Circadian rhythm of blood cardiac troponin T concentration.

Introduction: High-sensitivity cardiac troponin assays have significantly improved the sensitivity of myocardial infarction detection by using cutoff values and early absolute changes. However, variation in repeated measures also depends on biological variability. This study aimed to assess the potential circadian component of this biological variability.

Myocardial infarct size and mortality depend on the time of day-a large multicenter study.

Background: Different studies have shown circadian variation of ischemic burden among patients with ST-Elevation Myocardial Infarction (STEMI), but with controversial results. The aim of this study was to analyze circadian variation of myocardial infarction size and in-hospital mortality in a large multicenter registry.

Methods: This retrospective, registry-based study was based on data from AMIS Plus, a large multicenter Swiss registry of patients who suffered myocardial infarction between 1999 and 2013.

[Influence of circadian rhythms on myocardial infarction].

Myocardial infarction is one of the most important causes of mortality and its incidence exhibits a significant circadian pattern with a peak of maximum frequency between 10 am and 11 am. Furthermore, myocardial infarction size and related mortality rate also undergo a variation over 24 hours. Recent publications have shown greatest myocardial injury when symptoms onsets are around midnight and this was independent of ischemic time and quality of care.

Relationship between time of day and periprocedural myocardial infarction after elective angioplasty.

Objectives: To test if the time of day significantly influences the occurrence of type 4A myocardial infarction in elective patients undergoing percutaneous coronary intervention (PCI).

Background: Recent studies have suggested an influence of circadian rhythms on myocardial infarction size and mortality among patients with ST-elevation myocardial infarction. The aim of the study is to investigate whether periprocedural myocardial infarction (PMI) is influenced by the time of day in elective patients undergoing PCI.

Circadian variations of ischemic burden among patients with myocardial infarction undergoing primary percutaneous coronary intervention.

Background: Several parameters of cardiovascular physiology and pathophysiology exhibit circadian rhythms. Recently, a relation between infarct size and the time of day at which it occurs has been suggested in experimental models of myocardial infarction. The aim of this study is to investigate whether circadian rhythms could cause differences in ischemic burden in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).

Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery.

Background: Gene transfer to nociceptive neurons of the dorsal root ganglia (DRG) is a promising approach to dissect mechanisms of pain in rodents and is a potential therapeutic strategy for the treatment of persistent pain disorders such as neuropathic pain. A number of studies have demonstrated transduction of DRG neurons using herpes simplex virus, adenovirus and more recently, adeno-associated virus (AAV). Recombinant AAV are currently the gene transfer vehicles of choice for the nervous system and have several advantages over other vectors, including stable and safe gene expression.

Delayed priming promotes CNS regeneration post-rhizotomy in Neurocan and Brevican-deficient mice.

A wealth of literature has provided evidence that reactive tissue at the site of CNS injury is rich in chondroitin sulfate proteoglycans which may contribute to the non-permissive nature of the CNS. We have recently demonstrated using a murine model of human brachial plexus injury that the chondroitin sulfate proteoglycans Neurocan and Brevican are differentially expressed by two subsets of astrocytes in the spinal cord dorsal root entry zone (DREZ) following dorsal root lesion (Beggah et al., Neuroscience 133: 749-762, 2005).

Delayed sympathetic dependence in the spared nerve injury (SNI) model of neuropathic pain.

Background: Clinical and experimental studies of neuropathic pain support the hypothesis that a functional coupling between postganglionic sympathetic efferent and sensory afferent fibers contributes to the pain. We investigated whether neuropathic pain-related behavior in the spared nerve injury (SNI) rat model is dependent on the sympathetic nervous system.

Results: Permanent chemical sympathectomy was achieved by daily injection of guanethidine (50 mg/kg s.

[Spinal opioids: mechanisms of action and chronic pain management].

The efficacy of spinal opioids is well known, the analgesia is potent and long lasting, due to the central localization of the opioid receptors. The analgesia is intimately related to the inhibition of the nociceptive signal in the spinal cord but side effects are mainly mediated by the activation of the mu opioid receptor in the brain and the brain stem. Only a limited number of controlled clinical studies compared systemic versus spinal administration of morphine in chronic pain patients, and the real benefit for the intrathecal route remains controversial.

Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias.

Background: Life-threatening cardiac arrhythmia is a major source of mortality worldwide. Besides rare inherited monogenic diseases such as long-QT or Brugada syndromes, which reflect abnormalities in ion fluxes across cardiac ion channels as a final common pathway, arrhythmias are most frequently acquired and associated with heart disease. The mineralocorticoid hormone aldosterone is an important contributor to morbidity and mortality in heart failure, but its mechanisms of action are incompletely understood.

Lesion-induced differential expression and cell association of Neurocan, Brevican, Versican V1 and V2 in the mouse dorsal root entry zone.

Lack of regeneration in the CNS has been attributed to many causes, including the presence of inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs). However, little is known about the contribution of CSPGs to regeneration failure in vivo, in particular at the dorsal root entry zone (DREZ), a unique CNS region that blocks regeneration of sensory fibers following dorsal root injury without glial scar formation. The goal of the present study was to evaluate the presence, regulation, and cellular identity of the proteoglycans Brevican, Neurocan, Versican V1 and Versican V2 in the DREZ using CSPG-specific antibodies and nucleic acid probes.

Development of a targeted transgenesis strategy in highly differentiated cells: a powerful tool for functional genomic analysis.

Functional genomic analysis is a challenging step in the so-called post-genomic field. Identification of potential targets using large-scale gene expression analysis requires functional validation to identify those that are physiologically relevant. Genetically modified cell models are often used for this purpose allowing up- or down-expression of selected targets in a well-defined and if possible highly differentiated cell type.

Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes.

Cardiac failure is a common feature in the evolution of cardiac disease. Among the determinants of cardiac failure, the renin-angiotensin-aldosterone system has a central role, and antagonism of the mineralocorticoid receptor (MR) has been proposed as a therapeutic strategy. In this study, we questioned the role of the MR, not of aldosterone, on heart function, using an inducible and cardiac-specific transgenic mouse model.

Tetracycline-inducible gene expression in cultured rat renal CD cells and in intact CD from transgenic mice.

The renal collecting duct (CD) plays a key role in the control of ion and fluid homeostasis. Several genetic diseases that involve mutations in genes encoding for ion transporters or hormone receptors specifically expressed in CD have been described. Suitable cellular or transgenic animal models expressing such mutated genes in an inducible manner should represent attractive systems for structure-function relationship analyses and the generation of appropriate physiopathological models of related diseases.

Basolateral translocation by vasopressin of the aldosterone-induced pool of latent Na-K-ATPases is accompanied by alpha1 subunit dephosphorylation: study in a new aldosterone-sensitive rat cortical collecting duct cell line.

The regulation of plasma membrane Na(+)-K(+)-ATPases (NKA) expression by aldosterone and arginin vasopressin (AVP) in the cortical collecting duct (CCD) has been examined in a new rat CCD cell line, designated as RCCD(2). This cell line has maintained many characteristics of the CCD-in particular, the expression of the mineralocorticoid receptor. Mineralocorticoid receptor is expressed at the protein level and binds (3)H-aldosterone (approximately 15 to 20 fmol/mg protein).

Transport and pharmacological properties of nine different human Na, K-ATPase isozymes.

Na,K-ATPase plays a crucial role in cellular ion homeostasis and is the pharmacological receptor for digitalis in man. Nine different human Na,K-ATPase isozymes, composed of 3 alpha and beta isoforms, were expressed in Xenopus oocytes and were analyzed for their transport and pharmacological properties. According to ouabain binding and K(+)-activated pump current measurements, all human isozymes are functional but differ in their turnover rates depending on the alpha isoform.

The nongastric H+-K+-ATPases: molecular and functional properties.

