An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis.

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.

Targeting a cell-specific microRNA repressor of CXCR4 ameliorates atherosclerosis in mice.

The CXC chemokine receptor 4 (CXCR4) in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) is crucial for vascular integrity. The atheroprotective functions of CXCR4 in vascular cells may be counteracted by atherogenic functions in other nonvascular cell types. Thus, strategies for cell-specifically augmenting CXCR4 function in vascular cells are crucial if this receptor is to be useful as a therapeutic target in treating atherosclerosis and other vascular disorders. Here, we identified miR-206-3p as a vascular-specific CXCR4 repressor and exploited a target-site blocker (CXCR4-TSB) that disrupted the interaction of miR-206-3p with CXCR4 in vitro and in vivo. In vitro, CXCR4-TSB enhanced CXCR4 expression in human and murine ECs and VSMCs to modulate cell viability, proliferation, and migration. Systemic administration of CXCR4-TSB in Apoe-deficient mice enhanced Cxcr4 expression in ECs and VSMCs in the walls of blood vessels, reduced vascular permeability and monocyte adhesion to endothelium, and attenuated the development of diet-induced atherosclerosis. CXCR4-TSB also increased CXCR4 expression in B cells, corroborating its atheroprotective role in this cell type. Analyses of human atherosclerotic plaque specimens revealed a decrease in CXCR4 and an increase in miR-206-3p expression in advanced compared with early lesions, supporting a role for the miR-206-3p-CXCR4 interaction in human disease. Disrupting the miR-206-3p-CXCR4 interaction in a cell-specific manner with target-site blockers is a potential therapeutic approach that could be used to treat atherosclerosis and other vascular diseases.

Beyond Self-Recycling: Cell-Specific Role of Autophagy in Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall and underlies the development of cardiovascular diseases, such as myocardial infarction and ischemic stroke. As such, atherosclerosis stands as the leading cause of death and disability worldwide and intensive scientific efforts are made to investigate its complex pathophysiology, which involves the deregulation of crucial intracellular pathways and intricate interactions between diverse cell types. A growing body of evidence, including in vitro and in vivo studies involving cell-specific deletion of autophagy-related genes (ATGs), has unveiled the mechanistic relevance of cell-specific (endothelial, smooth-muscle, and myeloid cells) defective autophagy in the processes of atherogenesis. In this review, we underscore the recent insights on autophagy's cell-type-dependent role in atherosclerosis development and progression, featuring the relevance of canonical catabolic functions and emerging noncanonical mechanisms, and highlighting the potential therapeutic implications for prevention and treatment of atherosclerosis and its complications.

Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma.

The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms that are believed to include NLRP1 activation. This study investigated the expression and activity of the DPP4 family during the development of HCC and evaluated the efficacy of ARI-4175 in the treatment of early HCC in mice. This first report on this enzyme family in HCC-bearing mice showed DPP9 upregulation in HCC, whereas intrahepatic DPP8/9 and DPP4 enzyme activity levels decreased with age. We demonstrated that ARI-4175 significantly lowered the total number of macroscopic liver nodules in these mice. In addition, ARI-4175 increased intrahepatic inflammatory cell infiltration, including CD8+ T cell numbers, into the HCC-bearing livers. Furthermore, ARI-4175 activated a critical component of the inflammasome pathway, caspase-1, in these HCC-bearing livers. This is the first evidence of caspase-1 activation by a pan-DPP inhibitor in the liver. Our data suggest that targeting the DPP4 enzyme family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation.

Animal models for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents ~90% of all cases of primary liver cancer and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Establishing appropriate animal models for HCC is required for basic and translational studies, especially the models that can recapitulate one of the human disease settings. Current animal models can be categorized as chemically-induced, genetically-engineered, xenograft, or a combination of these with each other or with a metabolic insult. A single approach to resemble human HCC in animals is not sufficient. Combining pathogenic insults in animal models may more realistically recapitulate the multiple etiologic agents occurring in humans. Combining chemical injury with metabolic disorder or alcohol consumption in mice reduces the time taken to hepatocarcinogenesis. Genetically-engineering weak activation of HCC-promoting pathways combined with disease-specific injury models will possibly mimic the pathophysiology of human HCC in distinct clinical settings.

Multiple liver insults synergize to accelerate experimental hepatocellular carcinoma.

The urgent unmet need for hepatocellular carcinoma (HCC) therapies is addressed here by characterising a novel mouse model of HCC in the context of ongoing liver damage and overnutrition. Male C57Bl/6J mice were treated with diethylnitrosamine (DEN) and thioacetamide (TAA), and some were provided with an atherogenic high fat diet (HFD). Inflammation, steatosis, fibrosis, 87 genes, liver lesions and intratumoural leukocyte subsets were quantified up to 24 weeks of age. Adding HFD to DEN/TAA increased fibrosis, steatosis and inflammation, and the incidence of both HCC and non-HCC dysplastic lesions. All lesions contained α-SMA positive fibroblasts. Macrophage marker F4/80 was not significantly different between treatment groups, but the macrophage-associated genes Arg-1 and Cd47 were differentially expressed. Fibrosis, cancer and cell death associated genes were upregulated in DEN/TAA/HFD livers. Fewer Kupffer cells and plasmacytoid dendritic cells were in tumours compared to control liver. In conclusion, combining a hepatotoxin with an atherogenic diet produced more intrahepatic tumours, dysplastic lesions and fibrosis compared to hepatotoxin alone. This new HCC model provides a relatively rapid means of examining primary HCC and potential therapies in the context of multiple hepatotoxins including those derived from overnutrition.

