Physical Characterization and Innate Immunogenicity of Aggregated Intravenous Immunoglobulin (IGIV) in an In Vitro Cell-Based Model.

Purpose: To investigate in vitro the innate immune response to accelerated stress-induced aggregates of intravenous immunoglobulin (IGIV) using a well-defined human cell-line model, and to correlate the innate response to physical properties of the aggregates.

Methods: IGIV aggregates were prepared by applying various accelerated stress methods, and particle size, count and structure were characterized. Immune cell activation as tracked by inflammatory cytokines released in response to aggregates was evaluated in vitro using peripheral blood mononuclear cells (PBMC), primary monocytes and immortalized human monocyte-like cell lines.

AFM Imaging Reveals Topographic Diversity of Wild Type and Z Variant Polymers of Human α1-Proteinase Inhibitor.

α1-Proteinase inhibitor (antitrypsin) is a canonical example of the serpin family member that binds and inhibits serine proteases. The natural metastability of serpins is crucial to carry out structural rearrangements necessary for biological activity. However, the enhanced metastability of the mutant Z variant of antitrypsin, in addition to folding defect, may substantially contribute to its polymerization, a process leading to incurable serpinopathy.

Subvisible Particle Content, Formulation, and Dose of an Erythropoietin Peptide Mimetic Product Are Associated With Severe Adverse Postmarketing Events.

Peginesatide (Omontys(®); Affymax, Inc., Cupertino, CA) was voluntarily withdrawn from the market less than a year after the product launch. Although clinical trials had demonstrated the drug to be safe and efficacious, 49 cases of anaphylaxis, including 7 fatalities, were reported not long after market introduction.

Analyzing subvisible particles in protein drug products: a comparison of dynamic light scattering (DLS) and resonant mass measurement (RMM).

Aggregation is common in protein drug manufacture, and while the effects of protein particulates are under investigation, many techniques applicable for their characterization have been recently developed. Among the methods available to characterize and quantify protein aggregates, none is applicable over the full size range and different methods often give conflicting results. The studies presented here compare two such methods: dynamic light scattering (DLS) and resonant mass measurement (RMM).

Workshop on predictive science of the immunogenicity aspects of particles in biopharmaceutical products.

Particles in protein therapeutics and concerns for a potential correlation with product immunogenicity are increasingly becoming the focus of recent publications and scientific forums. The consensus of academic, industrial, and regulatory scientists is that this area is not well understood and will require in-depth research because of the potential impact on the product safety and efficacy. This commentary presents a summary of the 1-day workshop entitled "Predictive Science of the Immunogenicity Aspects of Particles in Biopharmaceutical Products," which discussed the current state of analytical resources for quantitation and characterization of protein aggregates and potential paths for developing predictive preclinical tools.

An international collaborative study to establish the WHO 1st international standard for alpha-1-antitrypsin.

Background And Objectives: The aim was to establish the 1st International Standard (IS) for alpha-1-antitrypsin (AAT) to standardise potency assignment of therapeutic products, calibrated in moles and mg active AAT in line with product labelling practice. Assigning total protein and antigen values to the IS was also investigated.

Materials And Methods: The active concentration of four candidate AAT preparations was determined in an international collaborative study by inhibition of trypsin (calibrated by active-site titration).

Melatonin and childhood refractory epilepsy--a pilot study.

Background: The aim of the study was to assess diurnal melatonin secretion in children with refractory epilepsy (N=74) as compared to children without epileptic seizures (N=37) and to compare melatonin secretion in children with focal and generalized refractory epilepsy.

Material/methods: In the study group 4 subgroups were defined: children with focal symptomatic epilepsy, focal cryptogenic epilepsy, generalized symptomatic epilepsy, and generalized cryptogenic epilepsy. Melatonin level was measured every 3 hours using the RIA method.

Meeting report on protein particles and immunogenicity of therapeutic proteins: filling in the gaps in risk evaluation and mitigation.

This meeting was successful in achieving its main goals: (1) summarize currently available information on the origin, detection, quantification and characterization of sub-visible particulates in protein products, available information on their clinical importance, and potential strategies for evaluating and mitigating risk to product quality, and (2) foster communication among academic, industry, and regulatory scientists to define the capabilities of current analytical methods, to promote the development of improved methods, and to stimulate investigations into the impact of large protein aggregates on immunogenicity. There was a general consensus that a considerable amount of interesting scientific information was presented and many stimulating conversations were begun. It is clear that this aspect of protein characterization is in its initial stages.

Association between lipids and fibrinogen levels and ischemic stroke in the population of the Polish children with arteriopathy and cardiac disorders.

Introduction: The ischemic stroke is a rare problem in childhood. Cardiac problems, arteriopathy, coaguopathies or dyslipidemia are traditional risk factors for stroke. The aim of the present study was to assess the relations between levels of lipids and fibrinogen and stroke among Polish children.

Platelet and intestinal 5-HT2A receptor mRNA in autistic spectrum disorders - results of a pilot study.

The etiology and pathogenesis of autistic spectrum disorders (ASD) are still unknown. Platelet hyperserotonemia has been detected in 25-60% of autistic children. Higher incidence of gastrointestinal problems in people with autism is observed.

Do children with Adams-Oliver syndrome require endocrine follow-up? New information on the phenotype and management.