The Na-K/H-K-ATPase gene family is divided in three subgroups including the Na-K-ATPases, mainly involved in whole body and cellular ion homeostasis, the gastric H-K-ATPase involved in gastric fluid acidification, and the newly described nongastric H-K-ATPases for which the identification of physiological roles is still in its infancy. The first member of this last subfamily was first identified in 1992, rapidly followed by the molecular cloning of several other members. The relationship between each member remains unclear.

beta-subunit assembly is essential for the correct packing and the stable membrane insertion of the H,K-ATPase alpha-subunit.

The alpha-subunits of H,K-ATPase (HKAalpha) and Na,K-ATPase require a beta-subunit for maturation. We investigated the role of the beta-subunit in the membrane insertion and stability of the HKAalpha expressed in Xenopus oocytes. Individual membrane segments M1, M2, M3, M4, and M9 linked to a glycosylation reporter act as signal anchor (SA) motifs, and M10 acts as a partial stop transfer motif.

Regulation of expression and function by subunits of oligomeric P-type ATPases.

Na,K-ATPase activity must be finely controlled to meet the constantly changing physiological demands and to avoid destabilization of body homeostasis. Recent experimental evidence suggests that certain regulatory mechanisms are closely linked to the multisubunit structure of the Na,K-pump molecule. Na,K-ATPase is composed of a catalytic alpha and a glycoprotein beta subunit and sometimes of a third component, the gamma subunit.

Membrane integration of Na,K-ATPase alpha-subunits and beta-subunit assembly.

The control of membrane insertion of polytopic proteins is still poorly understood. We carried out in vivo translation/insertion experiments in Xenopus oocytes with combined wild type or mutant membrane segments of the alpha-subunit of the heterodimeric Na, K-ATPase linked to a glycosylation reporter sequence. We confirm that the four N-terminal hydrophobic segments of the alpha-subunit behave as alternating signal anchor/stop transfer motifs necessary for two lipid-inserted membrane pairs.

Transgenic models in renal tubular physiology.

Animal transgenesis has proven to be useful for physiological as well as physiopathological studies. Besides the classical approach based on the random integration of a DNA construct in the mouse genome, gene targeting can be achieved using totipotent embryonic stem (ES) cells for targeted transgenesis. Transgenic mice are then derived from the transgenic ES cells.

Role of glycosylation and disulfide bond formation in the beta subunit in the folding and functional expression of Na,K-ATPase.

Initial folding is a prerequisite for subunit assembly in oligomeric proteins. In this study, we have compared the role of co-translational modifications in the acquisition of an assembly-competent conformation of the beta subunit, the assembly of which is required for the structural and functional maturation of the catalytic Na,K-ATPase alpha subunit. Cysteine or asparagine residues implicated in disulfide bond formation or N-glycosylation, respectively, in the Xenopus beta1 subunit were eliminated by site-directed mutagenesis, and the assembly efficiency of the mutants and the functional expression of Na+,K+ pumps were studied after expression in Xenopus oocytes.

Degradation and endoplasmic reticulum retention of unassembled alpha- and beta-subunits of Na,K-ATPase correlate with interaction of BiP.

Assembly of alpha- and beta-subunits in the endoplasmic reticulum is a prerequisite for the structural and functional maturation of oligomeric P-type ATPases. In Xenopus oocytes, overexpressed, unassembled alpha- and beta-subunits of Xenopus Na,K-ATPase are retained in the endoplasmic reticulum (ER) and are degraded with different kinetics, while unassembled beta-subunits of gastric H, K-ATPase leave the ER. In this study, we have investigated the role of the immunoglobulin-binding protein, BiP, in the folding, assembly, and ER retention of ATPase subunits.

Oligomerization and maturation of Na,K-ATPase: functional interaction of the cytoplasmic NH2 terminus of the beta subunit with the alpha subunit.

Subunit assembly plays an essential role in the maturation of oligomeric proteins. In this study, we have characterized the main structural and functional consequences of the assembly of alpha and beta subunits of Na,K-ATPase. Xenopus oocytes injected with alpha and/or beta cRNA were treated with brefeldin A, which permitted the accumulation of individual subunits or alpha-beta complexes in the ER.