Delayed-onset angioedema following a snakebite in a patient on ACE inhibitors: A case report

INTRODUCTION: Angiotensin converting enzyme inhibitors (ACEI) are a common class of medications prescribed to patients for hypertension. Anti-hypertensive use is not normally considered an important factor when treating patients with crotalid envenomations; however, in combination with the venom in this patient, it may have resulted in angioedema. CASE REPORT: A 65-year-old male on ACEI presented to his community emergency department following a snake envenomation to his thumb. Six vials of Crotalidae polyvalent immune fab were administered, and he was transferred to a referral center. Approximately 18 hours after the envenomation, the patient complained of tongue swelling and difficulty speaking. There was evidence of angioedema, with the right side of the tongue significantly enlarged compared to the left. He was intubated for airway protection and remained on a ventilator for three days. CONCLUSION: Angiotensin converting enzyme inhibitors may potentiate the effects of exogenous bradykinin as some snake venom has naturally occurring bradykinin, which may further amplify its effects. Extra vigilance may be warranted for the development of angioedema in patients receiving ACEI

Hepatoma cell density promotes claudin-1 and scavenger receptor BI expression and hepatitis C virus internalization.

Hepatitis C virus (HCV) entry occurs via a pH- and clathrin-dependent endocytic pathway and requires a number of cellular factors, including CD81, the tight-junction proteins claudin 1 (CLDN1) and occludin, and scavenger receptor class B member I (SR-BI). HCV tropism is restricted to the liver, where hepatocytes are tightly packed. Here, we demonstrate that SR-BI and CLDN1 expression is modulated in confluent human hepatoma cells, with both receptors being enriched at cell-cell junctions. Cellular contact increased HCV pseudoparticle (HCVpp) and HCV particle (HCVcc) infection and accelerated the internalization of cell-bound HCVcc, suggesting that the cell contact modulation of receptor levels may facilitate the assembly of receptor complexes required for virus internalization. CLDN1 overexpression in subconfluent cells was unable to recapitulate this effect, whereas increased SR-BI expression enhanced HCVpp entry and HCVcc internalization, demonstrating a rate-limiting role for SR-BI in HCV internalization

Clinical development of anti-RANKL therapy

The receptor activator of nuclear factor-κB ligand (RANKL), its cognate receptor RANK, and its natural decoy receptor osteoprotegerin have been identified as the final effector molecules of osteoclastic bone resorption. This has provided an ideal target for therapeutic interventions in metabolic bone disease. As described in previous reviews in this supplement, RANKL signaling is required for osteoclast differentiation, activation, and survival. Furthermore, in vivo inhibition of RANKL leads to immediate osteoclast apoptosis, and there are no in vivo models of bone resorption that are refractory to RANKL inhibition. Thus, the only step remaining in the development of a clinical intervention is the generation of a safe, effective, and specific drug that can inhibit RANKL in humans. Here we review the clinical development of denosumab (formerly known as AMG 162), which is a fully human mAb directed against RANKL. This discussion includes the breadth of 21 human studies that have led to the current phase 3 clinical trials seeking approval for use of this agent to treat postmenopausal women with low bone mineral density (osteoporosis) and patients with metastatic lytic bone lesions (multiple myeloma, and prostate and breast cancer)

L(2,1)-labelings of Cartesian products of two cycles

AbstractAn L(2,1)-labeling of a graph is an assignment of nonnegative integers to its vertices so that adjacent vertices get labels at least two apart and vertices at distance two get distinct labels. The λ-number of a graph G, denoted by λ(G), is the minimum range of labels taken over all of its L(2,1)-labelings. We show that the λ-number of the Cartesian product of any two cycles is 6, 7 or 8. In addition, we provide complete characterizations for the products of two cycles with λ-number exactly equal to each one of these values

Prostaglandin E Positively Modulates Endothelial Progenitor Cell Homeostasis: An Advanced Treatment Modality for Autologous Cell Therapy

Aims: The mobilization of endothelial progenitor cells (EPC) and their functioning in postnatal neovascularization are tightly regulated. To identify new modulators of EPC homeostasis, we screened biologically active prostaglandin E compounds for their effects on EPC production, trafficking and function. Methods and Results: We found that EPC are a rich source for prostaglandin E 2 (PGE 2), stimulating their number and function in an auto- and paracrine manner. In vivo blockade of PGE 2 production by selective cyclooxygenase-2 inhibition virtually abrogated ischemia-induced EPC mobilization demonstrating its crucial role in EPC homeostasis following tissue ischemia. Conversely, ex vivo treatment of isolated EPC with the clinically approved PGE 1 analogue alprostadil enhanced EPC number and function. These effects were mediated by increased expression of the chemokine receptor CXCR4 and were dependent on nitric oxide synthase activity. Most importantly, ex vivo PGE 1 pretreatment of isolated EPC significantly enhanced their neovascularization capacity in a murine model of hind limb ischemia as assessed by laser Doppler analysis, exercise stress test and immunohistochemistry. Conclusions: The conserved role for PGE in the regulation of EPC homeostasis suggests that ex vivo modulation of the prostaglandin pathway in isolated progenitor cells may represent a novel and safe strategy to facilitate cell-based therapies. Copyright (C) 2009 S. Karger AG, Base

Mandatory Disclosure and Operational Risk: Evidence from Hedge Fund Registration

Mandatory disclosure is a regulatory tool intended to allow market participants to assess operational risk. We examine the value of disclosure through the controversial SEC requirement, since overturned, which required major hedge funds to register as investment advisors and file Form ADV disclosures. Leverage and ownership structures suggest that lenders and equity investors were already aware of operational risk. However, operational risk does not mediate flow-performance relationships. Investors either lack this information or regard it as immaterial. These findings suggest that regulators should account for the endogenous production of information and the marginal benefit of disclosure to different investment clienteles

When does the zero fiber of the moment map have rational singularities?

