FIP1L1-PDGFRA molecular analysis in the differential diagnosis of eosinophilia

<p>Abstract</p> <p>Background</p> <p>Primary eosinophlia associated with the <it>FIP1L1-PDGFRA </it>rearrangement represents a subset of chronic eosinophilic leukaemia (CEL) and affected patients are very sensitive to imatinib treatment. This study was undertaken in order to examine the prevalence and the associated clinicopathologic and genetic features of <it>FIP1L1-PDGFRA </it>rearrangement in a cohort of 15 adult patients presenting with profound eosinophilia (> 1.5 × 10⁹/L).</p> <p>Methods</p> <p>Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the detection of <it>FIP1L1-PDGFRA </it>rearrangement and the results confirmed by direct sequencing. <it>C-KIT</it>-D816V mutation was analysed retrospectively by PCR and restriction-fragment-length-polymorphism (PCR-RFLP), in all cases with primary eosinophilia.</p> <p>Results</p> <p>Two male patients with splenomegaly carried the <it>FIP1L1-PDGFRA </it>rearrangement, whilst 2 others were ultimately classified as suffering from idiopathic hypereosinophlic syndrome (HES) and one from systemic mastocytosis. These patients were negative for the <it>C-KIT</it>-D816V mutation and received imatinib (100–400 mg daily). Patients with CEL and HES responded to imatinib and remained in complete haematological, clinical and molecular (for carriers of <it>FIP1L1-PDGFRA </it>rearrangement) remission for a median of 28.2 months (range: 11–54), whilst the patient with systemic mastocytosis did not respond. Interestingly, in both patients with <it>FIP1L1-PDGFRA </it>rearrangement, the breakpoints into <it>PDGFRA </it>were located within exon 12 and fused with exons 8 and 8a of <it>FIP1L1</it>, respectively.</p> <p>Conclusion</p> <p>An early diagnosis of <it>FIPIL1-PDGFRA</it>-positive CEL and imatinib treatment offer to the affected patients an excellent clinical therapeutic result, avoiding undesirable morbidity. Moreover, although the molecular mechanisms underlying disease pathogenesis remain to be determined, imatinib can be effective in patients with idiopathic HES.</p

Right pulmonary artery agenesis presenting with uncontrolled asthma in an adult: a case report

<p>Abstract</p> <p>Introduction</p> <p>Unilateral absence of the pulmonary artery (UAPA) or pulmonary artery agenesis is a rare congenital disorder presenting with a wide spectrum of symptoms. The clinical presentation is variable and many patients can be asymptomatic for many years and even throughout their lives.</p> <p>Case presentation</p> <p>We report the case of a 53-year-old African-American woman who was diagnosed with right pulmonary artery agenesis after presenting with uncontrolled asthma and recurrent bronchopulmonary infections.</p> <p>Conclusion</p> <p>In an unexplained case of recurrent respiratory infections and shortness of breath, the possibility of a rare congenital anomaly like UAPA should be considered and an appropriate evaluation should be done.</p

Vortex nucleation as a case study of symmetry breaking in quantum systems

Mean-field methods are a very powerful tool for investigating weakly interacting many-body systems in many branches of physics. In particular, they describe with excellent accuracy trapped Bose-Einstein condensates. A generic, but difficult question concerns the relation between the symmetry properties of the true many-body state and its mean-field approximation. Here, we address this question by considering, theoretically, vortex nucleation in a rotating Bose-Einstein condensate. A slow sweep of the rotation frequency changes the state of the system from being at rest to the one containing one vortex. Within the mean-field framework, the jump in symmetry occurs through a turbulent phase around a certain critical frequency. The exact many-body ground state at the critical frequency exhibits strong correlations and entanglement. We believe that this constitutes a paradigm example of symmetry breaking in - or change of the order parameter of - quantum many-body systems in the course of adiabatic evolution.Comment: Minor change

Inductively guided circuits for ultracold dressed atoms

Recent progress in optics, atomic physics and material science has paved the way to study quantum effects in ultracold atomic alkali gases confined to non-trivial geometries. Multiply connected traps for cold atoms can be prepared by combining inhomogeneous distributions of DC and radio-frequency electromagnetic fields with optical fields that require complex systems for frequency control and stabilization. Here we propose a flexible and robust scheme that creates closed quasi-one-dimensional guides for ultracold atoms through the ‘dressing’ of hyperfine sublevels of the atomic ground state, where the dressing field is spatially modulated by inductive effects over a micro-engineered conducting loop. Remarkably, for commonly used atomic species (for example, 7Li and 87Rb), the guide operation relies entirely on controlling static and low-frequency fields in the regimes of radio-frequency and microwave frequencies. This novel trapping scheme can be implemented with current technology for micro-fabrication and electronic control

