1.
Antimicrobial implications of vitamin D.
Source
Mountain Home VAMC Medicine Service; Mountain Home; TN USA.
Abstract
Evidence exists that vitamin D has a potential antimicrobial activity and its deficiency has deleterious effects on general well-being and longevity. Vitamin D may reduce the risk of infection through multiple mechanisms. Vitamin D boosts innate immunity by modulating production of anti-microbial peptides (AMPs) and cytokine response. Vitamin D and its analogues via these mechanisms are playing an increasing role in the management of atopic dermatitis, psoriasis, vitiligo, acne and rosacea. Vitamin D may reduce susceptibility to infection in patients with atopic dermatitis and the ability to regulate local immune and inflammatory responses offers exciting potential for understanding and treating chronic inflammatory dermatitides. Moreover, B and T cell activation as well as boosting the activity of monocytes and macrophages also contribute to a potent systemic anti-microbial effect. The direct invasion by pathogenic organisms may be minimized at sites such as the respiratory tract by enhancing clearance of invading organisms. A vitamin D replete state appears to benefit most infections, with the possible noteworthy exception of Leishmaniasis. Antibiotics remain an expensive option and misuse of these agents results in significant antibiotic resistance and contributes to escalating health care costs. Vitamin D constitutes an inexpensive prophylactic option and possibly therapeutic product either by itself or as a synergistic agent to traditional antimicrobial agents. This review outlines the specific antimicrobial properties of vitamin D in combating a wide range of organisms. We discuss the possible mechanisms by which vitamin D may have a therapeutic role in managing a variety of infections.
- PMID:
- 22259647
- [PubMed - in process]
Neuropeptides controlling energy balance: orexins and neuromedins.
Source
Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA.
Abstract
In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus-perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.
Neuroplasticity of sensory and sympathetic nerve fibers in the painful arthritic joint.
Source
Research Service, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, USA.
Abstract
OBJECTIVE.: Many forms of arthritis are accompanied by significant chronic joint pain. Here we studied whether there is significant sprouting of sensory and sympathetic nerve fibers in the painful arthritic knee joint and whether nerve growth factor (NGF) drives this pathological reorganization. METHODS.: A painful arthritic knee joint was produced by injection of complete Freund's adjuvant (CFA) into the knee joint of young adult mice. CFA-injected mice were then treated systemically with vehicle or anti-NGF antibody. Pain behaviors were assessed and at 28 days following the initial CFA injection, the knee joints were processed for immunohistochemistry using antibodies raised against calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), growth associated protein-43 (GAP43; sprouted nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), CD31 (endothelial cells) or CD68 (monocytes/macrophages). RESULTS.: In CFA-injected mice, but not vehicle-injected mice, there was a significant increase in the density of CD68(+) macrophages, CD31(+) blood vessels, CGRP(+) , NF200(+) , GAP43(+) , and TH(+) nerve fibers in the synovium as well as joint pain-related behaviors. Administration of anti-NGF reduced these pain-related behaviors and the ectopic sprouting of nerve fibers, but had no significant effect on the increase in density of CD31(+) blood vessels or CD68(+) macrophages. CONCLUSIONS.: Ectopic sprouting of sensory and sympathetic nerve fibers occurs in the painful arthritic joint and may be involved in the generation and maintenance of arthritic pain.
Copyright © 2012 by the American College of Rheumatology.
Interleukin 15 levels in serum may predict a severe disease course in patients with early arthritis.
Source
Rheumatology Service, Hospital Universitario de La Princesa, IIS Princesa, Madrid, Spain.
Abstract
BACKGROUND:
Interleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA).
METHODOLOGY AND RESULTS:
Data from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (β Coefficient [95% confidence interval]: 0.12 [0.06-0.18]; p<0.001) or ACPA (0.34 [0.01-0.67]; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18-2.7; p = 0.007).
CONCLUSIONS:
Patients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatment.
Tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's-associated esophageal adenocarcinoma.
Source
1Department of Surgery, Thoracic Service, Memorial Sloan-Kettering Cancer Center.
Abstract
BACKGROUND:
Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's esophagus (BE) and in esophageal adenocarcinoma (EAC).
METHODS:
Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum.
RESULTS:
Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean, 0.89 nM; range, 0.03-3.77 nM), but not in patients with acid reflux and/or BE.
CONCLUSIONS:
Mesothelin is commonly expressed in BE-associated esophageal adenocarcinoma. Based on this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin are potential markers of neoplastic progression in BE and in EAC (NCT01393483).Impact: Current surveillance methods in Barrett's esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation.
Effect of NF-κB inhibition on AAV9 minidystrophin gene transfer to the mdx mouse.
