Intravitreal Bevacizumab (Avastin) as an Adjuvant for the Treatment of Posterior Scleritis

We report a case of posterior scleritis effectively managed with intravitreal bevacizumab. A 71-year-old woman was diagnosed with posterior scleritis. Although she was initially treated with systemic steroids, her clinical presentation deteriorated. She was then treated with a single intravitreal injection of bevacizumab and aqueous humor collection. The aqueous level of vascular endothelial growth factor prior to the intravitreal injection was 880.51 pg/mL, greater than that in the healthy control group (p < 0.001). One month later, the scleritis was completely resolved, and the patient remained stable during six months of follow-up. Intravitreal bevacizumab appears to be an effective adjuvant therapy for patients with posterior scleritis

Isolation and Chimerization of a Highly Neutralizing Antibody Conferring Passive Protection against Lethal Bacillus anthracis Infection

Several studies have demonstrated that the passive transfer of protective antigen (PA)-neutralizing antibodies can protect animals against Bacillus anthracis infection. The standard protocol for the isolation of PA-neutralizing monoclonal antibodies is based upon a primary selection of the highest PA-binders by ELISA, and usually yields only few candidates antibodies. We demonstrated that by applying a PA-neutralization functionality-based screen as the primary criterion for positive clones, it was possible to isolate more than 100 PA-neutralizing antibodies, some of which exhibited no measurable anti-PA titers in ELISA. Among the large panel of neutralizing antibodies identified, mAb 29 demonstrated the most potent activity, and was therefore chimerized. The variable region genes of the mAb 29 were fused to human constant region genes, to form the chimeric 29 antibody (cAb 29). Guinea pigs were fully protected against infection by 40LD50 B. anthracis spores following two separate administrations with 10 mg/kg of cAb 29: the first administration was given before the challenge, and a second dose was administered on day 4 following exposure. Moreover, animals that survived the challenge and developed endogenous PA-neutralizing antibodies with neutralizing titers above 100 were fully protected against repeat challenges with 40LD50 of B. anthracis spores. The data presented here emphasize the importance of toxin neutralization-based screens for the efficient isolation of protective antibodies that were probably overlooked in the standard screening protocol. The protective activity of the chimeric cAb 29 demonstrated in this study suggest that it may serve as an effective immunotherapeutic agent against anthrax

On topological relaxations of chromatic conjectures

There are several famous unsolved conjectures about the chromatic number that were relaxed and already proven to hold for the fractional chromatic number. We discuss similar relaxations for the topological lower bound(s) of the chromatic number. In particular, we prove that such a relaxed version is true for the Behzad-Vizing conjecture and also discuss the conjectures of Hedetniemi and of Hadwiger from this point of view. For the latter, a similar statement was already proven in an earlier paper of the first author with G. Tardos, our main concern here is that the so-called odd Hadwiger conjecture looks much more difficult in this respect. We prove that the statement of the odd Hadwiger conjecture holds for large enough Kneser graphs and Schrijver graphs of any fixed chromatic number

MicroRNA expression in a phosphaturic mesenchymal tumour

Phosphaturic mesenchymal tumours are a heterogeneous set of bone and soft tissue neoplasms that can cause a number of paraneoplastic syndromes such as tumour induced osteomalacia. The term phosphaturic comes from the common finding that these tumours secrete high levels of fibroblast growth factor 23 which causes renal phosphate wasting leading to hypophosphatemia. Phosphaturic mesenchymal tumours are rare and diagnosis is difficult. A very active 68 year old male presented with bone pain and muscle weakness. He was hypophosphataemic and total alkaline phosphatase was markedly elevated. The patient was placed on vitamin D supplementation but his condition progressed. In the fifth year of presentation the patient required the use of a wheelchair and described “explosive” bone pain on physical contact. Serum 1,25 dihydroxyvitamin D was low and serum fibroblast growth factor 23 was significantly elevated, raising suspicion of a phosphaturic mesenchymal tumour. A lesion was detected in his left femoral head and the patient underwent a total hip replacement. The patient displayed a rapid improvement to his condition and during a three year follow up period he returned to an active lifestyle. As molecular testing may help provide a robust diagnosis and is particularly useful in rare diseases we took a next generation sequencing approach to identify a differential expression of small RNAs in the resected tumour. Small RNAs are non-coding RNA molecules that play a key role in regulation of gene expression and can be used as specific biomarkers. We found an upregulation of miR-197. We also found a downregulation of miR-20b, miR-144 and miR-335 which is a small RNA profile typical of osteosarcoma. MiR-21, the most frequently upregulated microRNA in cancer, was downregulated. We conclude that the specific small RNA profile is typical of osteosarcoma except for the downregulation of oncogenic miR-21. Transcriptional plasticity of miR-197, which is computationally predicted to target fibroblast growth factor 23 messenger RNA, may be upregulated in a cellular effort to correct the ectopic expression of the protein

