Comparative clinical performance of two types of drug-eluting stents with abluminal biodegradable polymer coating: Five-year results of the DESTINY randomized trial

Resumo Introdução e objetivos: Stents Coated with the Biodegradable Polymer on their Abluminal Faces and Elution of Sirolimus Versus Biolimus Elution for the Treatment of de Novo Coronary Lesions (Destiny Trial) é um estudo randomizado de não inferioridade que comparou o stent farmacológico eluído com Sirolimus Inspiron® (SES) ao controle o stent Biomatrix® Flex eluído com biolimus (BES). Relatórios dentro do primeiro ano mostraram resultados semelhantes para ambos os stents, em seguimento clínico, angiográfico e também em análise de tomografia de coerência ótica e ultrassom intracoronário. A presente análise tem como objetivo comparar o desempenho clínico desses dois stents farmacológicos com polímeros biodegradáveis após cinco anos do procedimento índice. Métodos: Foram randomizados 170 pacientes (194 lesões) em uma proporção de 2:1 para trata mento com SES ou BES, respetivamente. O desfecho primário para o presente estudo foi a taxa em cinco anos de eventos cardíacos adversos maiores combinados, definida como morte cardíaca, infarto do miocárdio ou revascularização da lesão-alvo. Resultados: Em cinco anos, o desfecho primário ocorreu em 12,5% e 17,9% para o grupo SES e BES, respectivamente (p=0,4). Não houve trombose de stent definitiva ou provável entre os pacientes tratados com o novo SES durante os cinco anos de seguimento e ausência de trombose de stent após o primeiro ano no grupo BES. Conclusões: O novo stent Inspiron® apresentou uma boa e semelhante performance clínica no seguimento em longo prazo, quando comparado com o controle o stent de última geração Biomatrix® Flex.

Relationships between cerebral autoregulation and markers of kidney and liver injury in neonatal encephalopathy and therapeutic hypothermia.

OBJECTIVE: We studied whether cerebral blood pressure autoregulation and kidney and liver injuries are associated in neonatal encephalopathy (NE). STUDY DESIGN: We monitored autoregulation of 75 newborns who received hypothermia for NE in the neonatal intensive care unit to identify the mean arterial blood pressure with optimized autoregulation (MAPOPT). Autoregulation parameters and creatinine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were analyzed using adjusted regression models. RESULTS: Greater time with blood pressure within MAPOPT during hypothermia was associated with lower creatinine in girls. Blood pressure below MAPOPT related to higher ALT and AST during normothermia in all neonates and boys. The opposite occurred in rewarming when more time with blood pressure above MAPOPT related to higher AST. CONCLUSIONS: Blood pressures that optimize cerebral autoregulation may support the kidneys. Blood pressures below MAPOPT and liver injury during normothermia are associated. The relationship between MAPOPT and AST during rewarming requires further study.

Regression analysis of correlated ordinal data using orthogonalized residuals.

Semi-parametric regression models for the joint estimation of marginal mean and within-cluster pairwise association parameters are used in a variety of settings for population-averaged modeling of multivariate categorical outcomes. Recently, a formulation of alternating logistic regressions based on orthogonalized, marginal residuals has been introduced for correlated binary data. Unlike the original procedure based on conditional residuals, its covariance estimator is invariant to the ordering of observations within clusters. In this article, the orthogonalized residuals method is extended to model correlated ordinal data with a global odds ratio, and shown in a simulation study to be more efficient and less biased with regards to estimating within-cluster association parameters than an existing extension to ordinal data of alternating logistic regressions based on conditional residuals. Orthogonalized residuals are used to estimate a model for three correlated ordinal outcomes measured repeatedly in a longitudinal clinical trial of an intervention to improve recovery of patients' perception of altered sensation following jaw surgery.

Altrenogest treatment associated with a farrowing induction protocol to avoid early parturition in sows.

This study investigated the effect of altrenogest treatment on the farrowing development of sows, and birth weight (BW) and piglet survival until the third day of life. Three control groups were used: (i) sows that farrowed spontaneously before 114 day of gestation (CONT <114); (ii) sows that spontaneously farrowed at ≥114 day of gestation (CONT ≥114); (iii) sows that farrowed at ≥114 day with cloprostenol treatment (CONTCLOPR). Other sows were treated with altrenogest (Regumate(®) ) for 3 days (days 111, 112 and 113 of gestation): one group gave birth spontaneously (ALT) and the other group received altrenogest until day 113 and cloprostenol on day 114 (ALTCLOPR). There were no differences (p > 0.05) in farrowing duration, BW, coefficient of variation (CV) of BW, stillborn piglets, mummified foetuses, percentage of light piglets and survival until Day 3 between sows with and without cloprostenol treatment, in both control (CONT ≥114 vs CONTCLOPR) and altrenogest-treated sows (ALT vs ALTCLOPR). Further comparisons were performed taking into account three groups: sows with early delivery (CONT <114 - farrowing before 114 days of gestation; n = 56), sows with longer gestation (CONT ≥114 - with and without cloprostenol treatment sows; n = 103) and ALT sows (with and without cloprostenol treatment; n = 105). Gestation length of CONT ≥114 and ALT sows was similar (p > 0.05), but higher than in CONT <114 sows. There were no differences (p > 0.05) between groups in farrowing duration, CV of BW, and percentages of stillborn piglets and mummified foetuses. Sows of CONT <114 group had a larger litter size and a lower BW than sows of the other two groups (p < 0.05). Sows of CONT <114 group had a higher percentage of lighter piglets and a lower piglet survival rate (p < 0.05) than ALT sows. In conclusion, altrenogest treatment proved to be an efficient method to avoid early parturition in 3-5 parity sows resulting in heavier piglets at birth.

Rare structural variation of synapse and neurotransmission genes in autism.

Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.

Regression models for patient-reported measures having ordered categories recorded on multiple occasions.

OBJECTIVES: The article reviews proportional and partial proportional odds regression for ordered categorical outcomes, such as patient-reported measures, that are frequently used in clinical research in dentistry. METHODS: The proportional odds regression model for ordinal data is a generalization of ordinary logistic regression for dichotomous responses. When the proportional odds assumption holds for some but not all of the covariates, the lesser known partial proportional odds model is shown to provide a useful extension. RESULTS: The ordinal data models are illustrated for the analysis of repeated ordinal outcomes to determine whether the burden associated with sensory alteration following a bilateral sagittal split osteotomy procedure differed for those patients who were given opening exercises only following surgery and those who received sensory retraining exercises in conjunction with standard opening exercises. CONCLUSIONS: Proportional and partial proportional odds models are broadly applicable to the analysis of cross-sectional and longitudinal ordinal data in dental research.

Bactericidal and hemolytic activities of synthetic peptides derived from granulysin.

Granulysin is a human polypeptide produced by cytolytic cells active against a broad range of microbes. Three peptides covering the regions 25-50 (Gr-1 and Gr-2) and 39-62 (Gr-3) of granulysin were synthesized, and their in vitro activity against Mycobacterium tuberculosis was evaluated. The most active peptide was Gr-1C, containing a disulphide bridge, with Minimal Inhibitory Concentration value of 10.1 microM. In concentrations of up to 50 microM, Gr-1 and Gr2 didn't exceed 30% of hemolysis.

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes.

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.

Upgrade of the CATS sample changer on FIP-BM30A at the ESRF: towards a commercialized standard.

An upgraded version of the sample changer ;CATS' (Cryogenic Automated Transfer System) that was developed on the FIP-BM30A beamline at the ESRF is presented. At present, CATS is installed at SLS (three systems), BESSY (one system), DLS (two systems) and APS (four systems for the LSCAT beamline). It consists mainly of an automated Dewar with an assortment of specific grippers designed to obtain a fast and reliable mounting/dismounting rate without jeopardizing the flexibility of the system. The upgraded system has the ability to manage any sample standard stored in any kind of puck.

Regulated expression of the proteoglycan SPOCK in the neuromuscular system.

SPOCK is prevalent in developing synaptic fields of the central nervous system (Charbonnier et al., 2000. Mech. Dev. 90, 317-321). The expression of SPOCK during neuromuscular junction (NMJ) formation was compared to agrin and acetylcholine receptor (AChR) distribution. SPOCK is detected within the myogenic masses during the early steps of embryonic development, and distributed in the cytoplasm of myotubes before coclustering with AChRs. In the adult, SPOCK is present in axons and is highly expressed by Schwann cells. SPOCK altered expression pattern after nerve lesioning, or cholinergic transmission blockade, strongly indicate that its cellular distribution at the NMJ depends on innervation.

Myoneurin, a novel member of the BTB/POZ-zinc finger family highly expressed in human muscle.

Initially characterized as Drosophila developmental regulators, the BTB/POZ and zinc finger proteins (BTB/POZ-ZF) constitute a growing family of proteins with gene expression regulatory functions since they have been shown to be involved in both transcriptional activation and repression of various genes in a broad range of species, including mammals. Here we report the cloning of a novel human transcript, coding for a 68-kDa deduced BTB/POZ-ZF protein. This molecule, called myoneurin on the basis of its prevalent expression in the neuromuscular system, contains an amino-terminal BTB/POZ domain and eight tandemly repeated zinc-finger motifs of the C(2)H(2) type. The murine myoneurin, identified in the mouse embryo, is highly homologous to the human protein.

Particle-associated retroviral RNA and tandem RGH/HERV-W copies on human chromosome 7q: possible components of a 'chain-reaction' triggered by infectious agents in multiple sclerosis?

Different groups have observed retrovirus particle (RVP) production in cell cultures from patients with multiple sclerosis (MS). This in vitro production appeared relatively specific for MS versus healthy controls, but was likely to be enhanced or activated by infectious triggers such as Herpesviruses (e.g. HSV, EBV). Independent molecular analysis of retroviral RNA associated with RVP revealed two different genetic families of endogenous retroviral elements (HERV): MSRV/HERV-W and RGH/HERV-H. Interestingly, these sequences were detected by mutually exclusive primers in RT - PCR amplifications. Surprisingly, these two HERV families both contain an ancestral proviral copy inserted in chromosome 7q21-22 region at about 1 kb of distance of each other. Another HERV-W proviral sequence is located within a T-cell alpha-delta receptor (TCR) gene in chromosome 14q11.2 region. Interestingly, these two regions correspond to genetic loci previously identified as potentially associated with 'multigenic' susceptibility to MS and TCR alpha chain genetic determinants have been reported to be statistically associated with MS. A plausible role for infectious agents triggering a co-activation of the chromosome 7q HERV tandem (replicative retrovirus and/or other virus and/or intracellular bacteria) and, eventually, other HERV copies, is discussed. The role of particular HERV polymorphism and the production of pathogenic molecules (gliotoxin and superantigen) possibly associated with retroviral expression are also evoked. An integrative concept of pathogenic 'chain-reaction' in MS involving several step-specific pathogenic 'agents' and 'products' somewhat interacting with particular genetic elements would federate most partial data obtained on MS, including retroviral expression.

New perspectives in multiple sclerosis: retroviral involvement and glial cell death.

Retroviral involvement in the pathogenic cascade in multiple sclerosis (MS) and a cytotoxic activity with narrow specificity towards glial cells have been recently considered as credible working hypotheses to explain some of the complex pathophysiological and neuropathological features of MS. The partial characterization of exogenous retroviral sequences, thought to be associated with MS, has led us to the identification of new human endogenous retroviruses closely related to the extracellular multiple sclerosis associated retrovirus (MSRV). These endogenous retroviruses (HERV-TcR and HERV-7q) have the potential to be transcribed into RNA and proteins. Interestingly, the env domain of HERV-7q could code for a 59.8 kDa secreted glycoprotein (called enverin) with an immunoregulatory region. The presence in various MS biological fluids of a cytotoxic activity able to induce programmed cell death for oligodendrocytes and astrocytes suggests the possibility of a demyelination phenomenon as part of direct glial cell damage. Moreover, both retroviral expression and cytotoxic factor production have been evidenced in MS monocyte/macrophage cultures and MS cerebrospinal fluid. It is now crucial to better characterize the endo/exo retroviruses possibly involved in MS and their pathogenic potential, and to identify the contributing factor(s) to the gliotoxicity found in the MS cerebrospinal fluid or serum, as well as to elucidate the mechanism of induction of the observed programmed glial cell death.

Expression of the proteoglycan SPOCK during mouse embryo development.

SPOCK is a modular proteoglycan, with homology with proteins involved in cell adhesion processes and neurogenesis. We have previously shown that SPOCK transcripts predominate in the adult mouse brain. Here, we report its expression during mouse embryonic development by in situ hybridization, and immunocytochemistry. SPOCK is actively expressed at the onset of neurogenesis during periods of neuron migration and axonal outgrowth. At a later developmental stage, its expression is particularly prevalent within developing synaptic fields. In the peripheral nervous system, SPOCK expression is also developmentally regulated particularly in dorsal root ganglion neurons.

Endogenous retroviruses and multiple sclerosis. II. HERV-7q.

The search for new endogenous retroviral sequences, on the basis of sequence homologies with the pol gene of the recently reported multiple sclerosis associated retrovirus (MSRV), allowed us to identify a full length endogenous retrovirus sequence located on the long arm of human chromosome 7. This retrovirus, HERV-7q, includes in its env region, within a single 1,620 bp open reading frame, a 664 bp domain almost identical to a 3' non-coding region of the rab7 gene. Transcripts encompassing both the env and the 3' LTR regions of HERV-7q have already been identified as expressed sequence tags, suggesting that this env-like gene might code for a 538 amino acid long deduced protein.

