Mannose-Binding Lectin 2 Polymorphisms Do Not Influence Frequency or Type of Infection in Adults with Chemotherapy Induced Neutropaenia

BACKGROUND: Mannose-binding Lectin protein (MBL) has been suggested to be relevant in the defence against infections in immunosuppressed individuals. In a Swedish adult cohort immunosuppressed from both the underlying disease and from iatrogenic treatments for their underlying disease we investigated the role of MBL in susceptibility to infection. METHODS: In this cross sectional, prospective study, blood samples obtained from 96 neutropaenic febrile episodes, representing 82 individuals were analysed for single nucleotide polymorphism (SNP) in the MBL2 gene. Concurrent measurement of plasma MBL protein concentrations was also performed for observation of acute response during febrile episodes. FINDINGS: No association was observed between MBL2 genotype or plasma MBL concentrations, and the type or frequency of infection. Adding to the literature, we found no evidence that viral infections or co-infections with virus and bacteria would be predisposed by MBL deficiency. We further saw no correlation between MBL2 genotype and the risk of fever. However, fever duration in febrile neutropaenic episodes was negatively associated with MBL2 SNP mutations (p<0.05). Patients with MBL2 SNP mutations presented a median febrile duration of 1.8 days compared with 3 days amongst patients with wildtype MBL2 genotype. INTERPRETATION: We found no clear association between infection, or infection type to MBL2 genotypes or plasma MBL concentration, and add to the reports casting doubts on the benefit of recombinant MBL replacement therapy use during iatrogenic neutropaenia

Viral Findings in Adult Hematological Patients with Neutropenia

BACKGROUND: Until recently, viral infections in patients with hematological malignancies were concerns primarily in allogeneic hematopoietic stem cell transplant (HSCT) recipients. During the last years, changed treatment regimens for non-transplanted patients with hematological malignancies have had potential to increase the incidence of viral infections in this group. In this study, we have prospectively investigated the prevalence of a broad range of respiratory viruses in nasopharyngeal aspirate (NPA) as well as viruses that commonly reactivate after allogeneic HSCT. METHODOLOGY/PRINCIPAL FINDINGS: Patients with hematological malignancies and therapy induced neutropenia (n = 159) were screened regarding a broad range of common respiratory viruses in the nasopharynx and for viruses commonly detected in severely immunosuppressed patients in peripheral blood. Quantitative PCR was used for detection of viruses. A viral pathogen was detected in 35% of the patients. The detection rate was rather similar in blood (22%) and NPA (18%) with polyoma BK virus and rhinovirus as dominating pathogens in blood and NPA, respectively. Patients with chronic lymphocytic leukemia (CLL) (p<0.01) and patients with fever (p<0.001) were overrepresented in the virus-positive group. Furthermore, viral findings in NPA were associated with upper respiratory symptoms (URTS) (p<0.0001). CONCLUSIONS/SIGNIFICANCE: Both respiratory viral infections and low titers of viruses in blood from patients with neutropenia were common. Patients with CLL and patients with fever were independently associated to these infections, and viral findings in NPA were associated to URTS indicating active infection. These findings motivate further studies on viruses' impact on this patient category and their potential role as causative agents of fever during neutropenia

The 6-Aminoquinolone WC5 Inhibits Different Functions of the Immediate-Early 2 (IE2) Protein of Human Cytomegalovirus That Are Essential for Viral Replication.

The human cytomegalovirus (HCMV) immediate-early 2 (IE2) protein is a multifunctional factor essential for viral replication. IE2 modulates both viral and host gene expression, deregulates cell cycle progression, acts as an immunomodulator, and antagonizes cellular antiviral responses. Based on these facts, IE2 has been proposed as an important target for the development of innovative antiviral approaches. We previously identified the 6-aminoquinolone WC5 as a promising inhibitor of HCMV replication, and here, we report the dissection of its mechanism of action against the viral IE2 protein. Using glutathione S-transferase (GST) pulldown assays, mutagenesis, cell-based assays, and electrophoretic mobility shift assays, we demonstrated that WC5 does not interfere with IE2 dimerization, its interaction with TATA-binding protein (TBP), and the expression of a set of cellular genes that are stimulated by IE2. On the contrary, WC5 targets the regulatory activity exerted by IE2 on different responsive viral promoters. Indeed, WC5 blocked the IE2-dependent negative regulation of the major immediate-early promoter by preventing IE2 binding to the crs element. Moreover, WC5 reduced the IE2-dependent transactivation of a series of indicator constructs driven by different portions of the early UL54 gene promoter, and it also inhibited the transactivation of the murine CMV early E1 promoter by the IE3 protein, the murine cytomegalovirus (MCMV) IE2 homolog. In conclusion, our results indicate that the overall anti-HCMV activity of WC5 depends on its ability to specifically interfere with the IE2-dependent regulation of viral promoters. Importantly, our results suggest that this mechanism is conserved in murine CMV, thus paving the way for further preclinical evaluation in an animal model

Could molecular effects of Caulerpa racemosa metabolites modulate the impact on fish populations of Diplodus sargus?

