Deficiency of Factor VII activating protease alters the outcome of ischemic stroke in mice.

Factor VII activating protease (FSAP) is a circulating protease with a putative role in hemostasis, remodeling and inflammation. A polymorphism giving rise to low proteolytic activity has been associated with an increased risk of stroke and carotid stenosis. To date, no in vivo studies or mechanistic information is available to explain these results. Based on the polymorphism data we hypothesize that a lack of endogenous FSAP will increase the severity of stroke. Stroke was induced by applying thrombin in the middle cerebral artery in wild-type (WT) and FSAP(-/-) mice. Increased stroke volume and worsened neurological deficit were observed in FSAP(-/-) mice. Raised levels of FSAP protein were detected in the infarcted area of WT mice together with enhanced leukocyte infiltration and apoptosis in FSAP(-/-) mice. There was a concomitant increase in the activation of the NFκB pathway and decrease in expression of the PI3K/AKT pathway proteins. At a cellular level, FSAP increased cell survival and decreased apoptosis in primary cortical neurons and astrocytes exposed to tPA/NMDA excitotoxicity or oxygen glucose deprivation (OGD)/reoxygenation, respectively. This was mediated via the PI3K/AKT pathway with involvement of the protease activated receptor-1. To corroborate the human epidemiological data, which link FSAP with stroke, we now show that the lack of FSAP in mice worsens the outcome of stroke. In the absence of FSAP there was a stronger inflammatory response and lower cell survival due to insufficient activation of the PI3K/AKT pathway.

Complementary regulation of heme oxygenase-1 and peroxiredoxin I gene expression by oxidative stress in the liver.

Heme oxygenase (HO)-1, the inducible isoform of the rate-limiting enzyme of heme degradation, and peroxiredoxin (Prx) I, a thioredoxin-dependent peroxidase, are multifunctional antioxidant stress proteins which are coordinately up-regulated by oxidative stress in cell cultures. HO-1 and Prx I exhibit a different hepatic cellular and subcellular localization. Here, a distinct expression pattern of the two genes was confirmed by in situ hybridization of normal rat liver. Moreover, expression of the HO-1 and Prx I genes was determined in a model of acutely damaged rat liver which was elicited by application of a single dose of carbon tetrachloride (CCl4). The mRNA levels of the HO-1 and Prx I genes were induced in whole livers of CCl4-treated rats with differential kinetics as determined by Northern blot analysis. While HO-1 mRNA was induced up to 48 hr, Prx I exhibited a maximum level of mRNA after 12 hr of treatment with CCl4. CCl4-dependent oxidative stress led to a focal increase of perivenous HO-1 positive liver cells with simultaneous loss of Prx I immunoreactivity. Taken together, the complementary hepatic gene expression pattern of HO-1 and Prx I in response to oxidative stress may suggest a functional interplay of these antioxidant genes.

Surgical Approach for Repair of Rectovaginal Fistula by Modified Martius Flap.

Rectovaginal fistulas (RVF) are rare but represent a challenge for both patients and surgeons. The most common cause of RVF is obstetric trauma, and treatment is based on fistula classification and localization of the fistula in relation to the vagina and rectum. Conventional therapy frequently fails, making surgery the most viable approach for fistula repair. One surgical procedure which offers adequate repair of lower and middle rectovaginal fistulas consists of interposition of a bulbocavernosus fat flap also called modified Martius flap. First described by Heinrich Martius in 1928, this approach has been continuously modified and adjusted over time and is used in the repair of various pelvic floor disorders. Overall success rates reported in the literature of the interposition of a Martius flap as an adjunct procedure in the surgical management of RVF are 65-100 %. We present a detailed description of the operation technique together with a discussion of the use of a dorsal-flapped modified Martius flap in the treatment of RVF.

RNase1 prevents the damaging interplay between extracellular RNA and tumour necrosis factor-α in cardiac ischaemia/reperfusion injury.

Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant, and the initial mechanistic trigger of myocardial "ischaemia/reperfusion (I/R) injury" remains greatly unexplained. Here we show that factors released from the damaged cardiac tissue itself, in particular extracellular RNA (eRNA) and tumour-necrosis-factor α (TNF-α), may dictate I/R injury. In an experimental in vivo mouse model of myocardial I/R as well as in the isolated I/R Langendorff-perfused rat heart, cardiomyocyte death was induced by eRNA and TNF-α. Moreover, TNF-α promoted further eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R with the massive production of oxygen radicals, mitochondrial obstruction, decrease in antioxidant enzymes and decline of cardiomyocyte functions. The administration of RNase1 significantly decreased myocardial infarction in both experimental models. This regimen allowed the reduction in cytokine release, normalisation of antioxidant enzymes as well as preservation of cardiac tissue. Thus, RNase1 administration provides a novel therapeutic regimen to interfere with the adverse eRNA-TNF-α interplay and significantly reduces or prevents the pathological outcome of ischaemic heart disease.