Long-Term Safety and Efficacy of Mepolizumab in Eosinophilic Granulomatosis With Polyangiitis.

Objectives: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, relapsing, inflammatory disease. Management of EGPA predominantly relies on oral corticosteroids (OCS), which are associated with many adverse effects. The Phase III MIRRA trial demonstrated efficacy and safety of mepolizumab, anti-interleukin-5 biologic, for EGPA.

GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis.

Background: GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell-mediated diseases, including atopic dermatitis (AD).

Objective: This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD.

Submillihertz magnetic spectroscopy performed with a nanoscale quantum sensor.

Precise timekeeping is critical to metrology, forming the basis by which standards of time, length, and fundamental constants are determined. Stable clocks are particularly valuable in spectroscopy because they define the ultimate frequency precision that can be reached. In quantum metrology, the qubit coherence time defines the clock stability, from which the spectral linewidth and frequency precision are determined.

Sarcoidosis in America. Analysis Based on Health Care Use.

Rationale: There have been no recent comprehensive studies of the epidemiology of sarcoidosis in the United States. Changes in health care use have made available access to data on large numbers of patients with sarcoidosis.

Objectives: To use a U.

Persistence of circulating endothelial microparticles in COPD despite smoking cessation.

Introduction: Increasing evidence links COPD pathogenesis with pulmonary capillary apoptosis. We previously demonstrated that plasma levels of circulating microparticles released from endothelial cells (EMPs) due to apoptosis are elevated in smokers with normal spirometry but low diffusion capacity, that is, with early evidence of lung destruction. We hypothesised that pulmonary capillary apoptosis persists with the development of COPD and assessed its reversibility in healthy smokers and COPD smokers following smoking cessation.

Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation.

Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to healthy nonsmokers. Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy.

Intraflagellar transport gene expression associated with short cilia in smoking and COPD.

Smoking and COPD are associated with decreased mucociliary clearance, and healthy smokers have shorter cilia in the large airway than nonsmokers. We hypothesized that changes in cilia length are consistent throughout the airway, and we further hypothesized that smokers with COPD have shorter cilia than healthy smokers. Because intraflagellar transport (IFT) is the process by which cilia of normal length are produced and maintained, and alterations in IFT lead to short cilia in model organisms, we also hypothesized that smoking induces changes in the expression of IFT-related genes in the airway epithelium of smokers and smokers with COPD.

Vasodilatory effect of the stable vasoactive intestinal peptide analog RO 25-1553 in murine and rat lungs.

Rationale: Stable analogs of vasoactive intestinal peptide (VIP) have been proposed as novel line of therapy in chronic obstructive pulmonary disease (COPD) based on their bronchodilatory and anti-inflammatory effects. We speculated that VIP analogs may provide additional benefits in that they exert vasodilatory properties in the lung, and tested this hypothesis in both ex vivo and in vivo models.

Methods: In isolated perfused mouse lungs and in an in vivo rat model, pulmonary blood vessels were preconstricted by hypoxia and hemodynamic changes in response to systemic (ex vivo) or inhaled (in vivo) administration of the cyclic VIP analog RO 25-1553 were determined.

Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease.

Rationale: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost.

Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemic biomarker identified in this study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics.

Methods: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study.

Microdeletion 5q14.3 and anomalies of brain development.

5q14.3 deletions spanning and flanking MEF2C as well as intragenic MEF2C mutations have recently been described as a cause of severe intellectual disability, epilepsy, and muscular hypotonia, with variable brain and other anomalies. With an increasing number of patients described, the clinical presentation of the patients appears to be relatively uniform, however the structural brain phenotypes described are variable.

Novel mutations including deletions of the entire OFD1 gene in 30 families with type 1 orofaciodigital syndrome: a study of the extensive clinical variability.

OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson-Golabi-Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1.

Mental health and quality of life after genetic testing for Huntington disease: a long-term effect study in Germany.

Predictive genetic testing for Huntington disease (HD) might cause severe short-term psychological reactions in patients with poor mental health. Very few studies exist on the long-term effects of genetic HD testing. The aim of this study was to assess mental health and quality of life in persons who were tested for HD mutation, to compare mental health depending on the result of the genetic test (non-carriers, gene carriers, and patients with HD) and to identify predictors of mental health and quality of life via linear regression.

Effects of the pan-selectin antagonist bimosiamose (TBC1269) in experimental human endotoxemia.

Selectins mediate the adhesion of leukocytes to activated endothelial cells and activated platelets. In addition to these cell-to-cell interactions, they influence the fibrin content and size of venous thrombi in different animal models. However, the exact role of selectins in human endotoxemia still remains unclear.

The pharmacokinetics of subcutaneously injected Bimosiamose disodium in healthy male volunteers.

Bimosiamose is a novel synthetic pan-selectin antagonist developed for the treatment of acute and chronic inflammatory disorders. Therefore the pharmacokinetics of Bimosiamose disodium were studied in healthy male volunteers after single and multiple subcutaneous injections. A randomized, double-blind, placebo-controlled dose escalation trial was carried out.