[Endogenous retroviral sequences analogous to that of the new retrovirus MSRV associated with multiple sclerosis (part 1)]. / Séquences rétrovirales endogènes analogues à celle du nouveau rétrovirus MSRV associé à la sclérose en plaques (1re partie).

Multiple sclerosis (MS) is still of unknown origin and may involve autoimmune, genetic and viral components in a pathogenic sequence whose relative importance is yet to be determined. A peptide, isolated from the cerebrospinal fluid of MS patients, is similar to a fragment of the pol protein reverse transcriptase (RT) of the newly reported MSRV retrovirus. The 700 amino acid sequence of MSRV-RT is closely related to a novel human retroviral-like sequences. We also identified a gag-like sequence upstream of this human genomic RT-like sequence, which allowed us to identify altogether 4,000 nucleotides, possibly coding for an endogenous retroviruses. Homologous sequences found in other locations in the human genome seem to characterize a new family of retroviral endogenous sequences, which may be of relevance to multiple sclerosis.

An endogenous retrovirus with nucleic acid sequences similar to those of the multiple sclerosis associated retrovirus at the human T-cell receptor alpha, delta gene locus.

Retroviruses are suspected to be involved in the pathogenesis of autoimmune diseases, such as multiple sclerosis (MS). Here, we describe a complete cartography of a novel human endogenous retroviral sequence with a pol domain which shares a high homology with the pol sequence of the multiple sclerosis associated retrovirus (MSRV). Since this new endogenous retroviral sequence is located in the close vicinity of the locus of the human gene coding for the T-cell receptor (TcR) alpha and delta chains on chromosome 14, it could be of potential interest for the understanding of MS pathogenesis.

Genomic organization of the human SPOCK gene and its chromosomal localization to 5q31.

SPOCK, previously identified as testican, is a modular proteoglycan that carries both chondroitin and heparan sulfate glycosaminoglycan side chains. The overall genomic organization has been established. The SPOCK gene spans at least 70 kb and is composed of 11 exons: the first half of the gene is dramatically expanded, but the second half is more compact. In situ hybridization and YAC mapping independently linked the SPOCK gene to 5q31, a region containing an impressive number of genes encoding growth factors, cytokines, and neurotransmitter and hormone receptors. The gene is located between the IL9 and the EGR1 genes, bordering the smallest commonly deleted region of chromosome 5.

[Cloning of testican/SPOCK in man and mouse. Neuromuscular expression perspectives in pathology]. / Clonage de la testicane/SPOCK chez l'homme et la souris. Expression au niveau neuromusculaire et perspectives en pathologie.

We have recently cloned a novel proteoglycan initially identified in human testis and hence previously called testican. A close examination of the overall protein structure reveals three main regions: four osteonectin/SPARC-like domains encompassing the amino-terminal and central part of the deduced protein, a Kazal-like motif overlapping the third domain, and the CWCV domain in the carboxyl-terminal end region of the protein core. We propose to call it SPOCK, the acronym of SPARC/Osteonectin CWCV and Kazal-like domains proteoglycan, according to its specific multidomain structure. To get further insight into the function, a Northern blot analysis was performed in order to determine the site of expression in various adult tissues; a 5.2 kb transcript appeared only but strongly in mouse brain. The structure of the murine brain proteoglycan was determined through molecular cloning; human and mouse deduced proteins are highly homologous with 95% overall amino acid identity. Murine brain serial sections hybridized with cDNA and immunological probes revealed identical distribution in discrete cerebral regions, such as CA3 hippocampal region and cerebellum. Immunoelectron microscopy showed the antigen selectively localized in the post-synaptic density of scattered pyramidal neurons and Purkinje cells. Structural analysis, a main expression in nervous system and preliminary assignment of the human gene in a critical region for neuropathologies, suggest that SPOCK may be of importance in neural development and neurodegenerative diseases.

Structure and cellular distribution of mouse brain testican. Association with the postsynaptic area of hippocampus pyramidal cells.

The complete deduced primary structure of mouse brain testican has been established from cDNA cloning. The cDNA encodes a polypeptide of 442 amino acids belonging to the proteoglycan family. The mouse brain testican core protein is 95% identical to its human testicular counterpart. In situ hybridization investigations revealed that mouse testican mRNA is mainly present in a subpopulation of pyramidal neurons localized in the CA3 area of the hippocampus. An immunocytochemical approach, with antibodies directed against an overexpressed chimeric antigen, produced in bacterial systems, showed that testican is associated with the postsynaptic region of these pyramidal neurons. Testican includes several putative functional domains related to extracellular or pericellular proteins associated with binding and/or regulatory functions. On the basis of its structural organization and its occurrence in postsynaptic areas, this proteoglycan might contribute to various neuronal mechanisms in the central nervous system.