Hepatocellular carcinoma: Mouse models and the potential roles of proteases.

Primary liver cancer is the second most common cause of mortality from cancer. The most common models of hepatocellular carcinoma, which use a chemical and/or metabolic insult, xenograft, or genetic manipulation, are discussed in this review. In the tumour microenvironment lymphocytes, fibroblasts, endothelial cells and antigen presenting cells are important determinants of cell fate. These cells make a range of proteases that modify the biological activity of other proteins, particularly extracellular matrix proteins that alter cell migration of tumour cells, fibroblasts and leucocytes, and chemokines that alter leucocyte migration. The DPP4 family of post-proline peptidase enzymes modifies cell movement and the activities of many bioactive molecules including growth factors and chemokines.

Secondary procedures in maxillofacial dermatology.

Dermatologic secondary procedures involve careful preoperative planning and patient preparation, skillful execution of the appropriate procedure, and thorough postoperative wound care. Many modalities of treatment are used, including skin preparation through elimination of inflammatory conditions, resurfacing of skin, and improvement of patient health. Proper selection of incisional design, local or regional flaps, and grafting techniques is key to successful revisional surgery. Care of the revised lesion or wound through medications, dressings and resurfacing techniques will optimize the end result.

Time to disease-modifying antirheumatic drug treatment in rheumatoid arthritis and its predictors: a national, multicenter, retrospective cohort.

OBJECTIVE: To determine the proportion of patients with rheumatoid arthritis (RA) under rheumatologic care treated with disease-modifying antirheumatic drugs (DMARD) within 6 months from symptom onset and the components of time to treatment and its predictors. METHODS: A historical inception cohort of 339 patients with RA randomly selected from 18 rheumatology practices was audited. The proportion that initiated DMARD treatment within 6 months from symptom onset was estimated using Kaplan-Meier analysis. Time to each component of the care pathway was estimated. Multivariable modeling was used to determine predictors of early treatment using 12 preselected variables available in the clinical charts. Bootstrapping was used to validate the model. RESULTS: Within 6 months from symptom onset, 41% (95% CI 36%-46%) of patients were treated with DMARD. The median time to treatment was 8.4 (interquartile range 3.8-24) months. Events preceding rheumatology referral accounted for 78.1% of the time to treatment. The most prominent predictor of increased time to treatment was a concomitant musculoskeletal condition, such as osteoarthritis or fibromyalgia. The significance of other variables was less consistent across the models investigated. Included variables accounted for 0.69 ± 0.03 of the variability in the model. CONCLUSION: Fewer than 50% of patients with RA are treated with DMARD within 6 months from symptom onset. Time to referral to rheumatology represents the greatest component delay to treatment. Concomitant musculoskeletal condition was the most prominent predictor of delayed initiation of DMARD. Implications of these and other findings warrant further investigation.

Early management of newly diagnosed rheumatoid arthritis by Canadian rheumatologists: a national, multicenter, retrospective cohort.

OBJECTIVE: To describe early rheumatologic management for newly diagnosed rheumatoid arthritis (RA) in Canada. METHODS: A retrospective cohort of 339 randomly selected patients with RA diagnosed from 2001-2003 from 18 rheumatology practices was audited between 2005-2007. RESULTS: The most frequent initial disease-modifying antirheumatic drugs (DMARD) included hydroxychloroquine (55.5%) and methotrexate (40.1%). Initial therapy with multiple DMARD (15.6%) or single DMARD and corticosteroid combinations (30.7%) was infrequent. Formal assessment measures were noted infrequently, including the Health Assessment Questionnaire (34.6%) and Disease Activity Score for 28 joints (8.9%). CONCLUSION: Initial pharmacotherapy is consistent with guidelines from the period. The infrequent reporting of multiple DMARD combinations and formal assessment measures has implications for current clinical management and warrants contemporary reassessment.

All-terrain vehicle-related maxillofacial trauma in the pediatric population.

PURPOSE: Nearly 40% of all-terrain vehicle (ATV) crash-related fatalities involve pediatric patients, with many of these patients dying from head and neck injuries. West Virginia is in a unique position to examine these injuries because of its high rate of ATV use. This study examines craniofacial ATV-related trauma in children. PATIENTS AND METHODS: We conducted a single-center, retrospective, descriptive study of 26 children presenting with a craniofacial injury(ies) resulting from an ATV crash from January 2001 to December 2004. RESULTS: Twenty-six children (65% boys) with a mean age of 13.1 years presented with craniofacial injuries during the study period. Two patients were helmeted. Mortality was 3.8% (n = 1, head injury related, postinjury day 3). Patients were most often drivers of the ATV (65%), although girls were more likely to be passengers (P = .03). Facial contusions, lacerations, and abrasions were highly prevalent (62%, 69%, 65%, respectively), as were fractures of the facial bones and skull (77%). Thirty-five percent sustained closed head injuries, which were significantly associated with mandible fractures (odds ratio 12.8%; 95% CI, 1.15-143). Mean length of hospital stay was 4.6 +/- 5 days, and 36% required an ICU stay (mean, 5.1 +/- 3 days). Twenty-four percent required ventilator support (mean, 107 +/- 43 hours; range, 48 to 168 hours). Operative intervention was required in 72% of patients (n = 18). CONCLUSION: Maxillofacial injury patterns from ATV-related crashes in children suggest a high percentage of significant facial injuries and closed head injuries. As new ATV legislation that addresses operator use is enacted, a decrease in the number and severity of craniofacial injuries may be seen.