Efficacy and Safety of Human Intravenous Immunoglobulin 10% (Panzyga®) in Patients with Primary Immunodeficiency Diseases : a Two-Stage, Multicenter, Prospective, Open-Label Study

PurposeTo assess the efficacy and safety of panzyga® (intravenous immunoglobulin 10%) in preventing serious bacterial infections (SBIs) in patients with primary immunodeficiency diseases (PIDs), a prospective, open-label, multicenter, phase 3 study and an open-label extension study were undertaken.MethodsInitially, the study drug (infusion rate ≤0.08 mL/kg/min) was administered at intervals of 3 or 4 weeks for 12 months, followed by 3 months of panzyga® at infusion rates increasing from 0.08 to 0.14 mL/kg/min. The primary endpoint in the main study was the rate of SBIs per patient-year on treatment. Secondary outcomes included non-serious infections, work/school absence, episodes of fever, quality of life, and adverse events (AEs).ResultsThe main study enrolled 51 patients (35% female, mean age 26.8 years), with 21 participating in the extension study. The rate of SBIs per patient-year was 0.08 in the total population; there were four SBIs in the 4-weekly treatment group (2/30 patients) and none in the 3-weekly group (n = 21). Compared with 4-weekly treatment, 3-weekly treatment was associated with a higher rate of upper respiratory tract infections (RTIs), ear infections, and work/school absences, but a lower rate of lower RTIs and fever. Treatment was generally well tolerated; no AE led to treatment withdrawal or death.ConclusionsOverall, the use of panzyga® in patients with antibody-deficient PID was associated with a low rate of AEs and was effective in preventing SBIs, exceeding US FDA and European Medicines Agency recommendations for efficacy

Clinical Efficacy, Safety and Tolerability of a New Subcutaneous Immunoglobulin 16.5% (Octanorm [Cutaquig®]) in the Treatment of Patients With Primary Immunodeficiencies

Introduction: Subcutaneously administered immunoglobulin (SCIG) is increasingly used to treat patients with primary immunodeficiencies (PIDs). Octanorm (marketed as cutaquig® in USA and Canada) is a new 16.5% solution of human SCIG, manufactured by a process based on that of the intravenous preparation (IVIG) octagam®.Objectives: To investigate the efficacy, safety and tolerability of octanorm in a prospective, open-label, single-arm phase 3 study involving adult and pediatric patients with PIDs (NCT01888484; clinicaltrials.gov/ct2/show/NCT01888484).Methods: Patients who were previously treated with IVIG received a total of 64 weekly SCIG infusions, including 12 weekly infusions during the wash-in/wash-out period, followed by 52 weekly infusions during the evaluation period.Results: A total of 61 patients aged 2–73 years received 3,497 infusions of octanorm. The mean dose per patient was 0.175 g/kg/infusion. The mean calculated dose conversion factor from the patients' previous IVIG dose for octanorm was 1.37. No serious bacterial infections developed during the study. The rate of other infections per person-year during the primary observation period was 3.43 (upper 95% CI 4.57). All but one non-bacterial infection were mild or moderate in intensity. IgG trough levels were constant during the course of the study. Eleven patients (18.0%) experienced 14 mild or moderate systemic adverse events (AEs) related to octanorm. The rate of related AEs per infusion was 0.004. In 76.7% of infusions, no infusion site reactions were observed and only two (0.3%) reactions were deemed severe. The incidence of site reactions decreased with successive infusions.Conclusion: The new 16.5% SCIG octanorm was shown to be efficacious in preventing infections in PIDs, and was well tolerated

Radio observational constraints on Galactic 3D-emission models

(Abridged) We constrain simulated all-sky maps in total intensity, linear polarization, and rotation measure (RM) by observations. We test a number of large-scale magnetic field configurations and take the properties of the warm interstellar medium into account. From a comparison of simulated and observed maps we are able to constrain the regular large-scale Galactic magnetic field in the disk and the halo of the Galaxy. The local regular field is 2 microG and the average random field is about 3 microG. The known local excess of synchrotron emission originating either from enhanced CR electrons or random magnetic fields is able to explain the observed high-latitude synchrotron emission. The thermal electron model (NE2001) in conjunction with a proper filling factor accounts for the observed optically thin thermal emission and low frequency absorption by optically thick emission. A coupling factor between thermal electrons and the random magnetic field component is proposed, which in addition to the small filling factor of thermal electrons increases small-scale RM fluctuations and thus accounts for the observed depolarization at 1.4 GHz. We conclude that an axisymmetric magnetic disk field configuration with reversals inside the solar circle fits available observations best. Out of the plane a strong toroidal magnetic field with different signs above and below the plane is needed to account for the observed high-latitude RMs. Our preferred 3D-model fits the observations better than other models over a wide frequency range.Comment: 20 pages, 19 figures, accepted for publication in A&A, for full resolution version see ftp://ftp.mpifr-bonn.mpg.de/outgoing/p098wre/sun-etal.pd

Induced pseudoscalar coupling of the proton weak interaction

The induced pseudoscalar coupling $g_p$ is the least well known of the weak coupling constants of the proton's charged--current interaction. Its size is dictated by chiral symmetry arguments, and its measurement represents an important test of quantum chromodynamics at low energies. During the past decade a large body of new data relevant to the coupling $g_p$ has been accumulated. This data includes measurements of radiative and non radiative muon capture on targets ranging from hydrogen and few--nucleon systems to complex nuclei. Herein the authors review the theoretical underpinnings of $g_p$, the experimental studies of $g_p$, and the procedures and uncertainties in extracting the coupling from data. Current puzzles are highlighted and future opportunities are discussed.Comment: 58 pages, Latex, Revtex4, prepared for Reviews of Modern Physic