Fatigue testing of three peristernal median sternotomy closure techniques

Failure of a sternotomy closure because of closure system fatigue is a complication that may result in dehiscence and put the individual at risk for serious complications. The purpose of this study was to assess the fatigue performance of three peristernal median sternotomy closure techniques (figure-of-eight stainless-steel wires, figure-of-eight stainless-steel cables, or Pectofix Dynamic Sternal Fixation [DSF] stainless-steel plates) in order to quantify the potential risk of fatigue failure of these devices when subject to cyclic loads in physiologically relevant loading directions

The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8+ T cell recognition of endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 c1-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV c2-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8+ T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed

Nets, Spray or Both? The Effectiveness of Insecticide-Treated Nets and Indoor Residual Spraying in Reducing Malaria Morbidity and Child Mortality in sub-Saharan Africa.

Malaria control programmes currently face the challenge of maintaining, as well as accelerating, the progress made against malaria with fewer resources and uncertain funding. There is a critical need to determine what combination of malaria interventions confers the greatest protection against malaria morbidity and child mortality under routine conditions. This study assesses intervention effectiveness experienced by children under the age of five exposed to both insecticide-treated nets (ITNs) and indoor residual spraying (IRS), as compared to each intervention alone, based on nationally representative survey data collected from 17 countries in sub-Saharan Africa. Living in households with both ITNs and IRS was associated with a significant risk reduction against parasitaemia in medium and high transmission areas, 53% (95% CI 37% to 67%) and 31% (95% CI 11% to 47%) respectively. For medium transmission areas, an additional 36% (95% CI 7% to 53%) protection was garnered by having both interventions compared with exposure to only ITNs or only IRS. Having both ITNs and IRS was not significantly more protective against parasitaemia than either intervention alone in low and high malaria transmission areas. In rural and urban areas, exposure to both interventions provided significant protection against parasitaemia, 57% (95% CI 48% to 65%) and 39% (95% CI 10% to 61%) respectively; however, this effect was not significantly greater than having a singular intervention. Statistically, risk for all-cause child mortality was not significantly reduced by having both ITNs and IRS, and no additional protectiveness was detected for having dual intervention coverage over a singular intervention. These findings suggest that greater reductions in malaria morbidity and health gains for children may be achieved with ITNs and IRS combined beyond the protection offered by IRS or ITNs alone

Bright ligand-activatable fluorescent protein for high-quality multicolor live-cell super-resolution microscopy

We introduce UnaG as a green-to-dark photoswitching fluorescent protein capable of high-quality super-resolution imaging with photon numbers equivalent to the brightest photoswitchable red protein. UnaG only fluoresces upon binding of a fluorogenic metabolite, bilirubin, enabling UV-free reversible photoswitching with easily controllable kinetics and low background under Epi illumination. The on- and off-switching rates are controlled by the concentration of the ligand and the excitation light intensity, respectively, where the dissolved oxygen also promotes the off-switching. The photo-oxidation reaction mechanism of bilirubin in UnaG suggests that the lack of ligand-protein covalent bond allows the oxidized ligand to detach from the protein, emptying the binding cavity for rebinding to a fresh ligand molecule. We demonstrate super-resolution single-molecule localization imaging of various subcellular structures genetically encoded with UnaG, which enables facile labeling and simultaneous multicolor imaging of live cells. UnaG has the promise of becoming a default protein for high-performance super-resolution imaging. Photoconvertible proteins occupy two color channels thereby limiting multicolour localisation microscopy applications. Here the authors present UnaG, a new green-to-dark photoswitching fluorescent protein for super-resolution imaging, whose activation is based on a noncovalent binding with bilirubin

Phase 1b randomized, double-blind study of namilumab, an anti-granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-moderate rheumatoid arthritis

Change from baseline in swollen (a) and tender (b) joint counts. *Error bars show upper SE for placebo and lower SE for namilumab. SE standard error, SJC swollen joint count, TJC tender joint count. (PDF 1292 kb