AimsAfrican trypanosomiasis, caused by Trypanosoma brucei species, leads to both neurological and cardiac dysfunction and can be fatal if untreated. While the neurological-related pathogenesis is well studied, the cardiac pathogenesis remains unknown. The current study exposed isolated ventricular cardiomyocytes and adult rat hearts to T. brucei to test whether trypanosomes can alter cardiac function independent of a systemic inflammatory/immune response.Methods and resultsUsing confocal imaging, T. brucei and T. brucei culture media (supernatant) caused an increased frequency of arrhythmogenic spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca2+ release (Ca2+ waves) in isolated adult rat ventricular cardiomyocytes. Studies utilising inhibitors, recombinant protein and RNAi all demonstrated that this altered SR function was due to T. brucei cathepsin-L (TbCatL). Separate experiments revealed that TbCatL induced a 10–15% increase of SERCA activity but reduced SR Ca2+ content, suggesting a concomitant increased SR-mediated Ca2+ leak. This conclusion was supported by data demonstrating that TbCatL increased Ca2+ wave frequency. These effects were abolished by autocamtide-2-related inhibitory peptide, highlighting a role for CaMKII in the TbCatL action on SR function. Isolated Langendorff perfused whole heart experiments confirmed that supernatant caused an increased number of arrhythmic events.ConclusionThese data demonstrate for the first time that African trypanosomes alter cardiac function independent of a systemic immune response, via a mechanism involving extracellular cathepsin-L-mediated changes in SR function.

The objective of this study was to assess whether the frontal sinuses in dogs with aspergillosis and of breeds typically affected by this condition were deeper at a more caudal location. CT scans of the head performed at the Small Animal Teaching Hospital, University of Liverpool, between April 2007 and March 2009 for dogs diagnosed with aspergillosis (group 1) and unaffected dogs of similar breeds (group 2) were selected for study. Sinus depth was measured at four standardised locations from reconstructed images of these CT scans. Data were compared for differences in sinus depth between groups and between landmarks. No significant difference was found between measurements within individual dogs or for each of the various landmarks between groups. Difference in depth of the sinuses between landmarks was significant (P<0.001). Sinus depth was significantly greater at the more caudal landmarks and was shallowest at the previously recommended landmark for sinus entry. In 54 per cent of dogs, the frontal sinus depth measured less than or equal to 2 cm at one or more of the landmarks. Sinus entry at the deepest point will reduce the risk of accidentally damaging underlying structures. This may be approximately 1 cm caudal, in breeds of dog that typically develop aspergillosis, to a previously suggested landmark.

following ischemia-reperfusion, indicating mg53-/mice are more susceptible to CS injury. rhMG53 protein (6 mg/kg) applied intravenously to the wild type mice prior to the onset of CS could protect skeletal muscle injury, as demonstrated by the reduction of CK in serum and Evans Blue positive (injured) muscle fibers. Histochemical studies revealed that rhMG53 treatment could ameliorate pathological changes in mouse skeletal muscle associated with CS. When rhMG53 was examined in a rat model of CS-induced muscle injury, we saw a lesser degree of muscle injury and minimum effect for the exogenous rhMG53 in protection against the development of CS. The lack of effect of rhMG53 in the rat model was likely due to the fact that serum level of endogenous MG53 protein in the rat is more than 20-fold higher than that in the mouse and other animal models. Taken together, our data suggest that rhMG53 can protect ischemia-reperfusion induced muscle injury as a potential therapy for protection against compartment syndrome.3688-Pos Board B416 . Cathepsins are lysosomal cysteine proteases involved in molecular signaling and protein degradation. Importantly, these proteases can also be secreted into the extracellular space. Cathepsin-L is elevated in the serum of patients with ischaemic heart disease and correlates with disease severity. Our data demonstrate that cathepsin-L levels are increased in the coronary effluent of ex vivo rat hearts after a period of 30 min ischaemia, however the contribution of cathepsin-L to cardiac contractile function remains unknown. Using a cathepsin-L inhibitor (CAA0225), we investigated the hypothesis that cathepsin-L contributes to contractile dysfunction post ischaemia. Langendorff perfused ex vivo adult rat hearts under went 30 min whole heart ischaemia followed by 90 min reperfusion. Left ventricular (LV) function was assessed using a solid-state pressure catheter within a balloon in the LV cavity. In separate cohorts of hearts, CAA0225 or DMSO (control) was applied for 25 min prior to ischaemia. CAA0225 had no effect on LV developed pressure prior to ischaemia. However, during reperfusion post-ischaemia CAA0225 led to a sustained increase of LV developed pressure to 177% of control levels at 90 min reperfusion (25.1 vs. 44.5 % developed LV pressure of pre-ischaemia level; DSMO [n=15] vs. CAA0225 [n=6]; P<0.05). The maximum rate of rise and fall in developed LV pressure were also elevated by CAA0225 by 169% and 151% respectively. Whilst there was no significant difference in the minimum LV pressure during the ischaemic period, this parameter was reduced during reperfusion which after 90 min was 68% of control levels (78.0 vs. 53.0 mmHg; DSMO [n=15] vs. CAA0225 [n=6]; P<0.05). These data demonstrate for the first time that the cathepsin-L inhibitor CAA0225 improves both systolic and diastolic cardiac functional parameters during ischaemia-reperfusion in ex vivo adult rat hearts. Chronic hypertension can cause atrial fibrillation. The cellular mechanisms responsible for hypertension-induced atri...

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