Estimating Genetic Variability in Non-Model Taxa: A General Procedure for Discriminating Sequence Errors from Actual Variation

Genetic variation is the driving force of evolution and as such is of central interest for biologists. However, inadequate discrimination of errors from true genetic variation could lead to incorrect estimates of gene copy number, population genetic parameters, phylogenetic relationships and the deposition of gene and protein sequences in databases that are not actually present in any organism. Misincorporation errors in multi-template PCR cloning methods, still commonly used for obtaining novel gene sequences in non-model species, are difficult to detect, as no previous information may be available about the number of expected copies of genes belonging to multi-gene families. However, studies employing these techniques rarely describe in any great detail how errors arising in the amplification process were detected and accounted for. Here, we estimated the rate of base misincorporation of a widely-used PCR-cloning method, using a single copy mitochondrial gene from a single individual to minimise variation in the template DNA, as 1.62×10−3 errors per site, or 9.26×10−5 per site per duplication. The distribution of errors among sequences closely matched that predicted by a binomial distribution function. The empirically estimated error rate was applied to data, obtained using the same methods, from the Phospholipase A2 toxin family from the pitviper Ovophis monticola. The distribution of differences detected closely matched the expected distribution of errors and we conclude that, when undertaking gene discovery or assessment of genetic diversity using this error-prone method, it will be informative to empirically determine the rate of base misincorporation

Up-regulation of multiple proteins and biological processes during maxillary expansion in rats

<p>Abstract</p> <p>Background</p> <p>Maxillary expansion (ME) is a common practice in orthodontics that aims to increase the constricted maxillary arch width. Relapse often occurs, however, and better treatment strategies are needed. In order to develop a more effective method, this study was designed to further examine the process of tissue remodeling during ME, to identify the changes in expression of several proteins of interest, and to clarify the molecular mechanism responsible for tissue remodeling.</p> <p>Methods</p> <p>Male Wistar rats were randomly divided into control and ME groups. The rats were euthanized at various intervals over 11 days, and the dissected palates were prepared for histological examination. The structure of the midpalatal sutures changed little during the first three days. Proteins from samples in the ground midpalatal tissues obtained on the third day were subjected to two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis. Validation of protein expression was performed by Western blot analyses.</p> <p>Results</p> <p>From day 5, chondrocytes in the inner layer of suture cartilage and osteoblasts at the end of the suture cartilage began to proliferate, and the skeletal matrix increased later adjacent to the cartilage in the ME group. Comparative proteomic analysis showed increases in 22 protein spots present in the ME group. The changes in three proteins closely related to osteogenesis (parathyroid hormone, osteoprotegerin and vimentin) were confirmed by Western blotting.</p> <p>Conclusion</p> <p>Many proteins are over-expressed during ME, and they may play an important role in the remodeling process.</p

LARGE Expression Augments the Glycosylation of Glycoproteins in Addition to α-Dystroglycan Conferring Laminin Binding

Mutations in genes encoding glycosyltransferases (and presumed glycosyltransferases) that affect glycosylation and extracellular matrix binding activity of α-dystroglycan (α-DG) cause congenital muscular dystrophies (CMDs) with central nervous system manifestations. Among the identified genes, LARGE is of particular interest because its overexpression rescues glycosylation defects of α-DG in mutations of not only LARGE but also other CMD-causing genes and restores laminin binding activity of α-DG. It is not known whether LARGE protein glycosylates other proteins in addition to α-DG. In this study, we overexpressed LARGE in DG-deficient cells and analyzed glycosylated proteins by Western blot analysis. Surprisingly, overexpression of LARGE in α-DG-deficient cells led to glycosylation dependent IIH6C4 and VIA4-1 immunoreactivity, despite the prevailing view that these antibodies only recognize glycosylated α-DG. Furthermore, the hyperglycosylated proteins in LARGE-overexpressing cells demonstrated the functional capacity to bind the extracellular matrix molecule laminin and promote laminin assembly at the cell surface, an effect that was blocked by IIH6C4 antibodies. These results indicate that overexpression of LARGE catalyzes the glycosylation of at least one other glycoprotein in addition to α-DG, and that this glycosylation(s) promotes laminin binding activity

Search for Higgs Bosons in e+e- Collisions at 183 GeV

The data collected by the OPAL experiment at sqrts=183 GeV were used to search for Higgs bosons which are predicted by the Standard Model and various extensions, such as general models with two Higgs field doublets and the Minimal Supersymmetric Standard Model (MSSM). The data correspond to an integrated luminosity of approximately 54pb-1. None of the searches for neutral and charged Higgs bosons have revealed an excess of events beyond the expected background. This negative outcome, in combination with similar results from searches at lower energies, leads to new limits for the Higgs boson masses and other model parameters. In particular, the 95% confidence level lower limit for the mass of the Standard Model Higgs boson is 88.3 GeV. Charged Higgs bosons can be excluded for masses up to 59.5 GeV. In the MSSM, mh > 70.5 GeV and mA > 72.0 GeV are obtained for tan{beta}>1, no and maximal scalar top mixing and soft SUSY-breaking masses of 1 TeV. The range 0.8 < tanb < 1.9 is excluded for minimal scalar top mixing and m{top} < 175 GeV. More general scans of the MSSM parameter space are also considered.Comment: 49 pages. LaTeX, including 33 eps figures, submitted to European Physical Journal