reactive oxygen species-mediated mPTP opening. While MMP inhibition was associated with increased Akt and ERK phosphorylation, neither Wortmannin nor PD98059 abrogated ilomastat-mediated protection. We demonstrate that MMP inhibition is cardioprotective, independent of Akt/ERK/CyPD/mPTP activity and is additive to the protection observed following inhibition of mPTP opening, indicative of a parallel pathway to protection in ischaemic/reperfused heart that may have clinical applicability in attenuating injury in acute coronary syndromes and deserve further investigation.

Tocilizumab, a monoclonal antibody against interleukin-6, has been used to treat cytokine release syndrome (CRS) in a subset of patients with severe COVID-19 disease. Acute ulcerative bowel disease has been only rarely documented in patients treated for rheumatological conditions. The gastrointestinal side effects seen when used in the context of COVID-19 are unknown. We present a case of COVID-19 CRS in which acute terminal ileum and perforated caecal ulceration evolved after tocilizumab exposure. We raise awareness of a possible causal relationship between even a single dose of tocilizumab and gut ulceration in patients with COVID-19. Any such drug enteropathy relationship requires watchful monitoring during upcoming trials of tocilizumab in patients with COVID-19.

was used to identify factors that increased length of stay beyond the median for the overall population. Results We identified 719 exacerbations between 1/4/2013-31/ 3/2014. The number of exacerbations ranged from 157-228/ quarter with the winter quarters (Q3/4) being associated with the highest exacerbation frequency. Exacerbators had a median (IQR) age of 46 (31-64) years, length of stay of 2 (1-5) days, Charlson score 4 . The majority of patients were female (72%). The percentage of repeat attender was 12% of the total population with the highest percentage in the winter quarters. Logistic regression models identified that ethnicity (non-white/ Caucasian), baseline admission CRP, neutrophil count, age, coding of status asthmaticus and Charlson co morbidity index significantly increased length of stay beyond the median of 2 days. In contrast neither admission or highest ever blood eosinophil count influenced the median length of stay.Conclusions We have identified a number of factors associated with an increased length of stay in asthma hospital exacerbations in Leicester. Our observations support the notion that age, comorbidity and biochemical features of infection rather than eosinophilic inflammation increase length of stay. Further research is required to examine the mechanisms that underpin asthma admissions in this population and to reduce length of stay. -2014-206260.199 Introduction Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder affecting about 1 in 3000 people in the UK commonly associated with early-onset emphysema. There are two common deficiency alleles -PiS and PiZ. PiZZ patients have severe AATD, with levels of 10-15% normal. PiSZ patients have less severe deficiency (≈ 40% normal) and are generally thought to have a minimal risk. We hypothesised that if PiSZ patients were at lower risk of COPD than PiZZ, and their lung disease would be more characteristic of usual COPD than that of PiZZ patients. Method 104 PiSZ patients and 638 PiZZ patients from the UK AATD registry (ADAPT) were compared for their demographics, lung function, risk factors for COPD (e.g. smoking, occupation), co-morbidities associated with COPD, index status (i.e. if diagnosed due to lung disease or family screening) and CT densitometry (where available). Outcome in terms of lung function decline and mortality was also assessed. Univariate statistics were used to guide subsequent regression analyses. Results Emphysema was more likely in PiZZ than PiSZ patients (OR 11.0 (5.7-21.3); p < 0.001) in the regression analysis after accounting for age, pack years and lung index status. PiZZ patients also had significantly worse FEV1 and DLCO than PiSZ patients in similar regression models (both p < 0.01). Emphysema was more severe in both upper and lower zone (both p < 0.01), and proportionately greater in the lower zone (UZ/LZ VI = 1.5 v 1.2) in PiZZ patients. Mortality and DLCO decline were also greater in PiZZ patients. Conclusion PiSZ patients have a milder form of AATD associated with better lung function. The ...

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