Background: The widely adopted Jablonski scoring system for reporting histological damage in kidney ischaemia reperfusion injury (IRI) provides a limited score documenting the degree of necrosis within tubular

Background—: Inflammatory bowel disease (IBD) is associated with increased cardiovascular risk. We examined the effect of active IBD on major adverse cardiovascular outcomes after myocardial infarction (MI). Methods and Results—: In nationwide registries, we identified 86 790 patients with first-time MI from the period 2002 to 2011. A total of 1030 patients had IBD, and we categorized their disease activity stages into either flare (120 days), persistent (>120 days) activity, or remission. Short-term mortality was estimated in a logistic regression-model, whereas risk of recurrent MI, all-cause mortality, and a composite of recurrent MI, cardiovascular death, and stroke were estimated by Cox regression-models. Odds ratio of death during hospitalization or within 30 days of discharge (n=13 339) corresponded to 3.29 (95% confidence interval [CI], 1.98–5.45) for patients in IBD flares, 1.62 (95% CI, 0.95–2.77) for persistent activity, and 0.97 (95% CI, 0.78–1.19) for remission when compared with the non-IBD group. Among 73 451 patients, including 863 with IBD, alive 30 days after discharge, IBD was associated with hazard ratios of 1.21 (95% CI, 0.99–1.49) for recurrent MI, 1.14 (95% CI, 1.01–1.28) for all-cause mortality, and 1.17 (95% CI, 1.03–1.34) for the composite end point. When compared with the non-IBD group, IBD flares, in particular, were associated with increased risks of recurrent MI (hazard ratio, 3.09; 95% CI, 1.79–5.32), all-cause mortality (hazard ratio, 2.25; 95% CI, 1.61–3.15), and the composite end point (hazard ratio, 2.04; 95% CI, 1.35–3.06), whereas no increased risk was identified in remission. Conclusions—: Active inflammatory bowel disease worsens prognosis after MI, in particular, in relation with flares.

Objective— Abdominal aortic aneurysm (AAA) is a complex multifactorial disease associated with a high morbidity and mortality. Increased inflammation including T-helper 17 cell–mediated effects has been implicated in AAA pathogenesis. Psoriasis is considered to be a T-helper 17-driven chronic inflammatory disease and in view of potentially overlapping inflammatory mechanisms, we investigated the risk of AAA in patients with psoriasis in a nationwide cohort. Approach and Results— The study comprised all Danish residents aged ≥18 years followed up from January 1, 1997, until diagnosis of AAA, December 31, 2011, migration or death. Information on comorbidity, concomitant medication, and socioeconomic status was identified by individual-level linkage of administrative registers. Incidence rates for AAA were calculated and incidence rate ratios adjusted for age, sex, comorbidity, medications, socioeconomic status, and smoking were estimated in Poisson regression models. A total of 5 495 203 subjects were eligible for analysis. During the study period, we identified 59 423 patients with mild psoriasis and 11 566 patients with severe psoriasis. The overall incidence rates of AAA were 3.72, 7.30, and 9.87 per 10 000 person-years for the reference population (23 696 cases), mild psoriasis (240 cases), and severe psoriasis (50 cases), respectively. The corresponding adjusted incidence rate ratios for AAA were increased in patients with psoriasis with incidence rate ratios of 1.20 (95% confidence interval, 1.03–1.39) and 1.67 (confidence interval, 1.21–2.32) for subjects with mild and severe disease, respectively. Conclusions— In a nationwide cohort, psoriasis was associated with a disease severity-dependent increased risk of AAA. The mechanisms and consequences of this novel finding require further investigation.

Hyaluronidase (HYAL)-2 is a weak, acid-active, hyaluronan-degrading enzyme broadly expressed in somatic tissues. Aberrant HYAL2 expression is implicated in diverse pathology. However, a significant proportion of HYAL2 is enzymatically inactive; thus the mechanisms through which HYAL2 dysregulation influences pathobiology are unclear. Recently, nonenzymatic HYAL2 functions have been described, and nuclear HYAL2 has been shown to influence mRNA splicing to prevent myofibroblast differentiation. Myofibroblasts drive fibrosis, thereby promoting progressive tissue damage and leading to multimorbidity. This study identifies a novel HYAL2 cytoplasmic function in myofibroblasts that is unrelated to its enzymatic activity. In fibroblasts and myofibroblasts, HYAL2 interacts with the GTPase-signaling small molecule ras homolog family member A (RhoA). Transforming growth factor beta 1-driven fibroblast-to-myofibroblast differentiation promotes HYAL2 cytoplasmic relocalization to bind to the actin cytoskeleton. Cytoskeletal-bound HYAL2 functions as a key regulator of downstream RhoA signaling and influences profibrotic myofibroblast functions, including myosin light-chain kinase-mediated myofibroblast contractility, myofibroblast migration, myofibroblast collagen/fibronectin deposition, as well as connective tissue growth factor and matrix metalloproteinase-2 expression. These data demonstrate that, in certain biological contexts, the nonenzymatic effects of HYAL2 are crucial in orchestrating RhoA signaling and downstream pathways that are important for full profibrotic myofibroblast functionality. In conjunction with previous data demonstrating the influence of HYAL2 on RNA splicing, these findings begin to explain the broad biological effects of HYAL2.

Background/Aim: Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC). Materials and Methods: We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury. Results: Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model. Conclusion: These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators.