422 research outputs found
International prospective study of distal intestinal obstruction syndrome in cystic fibrosis: Associated factors and outcome
No full textBackground Distal intestinal obstruction syndrome (DIOS) is a specific complication of cystic fibrosis. Methods A study was performed in 10 countries to prospectively evaluate the incidence, associated factors, and treatment modalities in children and adults. Results 102 patients presented 112 episodes. The incidence of DIOS was similar in children and adults. Medical treatment failed only in cases of complete DIOS (11%). Children with meconium ileus had a higher rate of surgery for DIOS (15% vs. 2%, p = 0.02). Complete DIOS entailed longer hospitalisation (4 [3; 7] days vs. 3 [1; 4], p = 0.002). Delayed arrival at hospital and prior weight loss had a significant impact on the time needed for DIOS resolution. Associated CF co-morbidities for DIOS included meconium ileus (40% vs. 18%, p < 0.0001), exocrine pancreatic insufficiency (92% vs. 84%, p = 0.03), liver disease (22% vs. 12%, p = 0.004), diabetes mellitus (49% vs. 25%, p = 0.0003), and Pseudomonas aeruginosa (68% vs. 52%, p = 0.01); low fibre intake and insufficient hydration were frequently observed. Female gender was associated with recurrent DIOS (75% vs. 52%, p = 0.04), constipation with incomplete episodes (39% vs. 11%, p = 0.03), and poor patient compliance in taking pancreatic enzyme therapy during complete episodes (25% vs. 3%, p = 0.02). Conclusion DIOS is a multifactorial condition having a similar incidence in children and adults. We show that delayed arrival at hospital after the initial symptoms causes significant morbidity. Early recognition and treatment would improve the prognosis
A Representative Survey of M.S. Patients on Attitudes toward the Benefits and Risks of Drug Therapy
No full textBackground: Although M.S. patients face significant trade-offs between risks and benefits of drug therapy, little is known of their attitudes toward these risks and benefits. Methods: A representative telephone survey of 200 patients with relapsing remitting M.S. Results: Respondents suffered substantial disability, most of them requiring a wheel chair or support for walking any significant distance, and over half suffering relapses in the past year. All were on drug therapy; half had switched drugs; 1/3 had switched at least twice.Most patients had seen their neurologist at least 4 times in the previous two years and said they and their physician were equally involved in drug decisions. About 55% said they would definitely or probably use a drug that significantly reduces frequency of relapse or progression in disability even if the drug involves a 1-in-1,000 chance of a fatal side-effect.Willingness to tolerate risk bore little relationship with disability levels. A substantial majority agreed that the FDA should tightly control drugs with safety concerns, but a larger majority agreed that once the FDA has provided a warning, patients should be free to decide with their physician whether to use such drugs. Virtually all said they were willing to visit their neurologist more often in order to use risky drugs. Conclusions: M.S. patients are accustomed to playing a large role in their own drug therapy but do so in close collaboration with their physicians.After the FDA has reviewed drug safety and provided reasonable warnings, many M.S. patients wish to be free to choose to incur a 1-in-1,000 (or even greater) risk of a fatal side-effect in return for significantly more effective drugs, and are willing to work with the physicians in doing so.