Adams-Oliver syndrome (AOS) is a rare genetic condition in which the main diagnostic criteria are terminal transverse limb defects and aplasia cutis congenita. Within the spectra of the clinical phenotype of AOS, anthropometric abnormalities have also been reported. We present growth pattern along with hormonal assays in three patients with AOS, one being treated with growth hormone (GH).

[Sudden infant death syndrome--current opinions on etiology and pathogenesis].

Sudden infant death syndrome (SIDS) remains still unsolved medical entity. At present about 80 theories and hypotheses concerning SIDS exist. The authors describe current opinions concerning SIDS pathogenesis and etiology.

Maternal phenylketonuria.

The maternal phenylketonuria (MPKU) syndrome is an example of biochemical teratogenesis caused by high phenylalanine concentrations in serum of a pregnant woman (over 360 micromol/L). Active transport through the placenta increases 1.5-fold the phenylalanine level in the child's blood as compared to concentrations recorded in the mother.

The T allele of the 677C>T polymorphism of methylenetetrahydrofolate reductase gene is associated with an increased risk of ischemic stroke in Polish children.

Ischemic stroke is a very rare and multifactorial disease in children. The aim of the study was to analyze the relationship between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and stroke in Polish children and to observe whether there is any significant transmission of MTHFR alleles from heterozygous parents to their affected offspring. We analyzed 64 patients with stroke, 122 parents, and 59 healthy children.

[Situation-related seizures in patients at developmental age].

The seizures which accompany specified situations occur in about 5% of population. They are frequent in patients at developmental age due to a different degree of brain maturity. A single, occasional seizure event which occurs in specified situations is not an epilepsy but it constitutes a significant clinical problem which requires a thorough diagnostics and procedure.

[Back pain in children].

Back pain and pain of the surrounding structures leads to significant diagnostic and therapeutic difficulties which result from a complex pathomechanism. They are the symptom of a large number of pathologic processes that may to a varying extent contribute to pain related manifestation of symptoms. In 80-90% of cases the cause of the back pain remains unknown, only in 10-20% adult patients it is feasible to establish the etiological factor during one year observation.

CDG type Ia and congenital cytomegalovirus infection: two coexisting conditions.

Congenital disorders of glycosylation are a heterogeneous group of disorders with multisystemic involvement. The most common form is phosphomannomutase deficiency or congenital disorders of glycosylation type Ia with an autosomal recessive inheritance and incidence estimated at 1/20000-1/50000 live born. Congenital disorders of glycosylation Ia can manifest as severe multisystemic disease of infancy or milder disorder with only neurological problems including ataxia, hypotonia, and psychomotor retardation.

[A first convulsive seizure in children--diagnostic procedures and treatment].

The Authors discusses in succession: acute symptomatic seizures, diagnostic program age-related (studies in neonatal convulsions and newborn seizures), general treatment principles as well as a seizure recurrence percentage after a single seizure and management after a first seizure.

[Diagnostic problems with long QT syndrome in 5-year-old boy].

The authors described the case of 5-year-old boy, in whom a proper diagnosis was established after 19 months. In differential diagnosis, epileptic, tetanic and conversion seizures were taken into consideration.

[Chickenpox--neurological complications in children].

Chickenpox is one of the most common infectious diseases in children. In most of the cases the disease is mild and no complications of it are being observed. However, in some of the paediatric patients, the disease may have a serious course with different complications.

Lipid raft disease? A new severe congenital myopathy.

We report a 5-year-old girl with a unique neuromuscular disorder manifested by early onset of the disease, delayed motor development, joint contractures, dysmorphy, cobbler's chest, generalized muscle hypoplasia and weakness. Morphological examination revealed muscle cell immaturity and the appearance of multilamellar myelin-like structures within and outside the sarcolemma. Overexpression of aberrant lipids on the surface of affected muscle cells may suggest some failure in lipid raft formation.

Clinical and neuropathological picture of familial encephalopathy with bifunctional protein deficiency.

Peroxisomal diseases are a heterogeneous group of genetic metabolic disorders which are caused by incorrect biogenesis of peroxisomes or a defect in activity of particular enzymes located in those organelles.D-bifunctional protein (D-BP) deficiency belongs to the second group of peroxisomal diseases characterised by dysfunction of a single peroxisomal enzyme. Bifunctional protein is a catalyst in the second and third stage of the beta-oxidation of fatty acids.

A novel PANK2 gene mutation: clinical and molecular characteristics of patients short communication.

Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive neurodegenerative disorder with autosomal recessive inheritance. The major symptoms of PKAN include the onset before the age of 20 years, progressive pyramidal and extrapyramidal signs, retinitis pigmentosa, optic atrophy, dementia, and iron depositions in the globus pallidus. The authors present 3 patients with proven molecular diagnosis of PKAN, in whom 2 novel mutations of PANK2 gene have been identified.

Angelman syndrome and hypothyroidism - coincidence or unique correlation?

Angelman Syndrome (AS, MIM 105830), classified among neurogenetic disorders, occurs with estimated frequency of 1:10 000 to 1:40 000. The characteristics features apart from neurodevelopmental impairment and seizures include peculiar face traits, absent speech, outburst of laughter, ataxia, stereotyped jerky (puppet-like) movements. The authors report three children with Angelman syndrome who were also diagnosed with hypothyroidism.