Ebolavirus and Marburgvirus: insight the Filoviridae family

Ebolavirus and Marburgvirus (belonging to the Filoviridae family) emerged four decades ago and cause epidemics of haemorrhagic fever with high case-fatality rates. The genome of filoviruses encodes seven proteins. No significant homology is observed between filovirus proteins and any known macromolecule. Moreover, Marburgvirus and Ebolavirus show significant differences in protein homology. The natural maintenance cycle of filoviruses is unknown, the natural reservoir, the mode of transmission, the epidemic disease generation, and temporal dynamics are unclear. Lastly, Ebolavirus and Marburgvirus are considered as potential biological weapons. Vaccine appears the unique therapeutic frontier. Here, molecular and clinical aspects of filoviral haemorrhagic fevers are summarized

Heterogeneity in the non-planarity and arterial curvature of arteriovenous fistulae in vivo

Objective: Native arteriovenous fistulae (AVF) for haemodialysis are susceptible to non-maturation. Adverse features of local blood flow have been implicated in the formation of peri-anastomotic neointimal hyperplasia which may underpin non-maturation. While computational fluid dynamic simulations of idealised models highlight the importance of geometry on fluid and vessel wall interactions, little is known in vivo about AVF geometry and its role in adverse clinical outcomes. This study set out to examine the three-dimensional geometry of native AVF and the geometric correlates of AVF failure. Methods: As part of an observational study between 2013 and 2016, patients underwent creation of an upper limb AVF according to current surgical best practice. Phase-contrast MRI was performed on the day of surgery to obtain luminal geometry along with ultrasound measurements of flow. MRI datasets were segmented and reconstructed for quantitative and qualitative analysis of local geometry. Clinical maturation was evaluated at six weeks. Results: 60 patients were successfully imaged on the day of surgery. Radiocephalic (n=17), brachiocephalic (n=40) and brachiobasilic (n=3) fistulae were all included in the study. Centrelines extracted from segmented vessel lumen exhibited significant heterogeneity in arterial non-planarity and curvature. Furthermore, these features are more marked in brachiocephalic as compared to radiocephalic fistulae. Across the cohort, the projected bifurcation angle was was 73° (±16°) mean (±sd). Geometry was preserved at two weeks in 20 patients who underwent repeat imaging. A greater degree of arterial non-planarity (log odds ratio (logOR) 0.95 per 0.1/vessel diameter (95% CI 0.22 to 1.90, P= .03)) along with a larger bifurcation angle (logOR 0.05 per degree (95% CI 0.01 to 0.09, P= .02)) are associated with a great rate of maturation, as is fistula location (upper vs lower arm) logOR -1.9 (95% CI -3.2 to 0.7, P = .002) . Conclusions: There is significant heterogeneity in the three-dimensional geometry of arteriovenous fistulae, in particular, arterial non-planarity and curvature. In this largest cohort of AVF geometry to date, the effect of individual geometric correlates on maturation is uncertain but supports the premise that future modelling studies will need to acknowledge the complex geometry of AVF

Phylogenetic analysis of West Nile virus isolates, Italy, 2008-2009.

To determine the lineage of West Nile virus that caused outbreaks in Italy in 2008 and 2009, several West Nile virus strains were isolated from human specimens and sequenced. On the basis of phylogenetic analyses, the strains isolated constitute a distinct group within the western Mediterranean cluster

Hypophosphataemia after intravenous iron therapy with ferric carboxymaltose—Real world experience from a tertiary centre in the UK

Background: Iron deficiency is the most common global cause of anaemia. Intravenous (IV) iron is used to correct iron deficiency anaemia (IDA) where oral iron cannot be used. Despite being effective, certain IV iron formulations cause significant hypophosphataemia. However, current knowledge on the clinical consequences of IV iron‐induced hypophosphataemia is broadly anecdotal or limited to isolated case reports. / Aims: To retrospectively examine the incidence and potential clinical consequences of hypophosphataemia post‐IV ferric carboxymaltose (FCM) in hospitalised patients with IDA (mixed aetiology). / Methods: Data were collected for 162 patients, who received a total of 169 FCM courses during a 2‐year audit period. Outcomes included incidence of moderate/severe hypophosphataemia (serum phosphate <0.65 mmol/L) ≤90 days post‐FCM, changes in alkaline phosphatase, need for phosphate replacement, and length of hospital stay. / Results: The incidence of moderate/severe hypophosphataemia post‐FCM was 33.7%; within this group the rate of severe hypophosphataemia (serum phosphate ≤0.32 mmol/L) was 8.8%. Moderate/severe hypophosphataemia persisted, with 35% of patients having a serum phosphate of <0.65 mmol/L for ≤90 days at the last measurement after IV FCM. Intervention with IV phosphate—an average of 4.4 infusions per person—was required in 29.8% of cases with moderate/severe hypophosphataemia. FCM‐induced moderate/severe hypophosphataemia was associated with a significantly longer hospital stay (P < 0.0035). / Conclusions: Moderate/severe hypophosphataemia is a frequent adverse drug reaction with FCM. In our study, FCM‐induced moderate/severe hypophosphataemia was also persistent, often required treatment, and was associated with longer hospital stay

Bell State Preparation using Pulsed Non-Degenerate Two-Photon Entanglement

We report a novel Bell state preparation experiment. High-purity Bell states are prepared by using femtosecond pulse pumped \emph{nondegenerate} collinear spontaneous parametric down-conversion. The use of femtosecond pump pulse {\em does not} result in reduction of quantum interference visibility in our scheme in which post-selection of amplitudes and other traditional mechanisms, such as, using thin nonlinear crystals or narrow-band spectral filters are not used. Another distinct feature of this scheme is that the pump, the signal, and the idler wavelengths are all distinguishable, which is very useful for quantum communications.Comment: 4 pages, submitted to PR

MSH3 protein expression and nodal status in MLH1-deficient colorectal cancers.