Pituitary Adenylate Cyclase-Activating Polypeptide: Development of Selective Ligands for Pac1, Vpac1 and Vpac2 Receptors
No full textAt the time of its isolation, purification and sequencing in 1970-1972 by Said and Mutt (Said and Mutt, 1972;Mutt and Said, 1974), VIP was the third identified member of a peptide group that included secretin (Mutt et al, 1970) and glucagon (Bromer et al, 1957). The family signature was a N-terminal histidylseryl sequence separated by three amino acid residues from a phenylalanylthreonyl sequence. Synthesis of secretin, VIP, glucagon and analogs as well as a careful study of their biological activities revealed that there was no, or only negligible, interference of glucagon with secretin and VIP mediated responses, nor of secretin and VIP with the glucagon response. It was also rapidly recognized that VIP and secretin shared common in vitro properties and that each peptide interacted with its cognate receptor and with the other receptors (Bataille et al, 1974; Robberecht et al, 1976). It was also established for the three peptides that the N-terminal sequence was necessary for the high affinity recognition of the receptor and for induction of the biological activity, and that the C-terminus was necessary for a high affinity recognition. It was thus not possible to shorten significantly the molecule without a loss of the biological properties or peptide potency. This was a major point for the rational design of agonists and antagonists as well as for the interest of industry. Binding studies of125I-labeled peptides characterized the receptors and for each peptide high and low affinity sites were described (Christophe et al, 1976; Laburthe et al, 1978; Prieto et al, 1979).info:eu-repo/semantics/publishe
Coexistence of non-adrenergic non-cholinergic inhibitory and excitatory neurotransmitters in a large neuronal subpopulation in the vaginal segment of the chicken oviduct
No full textThe presence, distribution and smooth muscle motor effects of galanin and pituitary adenylate cyclase activating peptide (PACAP) were studied in the nerves of the vaginal part of the oviduct of egg-laying hens. Galanin and PACAP immunoreactivity were found both in neuronal perikarya and nerve fibres within the wall of the vaginal segment. Both populations showed a similar distribution pattern. Particularly the circular muscle and the intramural vascular net were richly innervated. A few galanin- and PACAP-IR nerve fibres extended up to the mucosal folds. Multiple labelling showed galanin to be colocalised with PACAP as well as with vasoactive intestinal polypeptide (VIP) and nitric oxide synthase (NOS) in a large, partly intrinsic neuronal subpopulation innervating the smooth muscle wall. Pharmacological in vitro experiments showed that isolated vaginal muscle strips had a spontaneous basal activity that was not affected by the neuronal conductance blocker tetrodotoxin (TTX). Galanin induced concentration-dependent contractions that were TTX-insensitive. PACAP, VIP, nitric oxide (NO) and the NO donor nitroglycerin caused concentration-dependent relaxations that were TTX-insensitive. Electrical field stimulation of isolated muscle strips induced frequency-dependent relaxations that were blocked by TTX and reduced by the NOS blocker L-nitroarginine. These data provide evidence that the vaginal part of the oviduct contains a largely intrinsic, neuronal subpopulation, capable of releasing multiple non-adrenergic, non-cholinergic (NANC) motor agents for the control of local muscular activities. In addition, we provided pharmacological evidence that VIP, NO and PACAP exert an inhibitory and galanin an excitatory action on isolated muscle strips of the vaginal part of the chicken oviduct. Our results suggest that these NANC neurotransmitters play an important role in the regulation of neuromuscular activity in this region. © 2004 Elsevier B.V. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe
Transglutaminase-mediated polyamination of vasoactive intestinal peptide (VIP) Gln16 residue modulates the VIP/PACAP receptor activity.
No full textGlatiramer Acetate has no impact on disease progression in ALS at 40 mg/day: a double blind, randomized, multicenter, placebo controlled trial
No full textOur objective was to assess the efficacy and safety of 40 mg/day glatiramer acetate (GA) in patients with ALS. We conducted a double-blind, randomized, placebo-controlled, multicentre trial. Three hundred and sixty-six patients with definite, probable or probable laboratory supported ALS and a slow vital capacity ≥ 70% were randomly assigned to treatment with placebo or 40 mg GA daily. The primary intention-to-treat analysis was the comparison between the two treated groups of the rates of deterioration on the ALSFRSR scale. The secondary outcome measure was time to death, tracheostomy or permanent assisted ventilation. Safety and tolerability of GA were evaluated. After 52 weeks of follow-up, the slope of the ALSFRSR score was comparable in the both groups (placebo,-1.00±0.06/month; GA,-1.05±0.06/month; p=0.48). The secondary endpoint was non-significant with 159 patients (87.4%) alive in the placebo group and 162 patients (88.1%) in the GA group (log rank, p=0.75). The most common events were the injection site reactions (76.1% in the GA group, 14.8% in the placebo group), comparable to the known profile of 20 mg GA. In conclusion, GA at a dose of 40 mg/day did not show any beneficial effect in ALS patients, and safety and tolerability of GA were good in this population
