Evolution of Exchangeable Copper and Relative Exchangeable Copper through the Course of Wilson's Disease in the Long Evans Cinnamon Rat

Background

Wilson''s disease (WD) is an inherited disorder of copper metabolism leading to liver failure and/or neurological impairment. Its diagnosis often remains difficult even with genetic testing. Relative exchangeable copper (REC) has recently been described as a reliable serum diagnostic marker for WD.

Methodology/Principal Findings

The aim of this study was to validate the use of REC in the Long Evans Cinnamon (LEC) rat, an animal model for WD, and to study its relevance under different conditions in comparison with conventional markers. Two groups of LEC rats and one group of Long-Evans (LE) rats were clinically and biologically monitored from 6 to 28 weeks of age. One group of LEC rats was given copper-free food. The other groups had normal food. Blood samples were collected each month and different serum markers for WD (namely ceruloplasmin oxidase activity, exchangeable copper (CuEXC), total serum copper and REC) and acute liver failure (serum transaminases and bilirubinemia) were tested. Every LEC rat under normal food developed acute liver failure (ALF), with 40% global mortality. Serum transaminases and bilirubinemia along with total serum copper and exchangeable copper levels increased with the onset of acute liver failure. A correlation was observed between CuEXC values and the severity of ALF. Cut-off values were different between young and adult rats and evolved because of age and/or liver failure. Only REC, with values >19%, was able to discriminate LEC groups from the LE control group at every time point in the study. REC sensitivity and specificity reached 100% in adults rats.

Conclusions/Significance

REC appears to be independent of demographic or clinical data in LEC rats. It is a very simple and reliable blood test for the diagnosis of copper toxicosis owing to a lack of ATP7B function. CuEXC can be used as an accurate biomarker of copper overload.     

Activation of Notch Signaling Is Required for Cholangiocarcinoma Progression and Is Enhanced by Inactivation of p53 In Vivo

Cholangiocacinoma (CC) is a cancer disease with rising incidence. Notch signaling has been shown to be deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of CC is still not fully explored. In this study, we investigated the effects of Notch inhibition by γ-secretase inhibitor IX (GSI IX) in cultured human CC cell lines and we established a transgenic mouse model with liver specific expression of the intracellular domain of Notch (Notch-ICD) and inactivation of tumor suppressor p53. GSI IX treatment effectively impaired cell proliferation, migration, invasion, epithelial to mesenchymal transition and growth of softagar colonies. In vivo overexpression of Notch-ICD together with an inactivation of p53 significantly increased tumor burden and showed CC characteristics. Conclusion: Our study highlights the importance of Notch signaling in the tumorigenesis of CC and demonstrates that additional inactivation of p53 in vivo.     

Non-contiguous finished genome sequence and description of Bartonella senegalensis sp. nov.

Bartonella senegalensis sp. nov. strain OS02^T is the type strain of B. senegalensis sp. nov., a new species within the genus Bartonella. This strain, whose genome is described here, was isolated in Senegal from the soft tick Ornithodoros sonrai, the vector of relapsing fever. B. senegalensis is an aerobic, rod-shaped, Gram-negative bacterium. Here we describe the features of this organism, together with the complete genome sequence and its annotation. The 1,966,996 bp-long genome contains 1,710 protein-coding and 46 RNA genes, including 6 rRNA genes.     

Consortium diversity of a sulfate‐reducing biofilm developed at acidic pH influent conditions in a down‐flow fluidized bed reactor

Sulfate reduction is an appropriate approach for the treatment of effluents with sulfate and dissolved metals. In sulfate‐reducing reactors, acetate may largely contribute to the residual organic matter, because not all sulfate reducers are able to couple the oxidation of acetate to the reduction of sulfate, limiting the treatment efficiency. In this study, we investigated the diversity of a bacterial community in the biofilm of a laboratory scale down‐flow fluidized bed reactor, which was developed under sulfidogenic conditions at an influent pH between 4 and 6. The sequence analysis of the microbial community showed that the 16S rRNA gene sequence of almost 50% of the clones had a high similarity with Anaerolineaceae. At second place, 33% of the 16S rRNA phylotypes were affiliated with the sulfate‐reducing bacteria Desulfobacca acetoxidans and Desulfatirhabdium butyrativorans, suggesting that acetotrophic sulfate reduction was occurring in the system. The remaining bacterial phylotypes were related to fermenting bacteria found at the advanced stage of reactor operation. The results indicate that the acetotrophic sulfate‐reducing bacteria were able to remain within the biofilm, which is a significant result because few natural consortia harbor complete oxidizing sulfate‐reducers, improving the acetate removal via sulfate reduction in the reactor.     