Source
Neurology Service, Department of Veterans Affairs Medical Center, Pittsburgh, PA, USA Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
Abstract
Gene therapy studies for Duchenne muscular dystrophy (DMD) have focused on viral vector-mediated gene transfer to provide therapeutic protein expression or treatment with drugs to limit dystrophic changes in muscle. The pathological activation of the nuclear factor κB (NF-κB) signaling pathway has emerged as an important cause of dystrophic muscle changes in muscular dystrophy. Furthermore, activation of NF-κB may inhibit gene transfer by promoting inflammation in response to the transgene or vector. Therefore, we hypothesized that inhibition of pathological NF-κB activation in muscle would complement the therapeutic benefits of dystrophin gene transfer in the mdx mouse model of DMD. Systemic gene transfer using serotype 9 adeno-associated viral (AAV9) vectors is promising for treatment of preclinical models of DMD due to vector tropism to cardiac and skeletal muscle. In quadriceps of mdx mice, the addition of 8K-NBD peptide treatment to AAV9 minidystrophin gene delivery resulted in increased levels of recombinant dystrophin expression suggesting that 8K-NBD treatment promoted an environment in muscle tissue conducive to higher levels of expression. Indices of necrosis and regeneration were diminished with AAV9 gene delivery alone and to a greater degree with the addition of 8K-NBD treatment. In diaphragm muscle, transgene expression was sufficiently high that marked improvements in histological and physiological indices were comparable in the 2 treatment groups. The data support benefit from 8K-NBD treatment to complement gene transfer therapy for DMD in muscle tissue that receives incomplete levels of transduction by gene transfer which may be highly significant for clinical applications of muscle gene delivery.
Temporary transvenous VDD pacing as a bridge to permanent pacemaker implantation in patients with sepsis and haemodynamically significant atrioventricular block.
Source
Service de Cardiologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc 75015, Paris, France.
Abstract
AimsPermanent pacemaker (PM) implantation is temporarily contraindicated in patients (pts) with sepsis. In patients with symptomatic atrioventricular (AV) block and infection, prolonged VVI pacing is therefore usually ensured by a ventricular pacing lead (PL) connected to an external PM generator. In patients with normal sinus function and heart failure, the VVI mode can exacerbate haemodynamic dysfunction. A single AV PL can be attractive to achieve physiological pacing. This study was designed to assess the efficacy and safety of temporary VDD pacing as a bridge to permanent PM implantation in patients with complete AV block until control of infection.Methods and resultsThis study included eight patients with complete AV block and sepsis with negative blood culture. Due to the presence of congestive heart failure, a single bipolar AV PL connected to an external VDD PM generator. At VDD implantation, P-wave amplitude was 1.9 ± 1.6 mV and R-wave was 11.3 ± 5.2 mV. The ventricular pacing threshold was 0.53 ± 0.1 V for a 0.5 ms pulse. Antibiotic therapy was instituted in all patients. A permanent VDD or DDD PM was implanted after 8 ± 2.5 days of temporary VDD pacing. At permanent PM implantation, the mean brain natriuretic peptide level had decreased and sepsis was controlled in all patients. No recurrence of sepsis was observed with a mean follow-up of 15.8 ± 5.3 months.ConclusionTemporary VDD pacing is a safe and effective method to achieve prolonged AV physiological pacing in patients with AV block until infection has been controlled.
[What's new in dermatological research?].
Source
Université de Franche Comté, EA3181, IFR133 et Service de Dermatologie, CHU de Besançon, 2 place Saint-Jacques 25030 Besançon cedex, France.
Abstract
Dermatological research has been very active this year. Most of the numerous fields investigated involve the mechanisms of cutaneous regeneration and barrier function. A novel target of early ultraviolet-induced skin photodamage, the Syk kinase, has been recently identified. Synergistic relationship between telomere damage and cutaneous progerin production during cell senescence may also participate in the natural skin aging process. Interestingly, ultraviolet radiation induces an inhibitory effect on subcutaneous lipogenesis. Androgenetic alopecia or common baldness is not characterized by loss of hair follicle stem cells but by a defect in the conversion of hair follicle stem cells into active progenitor cells. It has been shown that the cornified envelope functions not only as a physicomechanical barrier, but also as both a biochemical line of antoxidant defense and an immunological line of defense. Like human papillomaviruses, Merckel cell polyomavirus belongs to the skin microbiome and different studies have demonstrated the protective role of epidermal resident microflora through the activation of innate immunity. Production of antimicrobial peptides and the activation of inflammasome and plasmacytoid dendritic cells are involved in the modulation of the cutaneous barrier function. Results from different studies suggest that IL-22 and IL-36 may be common mediators of both innate and adaptive immune responses. All these pathways interact not only to maintain cutaneous homeostasis and integrity (wound healing) but also to regulate autoinflammatory and autoimmune dermatoses (psoriasis, lupus, rosacea, atopic dermatitis, etc…). In addition, molecular mechanisms that regulate T helper type 2 differentiation and the retention at the site of inflammation of Th2 cells have been identified. New promising therapeutic targets for different chronic dermatosis are thus suggested. Mechanobiology and mechanotransduction are also emerging fields that investigate mechanical interactions between living cells and their environment and the conversion of mechanical cues into biochemical signals. Electronic second skin is now a current concept through bio-integrated epidermal electronics platforms used for different monitoring and stimulations of body functions.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
[Vitamin D and autoimmunity. First part: Fundamental aspects.]