Let $G$ be a complex reductive group and $V$ a $G$-module. There is a natural moment mapping $\mu\colon V\oplus V^*\to\mathfrak{g}^*$ and we denote $\mu^{-1}(0)$ (the shell) by $N_V$. We use invariant theory and results of Musta\c{t}\u{a} [Mus01] to find criteria for $N_V$ to have rational singularities and for the categorical quotient $N_V /\!\!/ G$ to have symplectic singularities, the latter results improving upon [HSS20]. It turns out that for ``most'' $G$-modules $V$, the shell $N_V$ has rational singularities. For the case of direct sums of classical representations of the classical groups, $N_V$ has rational singularities and $N_V /\!\!/ G$ has symplectic singularities if $N_V$ is a reduced and irreducible complete intersection. Another important special case is $V=p\,\mathfrak{g}$ (the direct sum of $p$ copies of the Lie algebra of $G$) where $p\geq 2$. We show that $N_V$ has rational singularities and that $N_V /\!\!/ G$ has symplectic singularities, improving upon results of [Bud19], [AA16], [Kap19] and [GH20]. Let $\pi=\pi_1(\Sigma)$ where $\Sigma$ is a closed Riemann surface of genus $p\geq 2$. Let $G$ be semisimple and let $\operatorname{Hom}(\pi,G)$ and $\mathscr X\!(\pi,G)$ be the corresponding representation variety and character variety. We show that $\operatorname{Hom}(\pi,G)$ is a complete intersection with rational singularities and that $\mathscr X\!(\pi,G)$ has symplectic singularities. If $p>2$ or $G$ contains no simple factor of rank $1$, then the singularities of $\operatorname{Hom}(\pi,G)$ and $\mathscr X\!(\pi,G)$ are in codimension at least four and $\operatorname{Hom}(\pi,G)$ is locally factorial. If, in addition, $G$ is simply connected, then $\mathscr X\!(\pi,G)$ is locally factorial.Comment: 21 pages. v2: 22 pages, clarified and improved arguments in Section 3, improved exposition and minor corrections. v3: 30 pages, reformatted, minor correction

VP24-Karyopherin alpha binding affinities differ between Ebolavirus species, nfluencing interferon inhibition and VP24 stability

Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Reston ebolavirus (RESTV) belong to the same genus but exhibit different virulence properties. VP24 protein, a structural protein present in all family members, blocks interferon (IFN) signaling and likely contributes to virulence. Inhibition of IFN signaling by EBOV VP24 (eVP24) involves its interaction with the NPI-1 subfamily of karyopherin alpha (KPNA) nuclear transporters. Here, we evaluated eVP24, BDBV VP24 (bVP24), and RESTV VP24 (rVP24) interactions with three NPI-1 subfamily KPNAs (KPNA1, KPNA5, and KPNA6). Using purified proteins, we demonstrated that each VP24 binds to each of the three NPI-1 KPNAs. bVP24, however, exhibited approximately 10-fold-lower KPNA binding affinity than either eVP24 or rVP24. Cell-based assays also indicate that bVP24 exhibits decreased KPNA interaction, decreased suppression of IFN induced gene expression, and a decreased half-life in transfected cells compared to eVP24 or rVP24. Amino acid sequence alignments between bVP24 and eVP24 also identified residues within and surrounding the previously defined eVP24-KPNA5 binding interface that decrease eVP24-KPNA affinity or bVP24-KPNA affinity. VP24 mutations that lead to reduced KPNA binding affinity also decrease IFN inhibition and shorten VP24 half-lives. These data identify novel functional differences in VP24-KPNA interaction and reveal a novel impact of the VP24-KPNA interaction on VP24 stability. IMPORTANCE The interaction of Ebola virus (EBOV) VP24 protein with host karyopherin alpha (KPNA) proteins blocks type I interferon (IFN) signaling, which is a central component of the host innate immune response to viral infection. Here, we quantitatively compared the interactions of VP24 proteins from EBOV and two members of the Ebolavirus genus, Bundibugyo virus (BDBV) and Reston virus (RESTV). The data reveal lower binding affinity of the BDBV VP24 (bVP24) for KPNAs and demonstrate that the interaction with KPNA modulates inhibition of IFN signaling and VP24 stability. The effect of KPNA interaction on VP24 stability is a novel functional consequence of this virus-host interaction, and the differences identified between viral species may contribute to differences in pathogenesis