Selection of antimalarial drug resistance after intermittent preventive treatment of infants and children (IPTi/c) in Senegal

Senegal has since 2003 used sulphadoxine-pyrimethamine (SP) for Intermittent Preventive Treatment (IPT) of malaria in risk groups. However, the large-scale IPT strategy may result in increasing drug resistance. Our study investigated the possible impact of SP-IPT given to infants and children on the prevalence of SP-resistant haplotypes in the Plasmodium falciparum genes Pfdhfr and Pfdhps, comparing sites with and without IPTi/c. P. falciparum positives samples (n = 352) were collected from children under 5 years of age during two cross-sectional surveys in 2010 and 2011 in three health districts (two on IPTi/c and one without IPTi/c intervention) located in the southern part of Senegal. The prevalence of SP-resistance-related haplotypes in Pfdhfr and Pfdhps was determined by nested PCR followed by sequence-specific oligonucleotide probe (SSOP)–ELISA. The prevalence of the Pfdhfr double mutant haplotypes (CNRN and CICN) was stable between years at < 10% in the control group (P = 0.69), while it rose significantly in the IPTi/c group from 2% in 2010 to 20% in 2011 (P = 0.008). The prevalence of the Pfdhfr triple mutant haplotype (CIRN) increased in both groups, but only significantly in the IPTi/c group from 41% to 65% in 2011 (P = 0.005). Conversely, the Pfdhps 437G mutation decreased in both groups from 44.6% to 28.6% (P = 0.07) and from 66.7% to 47.5% (P = 0.02) between 2010 and 2011 in the control and the IPTi/c groups, respectively. Combined with Pfdhfr, there was a weak trend for decreasing prevalence of quadruple mutants (triple Pfdhfr + Pfdhps 437G) in both groups (P = 0.15 and P = 0.34). During the two cross-sectional surveys, some significant changes were observed in the SP-resistance-related genes. However, since these changes were observed in the two groups, the IPTi/c strategy does only seem to have limited impact on resistance development and other factors as well. However, continuous monitoring will be needed, due to the up-scaling of the IPTi/c strategy in Senegal according to WHO recommendations.     

Incidence of Spinal Perineurial (Tarlov) Cysts among East-European Patients

The spinal perineurial cyst (Tarlov) is a dilatation between the perineurium and endoneurium of spinal nerve roots, located at level of the spinal ganglion and filled with cerebrospinal fluid but without communication with the perineurial subarachnoid space. The aim of the study was to evaluate it incidence among East-European patients. The retrospective data collected during various magnetic resonance spinal examinations and stored on the picture archiving and communication system was analyzed for an incidence of perineurial cysts. From among 842 patients that underwent examination, 75 cases perineurial cysts were revealed. In 22 cases single anomalies were found. In remaining 53 cases, multiple uni- or less frequently bilateral changes were noted. The most common position was the sacral canal, particularly the level of S2 and S3. Occasionally, cysts were also visible on the cervical, thoracic and lumbar level. Incidence of sacral perineurial cysts was significantly higher in females than in males. Similar data was found for single and multiple changes despite of their localization. Insignificant changes were seen for patient age and cyst size. Perineurial spinal cysts were the most frequently observed on the sacral level and such changes were more common in females.     

Focus: Allergic Diseases and Type II Immunity: Mast Cells as Regulators of Adaptive Immune Responses in Food Allergy

Mast cells are a critical first line of defense against endogenous and environmental threats. Their participation in innate immunity is well characterized; activation of toll like receptors as well as receptors for complement, adenosine, and a host of other ligands leads to mast cell release of preformed mediators contained within granules along with newly synthesized arachidonic acid metabolites, cytokines, and chemokines. These confer protective effects including the induction of mucus secretion, smooth muscle contraction, and activation of common itch and pain sensations, all of which act to promote expulsion of noxious agents. While their innate immune role as sentinel cells is well established, recent research has brought into focus their separate but also critical function in adaptive immunity particularly in the setting of IgE mediated food allergies. Crosslinking of FcεR1, the high affinity receptor for IgE, when bound to IgE and antigen, triggers the release of the same factors and elicits the same physiologic responses that occur after activation by innate stimuli. Though IgE-activated mast cells are best known for their role in acute allergic reactions, including the most severe manifestation, anaphylaxis, accumulating evidence has suggested an immunoregulatory effect in T cell-mediated immunity, modulating the balance between type 2 immunity and tolerance. In this review, we outline how mast cells act as adjuvants for food antigen driven Th2 cell responses, while curtailing Treg function.