BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation

Adult renal progenitor cells (ARPCs) isolated from the human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling, and regeneration processes in several tissues. The aim of this study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidneys, and it was upregulated in vivo after delayed graft function (DGF) of renal transplantation, a condition of AKI. ARPCs expressed BMP receptors, suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced reactive oxygen species (ROS) production, NADPH oxidase activity, and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2-expressing CD133+ cells at the tubular level after DGF. BMP-2 incubation induced α-smooth muscle actin (SMA), collagen I, and fibronectin protein expression in ARPCs. Moreover, α-SMA colocalized with CD133 in vivo after DGF. The oxidative stimulus (H(2)O(2)) induced α-SMA expression in ARPCs, while the antioxidant N-acetyl-cysteine inhibited BMP-2-induced α-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that 1) ARPCs express BMP-2, 2) this expression is increased in a model of AKI; 3) BMP-2 may induce the commitment of ARPCs toward a myofibroblastic phenotype in vitro and in vivo; and 4) this profibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage.     

Possible prognostic significance of p53 and Ki 67 in inverted sinonasal papilloma

The aim of this study is to test the possible prognostic significance of p53 and Ki67 expression in inverted papilloma of the lateral nasal wall and adjacent sinuses regarding their malignant potential and recurrence. 49 biopsies of the lateral nasal wall and adjacent sinuses obtained from 41 patients from three hospitals were investigated. Immunohistochemically demonstrated p53 and Ki67 expression was measured and statistically evaluated. p53 immunoreactivity was demonstrated in most of papillomas with carcinomas but only in two benign papillomas, while Ki67 demonstrated stronger immunoreactivity in carcinomas and surrounding epithelium. Immunohistochemical staining of inverted sinonasal papillomas for p53 and Ki67 can give useful information concerning the existence of synchronous carcinoma and, in case of high Ki67, a hint toward possible recurrence.     

Hepatitis C Virus Infection Epidemiology among People Who Inject Drugs in Europe: A Systematic Review of Data for Scaling Up Treatment and Prevention

Background

People who inject drugs (PWID) are a key population affected by hepatitis C virus (HCV). Treatment options are improving and may enhance prevention; however access for PWID may be poor. The availability in the literature of information on seven main topic areas (incidence, chronicity, genotypes, HIV co-infection, diagnosis and treatment uptake, and burden of disease) to guide HCV treatment and prevention scale-up for PWID in the 27 countries of the European Union is systematically reviewed.

Methods and Findings

We searched MEDLINE, EMBASE and Cochrane Library for publications between 1 January 2000 and 31 December 2012, with a search strategy of general keywords regarding viral hepatitis, substance abuse and geographic scope, as well as topic-specific keywords. Additional articles were found through structured email consultations with a large European expert network. Data availability was highly variable and important limitations existed in comparability and representativeness. Nine of 27 countries had data on HCV incidence among PWID, which was often high (2.7-66/100 person-years, median 13, Interquartile range (IQR) 8.7–28). Most common HCV genotypes were G1 and G3; however, G4 may be increasing, while the proportion of traditionally ‘difficult to treat’ genotypes (G1+G4) showed large variation (median 53, IQR 43–62). Twelve countries reported on HCV chronicity (median 72, IQR 64–81) and 22 on HIV prevalence in HCV-infected PWID (median 3.9%, IQR 0.2–28). Undiagnosed infection, assessed in five countries, was high (median 49%, IQR 38–64), while of those diagnosed, the proportion entering treatment was low (median 9.5%, IQR 3.5–15). Burden of disease, where assessed, was high and will rise in the next decade.

Conclusion

Key data on HCV epidemiology, care and disease burden among PWID in Europe are sparse but suggest many undiagnosed infections and poor treatment uptake. Stronger efforts are needed to improve data availability to guide an increase in HCV treatment among PWID.     

Improving heat stability of haemagglutinating antigens for avian influenza

The increasing demand for avian influenza diagnostic reagents worldwide, has included requests for significant supplies of product to developing countries. Difficulties in dispatching to remote areas and tropical countries are a major concern to suppliers, international organisations and donors as delays in forwarding parcels often result in storage at non-optimal or inadequate temperatures results in loss in titre and thus wastage of resources.In this study we demonstrate that the heat stability of avian influenza haemagglutination inhibition antigens of the H5, H7 and H9 subtype following 14 days of exposure to 37 °C and 45 °C is significantly increased by adding D-(+)-Trehalose to the freshly prepared antigen. Increased stability was detected both for freeze-dried antigens over an extended period of 6 months and also in heat exposed antigens that were then stored at +4 C for up to 35 days post reconstitution.     