The green alga Caulerpa racemosa is a non-native, invasive species in the Mediterranean, and an important stressor for several native organisms. The algal capacity to produce secondary metabolites has been suggested to modulate success of the C. racemosa invasion, although many of potentially involved biological pathways still remain unexplored. In this respect, the aim of the present study was to investigate some molecular and cellular effects in the white seabream Diplodus sargus, an ecologically key species, which included the alien C. racemosa in its diet. Organisms were sampled in 2 seasonal periods from 3 locations of Southern Italy, each characterized by different levels of algal abundance. The level of caulerpin, one of the main secondary algal metabolites, in fish tissues has been used as an indicator of the trophic exposure to the seaweed and related with molecular and cellular responses. Chemical analyses indicated that fish from invaded sites can accumulate caulerpin, with liver concentrations ranging from a few up to hundreds of mg/g. Biomarkers analyses revealed only limited alterations of the main antioxidant defences, such as glutathione reductase and levels of glutathione; on the other hand, increased enzymatic activities of cytochrome P450, glutathione S-transferases and acyl CoA oxidase, as well as enhanced gene transcription for peroxisome proliferator-activated receptor alpha, cytochrome P4501A and vitellogenin 1 were observed in fish more exposed to C. racemosa as indicated by liver concentrations of caulerpin higher than 50 mg/g. Despite a direct molecular relationship with this algal metabolite could not be established, our results suggest that a C. racemosa enriched diet can modulate biotransformation and fatty acids metabolism of D. sargus. Assessing whether similar effects represent short- or long-term effects will be of crucial importance to understand consequences on the general health status and reproductive performance of exposed key fish species in the Mediterranean region

PITER-HCV cohort study as part of the Italian platform for the study of viral hepatitis therapies

L’Italia è uno dei Paesi in Europa con il più alto tasso di prevalenza di infezione dal virus dell’epatite C (Hepatitis C Virus, HCV), causa principale di cirrosi, epatocarcinoma e mortalità correlata a malattie del fegato. Alla luce di questo, i farmaci antivirali “direct acting” (Direct Acting Antiviral Agents, DAA) potrebbero avere un enorme impatto sulla salute pubblica in Italia. Dalla collaborazione tra Istituto Superiore di Sanità, Associazione Italiana per lo Studio del Fegato, Società Italiana per le Malattie Infettive e più di 100 tra i Centri Clinici affiliati, è nato lo studio di coorte longitudinale prospettico PITER-HCV (Piattaforma Italiana per lo studio della Terapia delle Epatiti ViRali). La coorte consisterà di un campione rappresentativo di circa 10.000 pazienti consecutivi con infezione cronica da HCV con un follow-up atteso di almeno 10 anni. La prima finestra di arruolamento è iniziata nel maggio 2014; l’arruolamento sarà riaperto per periodi di tre mesi negli anni seguenti per cogliere l’introduzione dei nuovi DAA.Italy has one of the highest prevalence rates of Hepatitis C Virus (HCV) infection in Europe, and HCV infection is the leading cause of cirrhosis, hepatocellular carcinoma, and liver-related death. In light of this, Direct Acting Antiviral Agents (DAAs) would have a huge public health impact in Italy. A longitudinal prospective HCV cohort study known as PITER (Piattaforma Italiana per lo studio della Terapia delle Epatiti viRali: Italian Platform for the Study of Viral Hepatitis Therapies) has been developed as a collaboration among the Istituto Superiore di Sanità (the National Institute of Public Health in Italy), the Italian Society for the Study of the Liver, the Italian Society for Infectious Diseases, and their more than 100 affiliated Clinical Centres. The cohort will consist of a representative sample of approximately 10,000 consecutive patients with chronic HCV liver disease with an expected follow-up of at least 10 years. The first round of enrolment began in May 2014; enrolment will be re-opened for three-month periods during subsequent years to catch the introduction of new DAAs

La Piattaforma Italiana per lo studio della Terapia delle Epatiti Virali (PITER): il primo grande studio nazionale sull'infezione cronica da virus dell'epatite C

(The Italian Platform for the study of Viral Hepatitis Therapies (PITER): the first national study on chronic HCV infection) - In order to address challenges and unanswered questions in the field of HCV therapy, the Italian Platform for the study of Viral Hepatitis Therapies (PITER), which is a strong collaboration among the Italian National Institute of Health (ISS), the Italian Association for the Study of the Liver (AISF) and the Italian Society of Infective and Tropical Diseases (SIMIT), launched as the first activity the PITER-HCV observational cohort study. Its main goal is to evaluate the direct acting antivirals (DAAs) short and long term outcomes in the patients’ real life, in order to optimize treatment protocols and to ensure the cure equity. The results of 6,058 first enrolled patients represent the first Italian snapshot of patients with chronic hepatitis C in care