COL4A2 is associated with lacunar ischemic stroke and deep ICH : Meta-analyses among 21,500 cases and 40,600 controls
No full textObjective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. Results: A locus in COL4A2 was associated (significance threshold p , 3.5 3 1024) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95%confidence interval [CI] 1.11-1.24, p 56.62 31028) and deep ICH (lead SNP rs4771674: OR 1.28, 95%CI 1.13-1.44, p 55.76 3 1025). A SNP in HTRA1 was associated (significance threshold p , 5.5 3 1024) with lacunar IS (rs79043147: OR 1.23, 95%CI 1.10-1.37, p 5 1.90 3 1024) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype
Transglutaminase-mediated polyamination of vasoactive intestinal peptide (VIP) Gln16 residue modulates VIP/PACAP receptor activity
No full textPrevious data showing an increase of receptor binding activity of [R16]VIP, a vasoactive intestinal peptide (VIP) structural analogue containing arginine at the position 16 of its amino acid sequence, have pointed out the importance of a positive charge at this site. Here, the functional characterization of three VIP polyaminated adducts (VIPDap, VIPSpd, and VIPSpm), obtained by a transglutaminase-catalysed reaction between the VIP Gln16 residue and 1,3-diaminopropane (Dap), spermidine (Spd), or spermine (Spm), is reported. Appropriate binding assays and adenylate cyclase enzymatic determinations have shown that these VIP adducts act as structural VIP agonists, both in vitro and in vivo. In particular, their IC50 and EC50 values of human and rat VIP/pituitary adenylate cyclase activating peptide (PACAP)1 and VIP/PACAP2 receptors indicate that VIPDap is a VIP agonist, with an affinity and a potency higher than that of VIP, while VIPSpd and VIPSpm are also agonists but with affinities lower than that of VIP. These findings suggest that the difference in adduct agonist activity reflects the differences in the positive charge and carbon chain length of the polyamine covalently linked with the VIP Gln16 residue. In addition, the data obtained strongly suggest that the length of polyamine carbon chain could be critical for the interaction of the agonist with its receptor, even though possible hydrophobic interaction cannot be ruled out. In vivo experiments on murine J774 macrophage cell cultures have shown the ability of these compounds to stimulate the inducible nitric oxide synthase activity at the transcriptional level
Multicentre quality control evaluation of different biomarker candidates for amyotrophic lateral sclerosis
No full textAmyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that mainly causes degeneration of the upper and lower motor neurons, ultimately leading to paralysis and death within three to five years after first symptoms. The pathological mechanisms leading to ALS are still not completely understood. Several biomarker candidates have been proposed in cerebrospinal fluid (CSF). However, none of these has successfully translated into clinical routine. Part of the reason for this failure to translate may relate to differences across laboratories. For this reason, several of the most commonly used ALS biomarker candidates were evaluated on clinically well-defined ALS samples from six European centres in a multicentre sample-collection approach with centralized sample processing. Results showed that phosphorylated neurofilament heavy chain differentiated between ALS and control cases in all centres. We therefore propose that measurement of phosphorylated neurofilaments in CSF is the most promising candidate for translation into the clinical setting and might serve as a benchmark for other biomarker candidates
VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death
No full textVEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P. The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology and Department of Neurology, University Hospital Gasthuisberg, KU Leuven, Leuven, B-3000, Belgium. Amyotrophic lateral sclerosis (ALS) is an incurable degenerative disorder of motoneurons. We recently reported that reduced expression of Vegfa causes ALS-like motoneuron degeneration in Vegfa(delta/delta) mice. In a meta-analysis of over 900 individuals from Sweden and over 1,000 individuals from Belgium and England, we now report that subjects homozygous with respect to the haplotypes -2,578A/-1,154A/-634G or -2,578A/-1,154G/-634G in the VEGF promoter/leader sequence had a 1.8 times greater risk of ALS (P = 0.00004). These 'at-risk' haplotypes lowered circulating VEGF levels in vivo and reduced VEGF gene transcription, IRES-mediated VEGF expression and translation of a novel large-VEGF isoform (L-VEGF) in vivo. Moreover, SOD1(G93A) mice crossbred with Vegfa(delta/delta) mice died earlier due to more severe motoneuron degeneration. Vegfa(delta/delta) mice were unusually susceptible to persistent paralysis after spinal cord ischemia, and treatment with Vegfa protected mice against ischemic motoneuron death. These findings indicate that VEGF is a modifier of motoneuron degeneration in human ALS and unveil a therapeutic potential of Vegfa for stressed motoneurons in mice
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