Molecular modeling of the myosin-S1(A1) isoform.

Type II myosin is the molecular motor which drives contraction upon cyclic interaction with filamentous actin while consuming ATP. The contemporary crystallographic structure of the myosin subfragment-1 (S1) of myosin covers both the motor domain of the heavy chain (MHC) as well as the essential (ELC) and regulatory light chains (RLC). A part of the N-terminus of the ELC is, however, missing in the 3D-models of Type II myosin.

Rational design of novel, potent small molecule pan-selectin antagonists.

This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity.

Tolerability and pharmacokinetics of inhaled bimosiamose disodium in healthy males.

Aims: The aim of these first-in-human studies was to investigate the tolerability and the pharmacokinetics of bimosiamose disodium (TBC1269Z) administered by inhalation.

Methods: Two randomized, double-blind, placebo-controlled Phase I trials were performed in healthy males. In a single-dose escalating study 48 subjects received doses of 2-140 mg bimosiamose disodium by inhalation and in a multiple-dose study 32 subjects received 8-70 mg bimosiamose disodium twice daily.

Therapeutic potential of selectin antagonists in psoriasis.

Psoriasis is a systemic chronic inflammatory disorder. One of the major characteristics is an excess of infiltration of inflammatory cells, mainly lymphocytes, into the skin. Because the adhesion family of selectins is suggested to play a relevant role in this process, selectins have emerged as an interesting target for drug discovery and development in psoriasis.

Pan-selectin antagonism improves psoriasis manifestation in mice and man.

The selectin family of vascular cell adhesion molecules is comprised of structurally related carbohydrate binding proteins, which mediate the initial rolling of leukocytes on the activated vascular endothelium. Because this process is one of the crucial events in initiating and maintaining inflammation, selectins are proposed to be an attractive target for the development of new antiinflammatory therapeutics. Here, we demonstrate that the synthetic pan-selectin antagonist bimosiamose is effective in pre-clinical models of psoriasis as well as in psoriatic patients.

Bimosiamose, an inhaled small-molecule pan-selectin antagonist, attenuates late asthmatic reactions following allergen challenge in mild asthmatics: a randomized, double-blind, placebo-controlled clinical cross-over-trial.

Background: Asthma is characterized by increased recruitment of inflammatory cells from the circulation into the airways. As selectins mediate tethering and rolling of leukocytes on the vascular endothelium, they constitute a promising target for the therapeutic modulation of inflammation. We evaluated the effect of inhaled bimosiamose (TBC1269), a synthetic pan-selectin antagonist, on allergen-induced late asthmatic reactions (LAR) in mild asthmatics.

Assisted reproductive techniques in patients with Klinefelter syndrome: a critical review.

Objective: To summarize the existing experience with the use and success rate of assisted reproductive techniques (ART), in particular testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI), in Klinefelter patients.

Design: A systematic review of the literature, including all published case reports to date.

Patient(s): Thirty-nine reported successful pregnancies fathered by nonmosaic Klinefelter patients.

Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene.

Ehlers-Danlos syndrome (EDS) type VIIC, or dermatosparactic type, is a recessively inherited connective tissue disorder characterized, among other symptoms, by an extreme skin fragility resulting from mutations inactivating ADAMTS-2, an enzyme excising the aminopropeptide of procollagens type I, II, and III. All previously described mutations create premature stop codons leading to a marked reduction in the level of mRNA. In this study, we analyzed the ADAMTS2 cDNA sequences from five patients displaying clinical and/or biochemical features consistent with a diagnosis of either typical or potentially mild form of EDS type VIIC.

In focus. Has patient autonomy gone to far? Geneticists' views in 36 nations.

We surveyed genetics professionals, patients, and the public about rights to information, to requested services, and to parenthood, posing difficult cases found in practice. In all, 2906 genetics professionals (63%), 499 primary care physicians (59%), 476 North American genetics patients (67%), 394 French patients (51%), 593 German patients (65%), and 988 members of the American public (99%) returned anonymous questionnaires. Results suggest a trend toward increased respect for patient autonomy since an earlier survey in 1985; in most nations more would perform prenatal diagnosis for a couple with 4 daughters who desire a son.

[Genetic view of the development of the human embryo--the importance of chromosome abnormalities].

Normal embryonic and fetal development requires a diploid chromosome set consisting of a haploid maternal and a haploid paternal chromosome set. Chromosome abnormalities in the zygote are not a rare event, however. Moreover postzygotically different types of aberrations can occur, with different effects on embryonic development.

Analysis of the energetic state of heart cells after adenovirus-mediated expression of hALC-1.

Expression of the human atrial myosin light chain 1 (hALC-1) in the cardiac ventricle in vivo as well as in primary cultivated adult cardiomyocytes caused a pronounced positive inotropic effect. Therefore, it is one of the most promising candidate gene to treat congestive heart failure (CHF). In this work, we investigated, whether hALC-1 expression also modifies the energetic state of cardiomyocytes.