Profiling histidine dipeptides in plasma and urine after ingesting beef, chicken or chicken broth in humans

The in vitro metabolic stability of histidine-dipeptides (HD), carnosine (CAR) and anserine (ANS), in human serum, and their absorption kinetics after ingesting pure carnosine or HD rich foods in humans have been investigated. Healthy women (n = 4) went through four phases of taking one dose of either 450 mg of pure carnosine, 150 g beef (B), 150 g chicken (C), or chicken broth (CB) from 150 g chicken with a >2-week washout period between each phase. Blood samples were collected at 0, 30, 60, 100, 180, 240, and 300 min, and urine samples before and after (up to 7 h) ingesting pure carnosine or food. Both plasma and urine samples were analyzed for HD concentrations using a sensitive and selective LC–ESI-MS/MS method. CAR was undetectable in plasma after ingesting pure carnosine, B, C or CB. By contrast, plasma ANS concentration was significantly increased (P < 0.05) after ingesting C or CB, respectively. Urinary concentrations of both CAR and ANS were 13- to 14-fold increased after ingesting B, and 14.8- and 243-fold after CB ingestion, respectively. Thus, dietary HD, which are rapidly hydrolyzed by carnosinase in plasma, and excreted in urine, may act as reactive carbonyl species sequestering agents.     

Metabolic and molecular aspects of ethanolamine phospholipid biosynthesis: the role of CTP:phosphoethanolamine cytidylyltransferase (Pcyt2).

The CDP-ethanolamine branch of the Kennedy pathway is the major route for the formation of ethanolamine-derived phospholipids, including diacyl phosphatidylethanolamine and alkenylacyl phosphatidylethanolamine derivatives, known as plasmalogens. Ethanolamine phospholipids are essential structural components of the cell membranes and play regulatory roles in cell division, cell signaling, activation, autophagy, and phagocytosis. The physiological importance of plasmalogens has not been not fully elucidated, although they are known for their antioxidant properties and deficiencies in a number of inherited peroxisomal disorders. This review highlights important aspects of ethanolamine phospholipid metabolism and reports current molecular information on 1 of the regulatory enzymes in their synthesis, CTP:phosphoethanolamine cytidylyltransferase (Pcyt2). Pcyt2 is encoded by a single, nonredundant gene in animal species that could be alternatively spliced into 2 potential protein products. We describe properties of the mouse and human Pcyt2 genes and their regulatory promoters and provide molecular evidence for the existence of 2 distinct Pcyt2 proteins. The goal is to obtain more insight into Pcyt2 catalytic function and regulation to facilitate a better understanding of the production of ethanolamine phospholipids via the CDP-ethanolamine branch of the Kennedy pathway.     

Catch‐up and targeted growth following variable duration protein restriction: Effects on bone and body mass

Protein malnutrition leads to growth retardation that can be reversed through catch‐up growth, once normative nutrition is restored. Because growth is a dynamic process, catch‐up capacity is likely influenced by the maturity of the animal and/or the duration of the insult, in addition to the type of insult experienced. We compared length of malnutrition, sexual dimorphism, body mass, and skeletal growth. Eighty Rattus norvegicus were divided into 10 treatment groups (five diets; male and female) and followed for more than 1 year. At weaning, animals were placed on either a control or low‐protein isocaloric diet. Three experimental groups were switched to the control diet at 40, 60, or 90 days. Beginning with 21 days of age, animals were weighed daily and radiographed throughout the study. To determine the presence of catch‐up growth, growth rates (GRs) were calculated (linear regression) for 20‐day time spans before and after diet changes and compared among treatment groups. Targeted growth was measured as final size or as the coefficient of variation with age. These results show that 1) protein‐restricted animals experience catch‐up growth with dietary rehabilitation; 2) for females, catch‐up GRs are proportional to GRs in control animals at the same age as the timing of dietary rehabilitation but not for males; and 3) targeted growth was observed in some, but not all, aspects of anatomy. The length of the tibia and humerus was indistinguishable from controls, regardless of length of malnutrition or gender, whereas the ulna and male body mass exceeded control sizes. Although most measures decreased in variation with ontogeny, the tibia failed to do so. These results support a complex biological regulation of catch‐up and targeted growth. The implications for selection are that flexible and responsive developmental trajectories may have an advantage over those programed into a single size. J. Morphol., 2011. © 2011 Wiley‐Liss, Inc.