View the MathML source: Colorectal tumors manifesting high-frequency microsatellite instability (MSI-H) develop genetically as a consequence of mutations in genes harboring repetitive DNA sequences. The activin type 2 receptor (ACVR2), possessing 2 polyadenine coding sequences, was identified as a mutational target, but it is not clear if expression is abrogated. Here, we analyzed MSI-H colorectal cancers for ACVR2 mutation and expression to assess if biallelic inactivation occurs. View the MathML source: All 54 MSI-H colon cancers and 20 random microsatellite stable (MSS) tumors from a population-based cohort of 503 patients were analyzed for mutations in 2 A8 tracts (exon 3 and 10) of ACVR2 and the A10 tract of transforming growth factor \u3b2 receptor 2 (TGFBR2). Additionally, we sequenced exon 10 of ACVR2 in select cancers. ACVR2 expression was determined by immunohistochemistry using an antibody targeting an epitope beyond the predicted truncated protein. View the MathML source: Forty-five of 54 MSI-H cancers (83%) showed mutation (A8 to A7) in the polyadenine tract of exon 10 compared with no MSS tumors. Of tumors with mutant ACVR2, 62% lacked protein expression but all MSS and MSI-H tumors with wild-type ACVR2 expressed protein. We found no evidence of loss of heterozygosity at the ACVR2 locus in MSS tumors. Comparatively, 69% of MSI-H cancers had frameshift mutation in TGFBR2. View the MathML source:ACVR2 mutations are highly frequent in MSI-H colon cancers and in most cases cause loss of ACVR2 expression, indicating biallelic inactivation of the gene. Loss of activin signaling through mutation of ACVR2, similar to observations with TGFBR2, may be important in the genesis of MSI-H colorectal cancer

WHO collaborative study to assess the suitability of the 1st International Standard and the 1st International Reference Panel for antibodies to Ebola virus

A WHO international collaborative study was undertaken to evaluate preparations of Ebola virus disease (EVD) convalescent plasmas for their suitability to serve as the WHO 1st International Standard (IS) and the WHO 1st International Reference Panel (IRP) for Ebola virus antibodies for use in the standardization and control of assays. The study involved participants testing the convalescent plasma sample preparations and additional monoclonal antibody samples in a blinded manner alongside the WHO International Reference Reagent (NIBSC code 15/220) using anti-EBOV assays established in their laboratories. The candidate 1st IS for Ebola virus antibodies (study sample code 92, NIBSC 15/262) consists of ampoules containing the freeze-dried equivalent of 0.5 mL pooled convalescent plasma obtained from six Sierra Leone patients recovered from EVD. The candidate 1st IRP of anti-Ebola virus convalescent plasmas (NIBSC 16/344) consists of freeze-dried preparations of single donations of convalescent plasma obtained from four patients and one healthy blood donor. Each panel member is an ampoule containing the equivalent of 0.25mL plasma. All convalescent plasmas are confirmed PCR-negative for Ebola virus and underwent, along with the negative plasma, solvent detergent (SD) treatment prior to their development into candidate WHO biological reference materials. In this collaborative study, 17 laboratories from 4 countries used a range of live Ebola virus neutralization assays, pseudotyped virus neutralisation assays and enzyme immunoassays to test the collaborative study samples. Surface plasmon resonance and Western blot assessments were also undertaken. The study found that the candidate International Standard has the highest absolute titre among the convalescent plasma samples, although the geometric mean titres of all the convalescent plasmas fall within ~5-fold of each other. The potencies of three of the convalescent samples fall near the detection limit of some assays. This study also demonstrated that the agreement between laboratories for potencies relative to the candidate International Standard represents an improvement compared to the agreement in absolute titres; however, there is poor agreement between relative potencies for some assays. The results obtained from accelerated thermal degradation studies at 1year indicate that the candidate IS is stable and suitable for long-term use. The results of the collaborative study indicate the suitability of the candidates to serve as WHO reference materials and it is proposed that 15/262 is established as the WHO 1st IS for EBOV antibodies with an assigned potency of 1.5 IU/mL when reconstituted as directed in the instructions for use. It is also proposed that 16/344 is established as the WHO 1st IRP of anti-EBOV convalescent plasmas with panel member code 95 (NIBSC 15/280) assigned a unitage of 1.1 IU/mL when reconstituted as directed in the instructions for use. The other panel members have not been assigned a unitage. The implementation and use by laboratories of the proposed WHO reference materials for EBOV antibodies will facilitate the characterization of the factors that contribute to assay variability and standardization of results across assays and laboratorie

Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-\u3baB, I\u3ba-B\u3b1, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy

First human case of West Nile virus neuroinvasive infection in Italy, September 2008 - case report.

On 20 September 2008, the laboratory of the Regional Reference Centre for Microbiological Emergencies (Centro di Riferimento Regionale per le Emergenze Microbiologiche, CRREM) in Bologna, reported the detection of specific IgM and IgG antibodies against West Nile virus (WNV) in the serum of a female patient in her eighties who lived in a rural area between Ferrara and Bologna, Italy

Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy