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Purpose: Mutations in TCP-1 ring complex (TRiC) have been associated with Leber Congenital Amaurosis (LCA). TRiC is involved in protein folding and has 8 essential subunits including CCT5. Herein, we studied the retina of TRiC mutant zebrafish to evaluate the possible role of impaired actin and tubulin folding in LCA. Methods: The cct5tf 212b retina was histologically studied using Toluidine Blue staining as well as TUNEL, BrdU-labeling, and Phalloidin assays. Retinal organisation was assessed by quantification of the cellularity utilising DAPI. Results: Laminar organization of cct5tf 212b retinas was intact. Enhanced apoptosis throughout the cct5tf 212b retina was not compensated by higher proliferation rates, leaving the cct5tf 212b retina smaller in size. Quantification of retinal layer cellularity demonstrated that specifically the numbers of the amacrine and the retinal ganglion cells were depleted, suggesting that the cct5tf 212b retina was not uniformly affected by the reduced actin folding. Conclusion: Whereas the current literature suggests that LCA is predominantly affecting retinal photoreceptor cells and the retinal pigment epithelium, cct5tf 212b analyses demonstrated the important role of folding of actin by TRiC, suggesting that cct5

Duchenne muscular dystrophy is a severe muscle wasting disease caused by mutations in the dystrophin gene (dmd). Ataluren has been approved by the European Medicines Agency for treatment of Duchenne muscular dystrophy. Ataluren has been reported to promote ribosomal read‐through of premature stop codons, leading to restoration of full‐length dystrophin protein. However, the mechanism of Ataluren action has not been fully described. To evaluate the efficacy of Ataluren on all three premature stop codons featuring different termination strengths (UAA > UAG > UGA), novel dystrophin‐deficient zebrafish were generated. Pathological assessment of the muscle by birefringence quantification, a tool to directly measure muscle integrity, did not reveal a significant effect of Ataluren on any of the analysed dystrophin‐deficient mutants at 3 days after fertilization. Functional analysis of the musculature at 6 days after fertilization by direct measurement of the generated force revealed a significant improvement by Ataluren only for the UAA‐carrying mutant dmdta222a. Interestingly however, all other analysed dystrophin‐deficient mutants were not affected by Ataluren, including the dmdpc3 and dmdpc2 mutants that harbour weaker premature stop codons UAG and UGA, respectively. These in vivo results contradict reported in vitro data on Ataluren efficacy, suggesting that Ataluren might not promote read‐through of premature stop codons. In addition, Ataluren had no effect on dystrophin transcript levels, but mild adverse effects on wild‐type larvae were identified. Further assessment of N‐terminally truncated dystrophin opened the possibility of Ataluren promoting alternative translation codons within dystrophin, thereby potentially shifting the patient cohort applicable for Ataluren.

Significance Paneth cells provide intestinal host defense against pathogens and control the healthy microbiota by secreting antimicrobial peptides. We show that the most abundant secreted Paneth cell products, human defensin HD-5 and HD-6, show a distinct susceptibility to proteolytic digestion by human duodenal fluid. While HD-5 is digested in many fragments, HD-6 is stable and still able to form nanonets. The occurring fragments of HD-5 were antimicrobially active against microorganisms. We provide proof of concept about microbiome modulating capacities in vivo, which includes an increase of Akkermansia sp. Our results indicate that fragmentation of defensins increases antimicrobial diversity and further adds to the complexity of host microbial interaction at interfaces. Fragmentation could lead to new antimicrobial peptides with possible therapeutic usage., Antimicrobial peptides, in particular α-defensins expressed by Paneth cells, control microbiota composition and play a key role in intestinal barrier function and homeostasis. Dynamic conditions in the local microenvironment, such as pH and redox potential, significantly affect the antimicrobial spectrum. In contrast to oxidized peptides, some reduced defensins exhibit increased vulnerability to proteolytic degradation. In this report, we investigated the susceptibility of Paneth-cell–specific human α-defensin 5 (HD-5) and -6 (HD-6) to intestinal proteases using natural human duodenal fluid. We systematically assessed proteolytic degradation using liquid chromatography–mass spectrometry and identified several active defensin fragments capable of impacting bacterial growth of both commensal and pathogenic origins. Of note, incubation of mucus with HD-5 resulted in 255–8,000 new antimicrobial combinations. In contrast, HD-6 remained stable with consistent preserved nanonet formation. In vivo studies demonstrated proof of concept that a HD-5 fragment shifted microbiota composition (e.g., increases of Akkermansia sp.) without decreasing diversity. Our data support the concept that secretion of host peptides results in an environmentally dependent increase of antimicrobial defense by clustering in active peptide fragments. This complex clustering mechanism dramatically increases the host’s ability to control pathogens and commensals. These findings broaden our understanding of host modulation of the microbiome as well as the complexity of human mucosal defense mechanisms, thus providing promising avenues to explore for drug development.

The liver-derived plasma protein fetuin B is associated with nonalcoholic fatty liver disease (NAFLD) and impaired glucose homeostasis in mice. However, its association with non-invasive ultrasound- and magnetic resonance (MR)-based markers of liver fibrosis and steatosis, the enhanced liver fibrosis (ELF) score, liver biopsy, as well as rs738409 in PNPLA3, has not been elucidated in NAFLD, so far. The association of circulating fetuin B and transient elastography (TE), controlled attenuation parameter (CAP), 1H-MR-spectroscopy, the ELF score, liver biopsy, as well as risk alleles in rs738409 in PNPLA3, was studied in 101 NAFLD patients as compared to 15 healthy controls. Serum fetuin B levels did not differ between NAFLD patients and controls (p = 0.863). Fetuin B was independently and negatively associated with transient elastography liver stiffness measurement (LSM) (p = 0.002), but not with the steatosis markers CAP or 1H-MR-spectroscopy. Fetuin B serum concentrations were significantly lower in individuals with LSM > 7.0 kPa as compared to patients with LSM

How could the ideal of a universal brotherhood of mankind be realized in an age of nationalism, colonialism and culture wars? "With God, for fatherland and humanity?" is the first comprehensive study of masonic internationalism. It explores, with a focus on England, France, Germany, and Italy, how European masonic associations promoted or opposed a worldwide organisation of the "brotherhood". It argues that the transnational efforts before and after the First World War ended up reinforcing the differences they set out to overcome.

This article demonstrates the interplay between national, international and transatlantic dimensions within fraternalism. From the late nineteenth century, masonic lodges took part in the broader push towards the formation of transnational organisations and institutions. They were mainly based in western and southwestern Europe. However, transatlantic channels were established that went beyond the individual and local level. The article analyses these waves of transatlantic brothering and relates them to the tides of confrontation and rapprochement between the United States and Europe. It argues that the First World War marked a moment of intensified interactions when English and French masonries rivalled over the Americans’ favour, followed by a period in which transatlantic internationalist initiatives were shaped by masons based in New York. These inner-masonic alliances embraced the rationale of international relations in the realm of state policy and promised to overcome the divides between the various camps in European and World freemasonry.

Klippel–Feil syndrome is a congenital vertebral anomaly, which is characterised by the fusion of at least two cervical vertebrae and a clinically broad set of symptoms, including congenital scoliosis and elevated scapula (Sprengel's deformity). Klippel–Feil syndrome is associated with mutations in MEOX1. The zebrafish mutant choker (cho) carries a mutation in its orthologue, meox1. Although zebrafish is being increasingly employed as fidelitous models of human spinal disease, the vertebral column of Meox1‐deficient fish has not been assessed for defects. Here, we describe the skeletal defects of meox1 (cho) mutant zebrafish utilising alizarin red to stain bones and chemical maceration of soft tissue to detect fusions in an unbiased manner. Obtained data reveal that meox1 (cho) mutants feature aspects of a number of described symptoms of patients who suffer from Klippel–Feil syndrome and have mutations in MEOX1. These include vertebral fusion, congenital scoliosis and an asymmetry of the pectoral girdle, which resembles Sprengel's deformity. Thus, the meox1 (cho) mutant zebrafish may serve as a useful tool to study the pathogenesis of the symptoms associated with Klippel–Feil syndrome.

The ADAMTS5 metzincin, a secreted zinc-dependent metalloproteinase, modulates the extracellular matrix (ECM) during limb morphogenesis and other developmental processes. Here, the role of ADAMTS5 was investigated by knockdown of zebrafish adamts5 during embryogenesis. This revealed impaired Sonic Hedgehog (Shh) signaling during somite patterning and early myogenesis. Notably, synergistic regulation of myod expression by ADAMTS5 and Shh during somite differentiation was observed. These roles were not dependent upon the catalytic activity of ADAMTS5. These data identify a non-enzymatic function for ADAMTS5 in regulating an important cell signaling pathway that impacts on muscle development, with implications for musculoskeletal diseases in which ADAMTS5 and Shh have been associated.

Summary: The TCP-1 ring complex (TRiC) is a multi-subunit group II chaperonin that assists nascent or misfolded proteins to attain their native conformation in an ATP-dependent manner. Functional studies in yeast have suggested that TRiC is an essential and generalized component of the protein-folding machinery of eukaryotic cells. However, TRiC’s involvement in specific cellular processes within multicellular organisms is largely unknown because little validation of TRiC function exists in animals. Our in vivo analysis reveals a surprisingly specific role of TRiC in the biogenesis of skeletal muscle α-actin during sarcomere assembly in myofibers. TRiC acts at the sarcomere’s Z-disk, where it is required for efficient assembly of actin thin filaments. Binding of ATP specifically by the TRiC subunit Cct5 is required for efficient actin folding in vivo. Furthermore, mutant α-actin isoforms that result in nemaline myopathy in patients obtain their pathogenic conformation via this function of TRiC. : TRiC-deficient zebrafish feature specific defects in sarcomere and neurite formation. Berger et al. demonstrate a role for TRiC as a multiprotein scaffold positioned at the sarcomere’s Z-disk, where it enhances the processing of skeletal muscle α-actin. Accordingly, TRiC causes aggregation of myopathic α-actin variants in nemaline myopathy. Keywords: CCT, TRiC, chaperonin, folding, actin, zebrafish, muscle, myofibril, tubulin, nemaline myopathy

Nemaline myopathy is an inherited muscle disease that is mainly diagnosed by the presence of nemaline rods in muscle biopsies. Of the nine genes associated with the disease, 5 encode for components of striated muscle sarcomeres. In a genetic zebrafish screen the mutant träge (trg) was isolated based on its reduction in muscle birefringence, indicating muscle damage. Myofibres in trg appeared disorganized and showed inhomogeneous cytoplasmic eosin staining alongside malformed nuclei. Linkage analysis of trg combined with sequencing identified a nonsense mutation in tropomodulin4 (tmod4), a regulator of thin filament length and stability. Accordingly, although actin monomers polymerise to form thin filaments in the skeletal muscle of tmod4trg mutants, thin filaments often appeared to be dispersed throughout myofibres. Organised myofibrils with the typical striation rarely assemble, leading to severe muscle weakness, impaired locomotion, and early death. Myofibrils of tmod4trg mutants often featured thin filaments of various lengths, widened Z-disks, undefined H-zones, and electron-dense aggregations of various shapes and sizes. Importantly, Gomori trichrome staining and the lattice pattern of the detected cytoplasmic rods together with the reactivity of rods with phalloidin and an antibody against actinin is reminiscent of nemaline rods found in nemaline myopathy, suggesting that misregulation of thin filament length causes cytoplasmic rod formation in tmod4trg mutants. Although Tropomodulin4 has not been associated with myopathy, the results presented here implicate TMOD4 as a novel candidate for unresolved nemaline myopathies and suggest that the tmod4trg mutant will be a valuable tool to study human muscle disorders.

The muscle-specific UNC-45b assists in the folding of sarcomeric myosin. Analysis of the zebrafish unc-45b upstream region revealed that unc-45b promoter fragments reliably drive GFP expression after germline transmission. The muscle-specific 503-bp minimal promoter 503unc was identified to drive gene expression in the zebrafish musculature. In transgenic Tg(-503unc:GFP) zebrafish, GFP fluorescence was detected in the adaxial cells, their slow fiber descendants, and the fast muscle. At later stages, robust GFP fluorescence is eminent in the cardiac, cranial, fin, and trunk muscle, thereby recapitulating the unc-45b expression pattern. We propose that the 503unc promoter is a small and muscle-specific promoter that drives robust gene expression throughout the zebrafish musculature, making it a valuable tool for the exploration of zebrafish muscle.

Congenital myopathies are muscle degenerative disorders with a broad clinical spectrum. A number of myopathies have been associated with molecular defects within sarcomeres, the force-generating component of the muscle cell. Whereas the highly regular organization of the myofibril has been studied in detail, in vivo assembly of sarcomeres remains a poorly understood process. Therefore, a more detailed knowledge of sarcomere assembly is crucial to better understand the pathogenic mechanisms within myopathies. Recently, mutations in myosin XVIIIB (MYO18B) have been associated with cases of myopathies, although the underlying mechanism for the resulting pathology remains to be defined. To analyze the role of myosin XVIIIB in skeletal muscle disease, zebrafish mutants for myo18b were generated. Full loss of myo18b function results in a complete lack of sarcomeric structure, revealing a highly surprising and essential role for myo18b in sarcomere assembly. Importantly, scattered thin and thick filaments assemble throughout the sarcoplasm; but fail to organize into recognizable sarcomeric structures in myo18b null mutants. In myo18b partial loss-of-function mutants sarcomeric structures are assembled, but thin and thick filaments remain misaligned within these structures. These observations suggest a novel model of sarcomere assembly where Myo18b coordinates the integration of preformed thick and thin filaments into the sarcomere. Disruption of this highly coordinated process results in a block in sarcomere biogenesis and the onset of myopathic pathology.

Duchenne muscular dystophy (DMD) is a severe muscle wasting disease caused by mutations in the dystrophin gene. By utilizing antisense oligonucleotides, splicing of the dystrophin transcript can be altered so that exons harbouring a mutation are excluded from the mature mRNA. Although this approach has been shown to be effective to restore partially functional dystrophin protein, the level of dystrophin protein that is necessary to rescue a severe muscle pathology has not been addressed. As zebrafish dystrophin mutants (dmd) resemble the severe muscle pathology of human patients, we have utilized this model to evaluate exon skipping. Novel dmd mutations were identified to enable the design of phenotype rescue studies via morpholino administration. Correlation of induced exon-skipping efficiency and the level of phenotype rescue suggest that relatively robust levels of exon skipping are required to achieve significant therapeutic ameliorations and that pre-screening analysis of exon-skipping drugs in zebrafish may help to more accurately predict clinical trials for therapies of DMD.

The interactions between herbivores and plants are of general interest in ecology. Even though the extensive research carried out during the last decades has culminated in many theories, additional studies are necessary to validate these findings. In particular, the hypotheses dealing with the complex interrelations of plant defense mechanisms and herbivores continue to be debated. In this paper, we develop a new indicator value that quantifies the defense mechanisms of Central European woody plants against large mammalian herbivores. The indicator value is based on three plant-specific traits: chemical defense (toxic compounds, digestion inhibitors), mechanical defense and leaf size. Our validation of the newly established indicator shows that evergreen woody plants have a significantly higher indicator value than deciduous woody plants. Moreover, plant defense is correlated with growth height: woody plants growing in the browsing zone preferred by large mammalian herbivores have significantly higher levels of defense compared with woody plants capable of growth high above the reach of large herbivores. We conclude that the new plant defense indicator value is a valuable tool for the validation of existing hypotheses and habitat calibration on a statistical basis. The quantification of plant mechanisms of defense against large herbivores produces a significantly better understanding of the multifaceted nature of plant–animal interactions and should contribute positively to future studies.

How did (Western) European freemasonries on a transnational level came to terms with the idea of a closer union of the European peoples? Concepts of “Europe” and “Europeanness” were the background music of the formation of masonic pan-European networks, building on transnational encounters either by individual freemasons (in the Ligue internationale de francs-maçons or at the international masonic manifestations for peace) or by Grand Lodge representatives (at “universal” congresses or via the Bureau international de relations maçonniques and the Association maçonnique internationale). Like all masonic relations, these transnational movements suffered from schisms on religious obligations and political commitments of the lodges. Generally, masonic discourse on a transnational level was characterized by a tension between geographically and politically confined ideas of “Europe” on the one hand and the general ideal of humanitarianism and universal brotherhood on the other.

Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. As in humans, zebrafish dystrophin is initially expressed at the peripheral ends of the myofibres adjacent to the myotendinous junction and gradually shifts to non-junctional sites. Dystrophin-deficient zebrafish larvae are characterised by abundant necrotic fibres being replaced by mono-nucleated infiltrates, extensive fibrosis accompanied by inflammation, and a broader variation in muscle fibre cross-sectional areas. Muscle progenitor proliferation cannot compensate for the extensive skeletal muscle loss. Live imaging of dystrophin-deficient zebrafish larvae documents detaching myofibres elicited by muscle contraction. Correspondingly, the progressive phenotype of dystrophin-deficient zebrafish resembles many aspects of the human disease, suggesting that specific advantages of the zebrafish model system, such as the ability to undertake in vivo drug screens and real time analysis of muscle fibre loss, could be used to make novel insights relevant to understanding and treating the pathological basis of dystrophin-deficient muscular dystrophy.

Freemasons often referred to an ideal of “humanité” (Humanität, umanità, humanity) in order to bridge all differences separating mankind. In doing so, they rendered these differences all the more visible, especially in the international arenas. This was definitely the case when freemasons tried to deduce from this ideal “universal” standards and norms for masonic practice. In the national masonic bodies, the virtue of (brotherly) love as an emanation of “pure humanity” was applied to diverging fields of action. They encompassed relief for needy fellow-masons and their families, aid and assistance for underprivileged groups in the service of social reform as well as solidarity with all forces in society that fought for peace, freedom (of conscience), and justice. Speaking “in the name of humanity” on an international level thus became a testing ground for negotiating religious, ideological, societal, and national differences.

The identification and exploration of new drug candidates to fight diseases is a major imperative for improving human health. The traditional mechanism utilised to identify new compounds with therapeutic potential has been to systematically analyse large libraries of small molecules for lead compounds with a desired bioactivity in protein or cell based assays. Identified lead compounds were subsequently assessed for their potential as lead drugs. In the last few years, small molecule screens were also carried out in vivo, on whole organisms such as the zebrafish. Cost efficient maintenance together with abundant manipulatory techniques and molecular tools have made the zebrafish a preferred system in which to perform large-scale screens. Numerous studies have revealed that zebrafish mutants can accurately model many aspects of human diseases. Therefore, small molecules identified in zebrafish-based screens can be particularly valuable in identifying lead compounds with direct therapeutic relevance to specific human disease states. Here, we review the role of zebrafish-based screens in the emerging field of chemical genetics.

Mutations in the human laminin α 2 ( LAMA2 ) gene result in the most common form of congenital muscular dystrophy (MDC1A). There are currently three models for the molecular basis of cellular pathology in MDC1A: ( i ) lack of LAMA2 leads to sarcolemmal weakness and failure, followed by cellular necrosis, as is the case in Duchenne muscular dystrophy (DMD); ( ii ) loss of LAMA2-mediated signaling during the development and maintenance of muscle tissue results in myoblast proliferation and fusion defects; ( iii ) loss of LAMA2 from the basement membrane of the Schwann cells surrounding the peripheral nerves results in a lack of motor stimulation, leading to effective denervation atrophy. Here we show that the degenerative muscle phenotype in the zebrafish dystrophic mutant, candyfloss ( caf ) results from mutations in the laminin α 2 ( lama2 ) gene. In vivo time-lapse analysis of mechanically loaded fibers and membrane permeability assays suggest that, unlike DMD, fiber detachment is not initially associated with sarcolemmal rupture. Early muscle formation and myoblast fusion are normal, indicating that any deficiency in early Lama2 signaling does not lead to muscle pathology. In addition, innervation by the primary motor neurons is unaffected, and fiber detachment stems from muscle contraction, demonstrating that muscle atrophy through lack of motor neuron activity does not contribute to pathology in this system. Using these and other analyses, we present a model of lama2 function where fiber detachment external to the sarcolemma is mechanically induced, and retracted fibers with uncompromised membranes undergo subsequent apoptosis.

During development, Pax6 is expressed in a rostrolateral-high to caudomedial-low gradient in the majority of the cortical radial glial progenitors and endows them with neurogenic properties. Using a Cre/ loxP -based approach, we studied the effect of conditional activation of two Pax6 isoforms, Pax6 and Pax6-5a , on the corticogenesis of transgenic mice. We found that activation of either Pax6 or Pax6-5a inhibits progenitor proliferation in the developing cortex. Upon activation of transgenic Pax6 , specific progenitor pools with distinct endogenous Pax6 expression levels at different developmental stages show defects in cell cycle progression and in the acquisition of apoptotic or neuronal cell fate. The results provide new evidence for the complex role of Pax6 in mammalian corticogenesis.

In skeletal muscle, the dystrophin-associated glycoprotein complex forms a link between the actin cytoskeleton and the extracellular matrix that is critical for muscle integrity. Within this complex resides the sarcoglycan subcomplex, which consists of four transmembrane glycoproteins (alpha-, beta-, gamma-, and delta-sarcoglycan). During assembly, beta-sarcoglycan tightly associates with delta-sarcoglycan to form a functional core that then recruits gamma- and alpha-sarcoglycan to form the sarcoglycan complex. Together with sarcospan, the sarcoglycan complex binds other components of the dystrophin-associated glycoprotein complex and integrates into the myofibre's membrane. Once integrated, the sarcoglycan complex plays a pivotal role in mechanically stabilising the sarcolemma as well as the dystrophin-associated glycoprotein complex. Additionally, the sarcoglycan complex undergoes chemical modifications in response to muscle contractions, thereby transducing mechanical information into a cellular signal. Mutations in the sarcoglycans induce limb girdle muscular dystrophy, and several animal models have been established to study the molecular biology and function of the sarcoglycan complex. This review discusses the role of the sarcoglycan complex in skeletal muscle and describes the functional deficiencies that lead to muscular dystrophies.

Dividing asymmetrically to fix muscle Resident tissue stem cells called satellite cells repair muscle after injury. However, how satellite cells operate inside living tissue is unclear. Gurevich et al. exploited the optical clarity of zebrafish larvae and used a series of genetic approaches to study muscle injury. After injury, satellite cells divide asymmetrically to generate a progenitor pool for muscle replacement and at the same time “self-renew” the satellite stem cell. This results in regeneration that is highly clonal in nature, validating many decades of in vitro analyses examining the regenerative capacity of skeletal muscle. Science , this issue p. 136

Aims The German Angioplasty Bypass Surgery Investigation was designed to compare symptomatic efficacy and safety of percutaneous coronary balloon angioplasty (PTCA) with coronary artery bypass surgery (CABG) in patients with symptomatic multi-vessel disease. This follow-up study was performed to determine the long-term outcome of patients following these interventions. Methods and results From 1986 to 1991, 359 patients with angina CCS class II–IV, age below 75 years, and coronary multi-vessel disease requiring revascularization of at least two major coronary vessels were recruited at eight German centres and randomized to PTCA or CABG. From 337 patients undergoing the planned procedure, 324 patients could be followed-up (96%). Baseline parameters were identical in both groups, 2.2 + 0.6 vessels were treated in CABG patients, whereas 1.9 + 0.5 vessels were treated in PTCA patients. Thirty-seven per cent of surgical patients received internal mammary artery grafts, while no stents were used in patients undergoing PTCA. At the end of the 13-year follow-up period, the degree of angina, the degree of dyspnea, and the utilization of nitrates were comparable in both groups. With a total number of 76 deaths, Kaplan–Meier analysis revealed a comparable distribution in both groups. Although time to first re-intervention was significantly shorter in the PTCA group, P , 0.001, frequencies of re-intervention (CABG, n ¼ 94; PTCA, n ¼ 136) and crossover rates (CABG to PTCA, n ¼ 49; PTCA to CABG, n ¼ 51) were comparable in both groups. Conclusion The results of our 13-year follow-up suggest that in patients with symptomatic multi-vessel disease, both PTCA and CABG are associated with a comparable long-term survival and symptomatic efficacy. How far these results may be altered by developments such as drug-eluting stents or offpump surgery remains to be determined.

BACKGROUND AND OBJECTIVE Symptomatic patients with multivessel coronary disease (MVD) benefit from both coronary artery bypass grafting (CABG) and percutaneous coronary angioplasty (PTCA). The >>German Angioplasty Bypass Investigation<< (GABI-I) trial randomized patients to one of these treatment strategies between 1986 and 1991. In order to evaluate the impact of current technology, in particular coronary stents, the GABI-II trial was initiated, which in 1996 and 1997 prospectively enrolled patients according to the initial GABI-I criteria. PATIENTS AND METHODS Into the study 136 consecutive patients (108 men, 28 women; 63 +/- 12 years) were included. Patients from GABI-I served as controls. RESULTS A mean of 2.1 +/- 0.5 vessels were treated per patient (vs. 1.9 +/- 0.5 vessels in the PTCA arm of GABI-I) and 63 % of the lesions were covered with stents. With respect to the primary endpoint less patients remained with a CCS class III or IV in GABI-II after 12 months (1,5 % vs. 8 % in the PTCA arm of GABI-I, p

Patients with coronary artery disease frequently have elevated antibody titers against Chlamydia pneumoniae, but whether antichlamydial antibody titers are correlated with prognosis in unstable angina remains unclear. We therefore investigated the sera of 1,096 patients with unstable angina regarding immunoglobulin (Ig) IgG, IgA, and IgM antibody titers against chlamydial lipopolysaccharides (LPS) and the concentrations of C-reactive protein (CRP) and troponin T (TnT). Anti-LPS IgG titers were increased in 45% of patients at enrollment and in 48% of patients at discharge (p

Aims Rotablation is a widely used technique for the treatment of complex coronary artery lesions but is so far only poorly supported by controlled studies. The Comparison of Balloon-Angioplasty versus Rotational Atherectomy study (COBRA) is a multicentre, prospective, randomized trial to compare short- and long-term effects of percutaneous transluminal coronary angioplasty (PTCA) and rotablation in patients with angiographically pre-defined complex coronary artery lesions. Methods and Results At seven clinical sites 502 patients with pre-defined complex coronary artery lesions were assigned to either PTCA (n=250) or rotablation (n=252). Primary end-points were procedural success, 6-month restenosis rates in the treated segments, and major cardiac events during follow-up. Procedural success was achieved in 78% (PTCA), and 85% (rotablation) ( P =0·038) of cases. Crossover from PTCA to rotablation was 4% and 10% vice versa ( P =0·019). There was no difference between PTCA and rotablation with respect to procedure-related complications such as Q wave infarctions (2·4% each), emergency bypass surgery (1·2% versus 2·4%), and death (1·6% versus 0·4%). However, more stents were required after PTCA (14·9% versus 6·4%, P

International audience; Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. The subcellular mechanisms of DMD remain poorly understood and there is currently no curative treatment available. Using a Caenorhabditis elegans model for DMD as a pharmacologic and genetic tool, we found that cyclosporine A (CsA) reduces muscle degeneration at low dose and acts, at least in part, through a mitochondrial cyclophilin D, CYN-1. We thus hypothesized that CsA acts on mitochondrial permeability modulation through cyclophilin D inhibition. Mitochondrial patterns and dynamics were analyzed, which revealed dramatic mitochondrial fragmentation not only in dystrophic nematodes, but also in a zebrafish model for DMD. This abnormal mitochondrial fragmentation occurs before any obvious sign of degeneration can be detected. Moreover, we demonstrate that blocking/delaying mitochondrial fragmentation by knocking down the fission-promoting gene drp-1 reduces muscle degeneration and improves locomotion abilities of dystrophic nematodes. Further experiments revealed that cytochrome c is involved in muscle degeneration in C. elegans and seems to act, at least in part, through an interaction with the inositol trisphosphate receptor calcium channel, ITR-1. Altogether, our findings reveal that mitochondria play a key role in the early process of muscle degeneration and may be a target of choice for the design of novel therapeutics for DMD. In addition, our results provide the first indication in the nematode that (i) mitochondrial permeability transition can occur and (ii) cytochrome c can act in cell death.