k-Ary spanning trees contained in tournaments

A rooted tree is called a $k$-ary tree, if all non-leaf vertices have exactly $k$ children, except possibly one non-leaf vertex has at most $k-1$ children. Denote by $h(k)$ the minimum integer such that every tournament of order at least $h(k)$ contains a $k$-ary spanning tree. It is well-known that every tournament contains a Hamiltonian path, which implies that $h(1)=1$. Lu et al. [J. Graph Theory {\bf 30}(1999) 167--176] proved the existence of $h(k)$, and showed that $h(2)=4$ and $h(3)=8$. The exact values of $h(k)$ remain unknown for $k\geq 4$. A result of Erd\H{o}s on the domination number of tournaments implies $h(k)=\Omega(k\log k)$. In this paper, we prove that $h(4)=10$ and $h(5)\geq13$.Comment: 11 pages, to appear in Discrete Applied Mathematic

Strong negative self regulation of Prokaryotic transcription factors increases the intrinsic noise of protein expression

Background Many prokaryotic transcription factors repress their own transcription. It is often asserted that such regulation enables a cell to homeostatically maintain protein abundance. We explore the role of negative self regulation of transcription in regulating the variability of protein abundance using a variety of stochastic modeling techniques. Results We undertake a novel analysis of a classic model for negative self regulation. We demonstrate that, with standard approximations, protein variance relative to its mean should be independent of repressor strength in a physiological range. Consequently, in that range, the coefficient of variation would increase with repressor strength. However, stochastic computer simulations demonstrate that there is a greater increase in noise associated with strong repressors than predicted by theory. The discrepancies between the mathematical analysis and computer simulations arise because with strong repressors the approximation that leads to Michaelis-Menten-like hyperbolic repression terms ceases to be valid. Because we observe that strong negative feedback increases variability and so is unlikely to be a mechanism for noise control, we suggest instead that negative feedback is evolutionarily favoured because it allows the cell to minimize mRNA usage. To test this, we used in silico evolution to demonstrate that while negative feedback can achieve only a modest improvement in protein noise reduction compared with the unregulated system, it can achieve good improvement in protein response times and very substantial improvement in reducing mRNA levels. Conclusions Strong negative self regulation of transcription may not always be a mechanism for homeostatic control of protein abundance, but instead might be evolutionarily favoured as a mechanism to limit the use of mRNA. The use of hyperbolic terms derived from quasi-steady-state approximation should also be avoided in the analysis of stochastic models with strong repressors

Maria Auxiliadora Hospital in Lima, Peru as a model for neurosurgical outreach to international charity hospitals

A myriad of geopolitical and financial obstacles have kept modern neurosurgery from effectively reaching the citizens of the developing world. Targeted neurosurgical outreach by academic neurosurgeons to equip neurosurgical operating theaters and train local neurosurgeons is one method to efficiently and cost effectively improve sustainable care provided by international charity hospitals. The International Neurosurgical Children’s Association (INCA) effectively improved the available neurosurgical care in the Maria Auxiliadora Hospital of Lima, Peru through the advancement of local specialist education and training. Neurosurgical equipment and training were provided for the local neurosurgeons by a mission team from the University of California at San Diego. At the end of 3 years, with one intensive week trip per year, the host neurosurgeons were proficiently and independently applying microsurgical techniques to previously performed operations, and performing newly learned operations such as neuroendoscopy and minimally invasive neurosurgery. Our experiences may serve as a successful template for the execution of other small scale, sustainable neurosurgery missions worldwide

Peptide interactions with bacterial lipopolysaccharides

Peptide and protein interactions with (lipo)polysaccharides are important in various biological contexts, including lipoprotein deposition at proteoglycan-covered endothelial surfaces in atherosclerosis, lectin functionality, and the interaction of antimicrobial and anti-inflammatory peptides and proteins with (lipo)polysaccharides. The latter of these areas, which is the topic of this review, has attracted considerable interest during the last few years, since antimicrobial peptides may offer novel therapeutic opportunities in an era of growing problems with antibiotic resistance, and persisting problems with both acute and chronic inflammation. In the present overview, physicochemical factors affecting peptide interactions with bacterial (lipo)polysaccharides are discussed, both in solution and at membrane interfaces. In doing so, an attempt is made to illustrate how physicochemical factors affect the antimicrobial and anti-endotoxic functionality of such peptides, and how knowledge on this can be translated into therapeutic opportunities, e.g., in sepsis. (C) 2013 Elsevier Ltd. All rights reserved

Single \pi^- production in np collisions for excess energies up to 90 MeV

The quasifree reaction np\to pp\pim was studied in a kinematically complete experiment by bombarding a liquid hydrogen target with a deuteron beam of momentum 1.85 GeV/c and analyzing the data along the lines of the spectator model. In addition to the three charged ejectiles the spectator proton was also detected in the large-acceptance time-of-flight spectrometer COSY-TOF. It was identified by its momentum and flight direction thus yielding access to the Fermi motion of the bound neutron and to the effective neutron 4-momentum vector $\mathbb{P}_n$ which differed from event to event. A range of almost 90 MeV excess energy above threshold was covered. Energy dependent angular distributions, invariant mass spectra as well as fully covered Dalitz plots were deduced. Sizeable $pp$ FSI effects were found as were contributions of $p$ and $d$ partial waves. The behavior of the elementary cross section $\sigma_{01}$ close to threshold is discussed in view of new cross section data. In comparison with existing literature data the results provide a sensitive test of the spectator model.Comment: 21 pages, 9 figures, 4 tables, submitted to EPJ

Complementary roles for scavenger receptor A and CD36 of human monocyte-derived macrophages in adhesion to surfaces coated with oxidized low-density lipoproteins and in secretion of H2O2

Oxidized low-density lipoprotein (oxLDL) is considered one of the principal effectors of atherogenesis. To explore mechanisms by which oxLDL affects human mononuclear phagocytes, we incubated these cells in medium containing oxLDL, acetylated LDL (acLDL), or native LDL, or on surfaces coated with these native and modified lipoproteins. The presence of soluble oxLDL, acLDL, or native LDL in the medium did not stimulate H2O2 secretion by macrophages. In contrast, macrophages adherent to surfaces coated with oxLDL secreted three- to fourfold more H2O2 than macrophages adherent to surfaces coated with acLDL or native LDL. Freshly isolated blood monocytes secreted little H2O2 regardless of the substrate on which they were plated. H2O2 secretion was maximal in cells maintained for 4–6 d in culture before plating on oxLDL-coated surfaces. Fucoidan, a known ligand of class A macrophage scavenger receptors (MSR-A), significantly reduced macrophage adhesion to surfaces coated with oxLDL or acLDL. Monoclonal antibody SMO, which blocks oxLDL binding to CD36, did not inhibit adhesion of macrophages to oxLDL-coated surfaces but markedly reduced H2O2 secretion by these cells. These studies show that MSR-A is primarily responsible for adhesion of macrophages to oxLDL-coated surfaces, that CD36 signals H2O2 secretion by macrophages adherent to these surfaces, and that substrate-bound, but not soluble, oxLDL stimulates H2O2 secretion by macrophages