Source
Service de médecine interne, université Versailles Saint-Quentin-en-Yvelines, hôpital Foch, 40, rue Worth, 92151 Suresnes cedex, France.
Abstract
The effects of vitamin D on calcium homeostasis and bone metabolism are well known. In recent years, suboptimal vitamin D status has been recognized as a pandemic. Meanwhile, extra-skeletal effects of vitamin D are becoming better documented, particularly its effects on immunity. The authors present their actions on myeloid dendritic cells, T cells, B cells, as well as on the synthesis of antimicrobial peptides and autophagy, and the potential beneficial effects in autoimmune and inflammatory diseases.
Copyright © 2011. Published by Elsevier SAS.
[Thrombolytic therapy for pulmonary embolism].
Source
Service de Pneumologie, Université Paris Descartes, Assistance Publique - Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France.
Abstract
Pulmonary embolism with choc carries a 25 to 50% mortality rate. Although no large randomized clinical trial is available, some insights of a meta-analysis suggest that thrombolysis decreases the mortality rate in these patients. In patients without clinical evidence of haemodynamic impairment, the mortality rate is much lower and does not justify more aggressive therapy other than anticoagulants. Recent data however suggest that among clinically stable patients, some may have a higher mortality risk. These so called sub-massive or intermediate-risk pulmonary embolism are defined either by right ventricular dysfunction assessed by echocardiography or by elevated troponin or brain natriureticpeptide. The role of thrombolytic treatment in these patients remains controversial. A large randomized controlled trial is underway to resume the debate.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
Identification of Highly Active Flocculant Proteins in Bovine Blood.
Source
U. S. Department of Agriculture, Agricultural Research Service, Eastern Regional Research Center, Biobased and Other Animal Coproducts Research Unit, 600 East Mermaid Lane, Wyndmoor, PA, 19038, USA, george.piazza@ars.usda.gov.
Abstract
Synthetic polymeric flocculants are used extensively for wastewater remediation, soil stabilization, and reduction in water leakage from unlined canals. Sources of highly active, inexpensive, renewable flocculants are needed to replace synthetic flocculants. High kaolin flocculant activity was documented for bovine blood (BB) and blood plasma with several anticoagulant treatments. BB serum also had high flocculant activity. To address the hypothesis that some blood proteins have strong flocculating activity, the BB proteins were separated by SEC. Then, the major proteins of the flocculant-active fractions were separated by SDS-PAGE. Identity of the major protein components was determined by tryptic digestion and peptide analysis by MALDI TOF MS. The sequence of selected peptides was confirmed using TOF/TOF-MS/MS fragmentation. Hemoglobin dimer (subunits α and β) was identified as the major protein component of the active fraction in BB; its high flocculation activity was confirmed by testing a commercial sample of hemoglobin. In the same manner, three proteins from blood plasma (fibrinogen, γ-globulin, α-2-macroglobulin) were found to be highly active flocculants, but bovine serum albumin, α-globulin, and β-globulin were not flocculants. On a mass basis, hemoglobin, γ-globulin, α-2-macroglobulin were as effective as anionic polyacrylamide (PAM), a widely used synthetic flocculant. The blood proteins acted faster than PAM, and unlike PAM, the blood proteins flocculants did not require calcium salts for their activity.
Familial hCG Syndrome.
Source
USA hCG Reference Service, Albuquerque, NM 87104, USA.
Abstract
An explanation is needed for why some men and women show positive in hCG screening tests when they are not pregnant, do not have cancer and are otherwise asymptomatic. In this study, a total of 10 families comprising 30 persons with a history of positive hCG tests were investigated. Total hCG was measured in serum and urine samples using the Siemens Immulite hCG test. Total hCG, C-terminal peptide determinant, and hCGβ were measured in 96 well plate assays. Twenty-four of 30 family members produced only hCGβ, and hCG or hCGβ missing the β-subunit C-terminal peptide, two rarely detected hCG degradation products as the only source of hCG immunoreactivity. In every one of the 10 families, hCG related molecules were detected first in one member and then later detected in other family members. In 8 of 10 families, all members produced comparable hCG concentration (Cases 1-8). All of the 10 original family members investigated were otherwise asymptomatic, and tested negative in ordered head and pelvis MRI scans and CT chest cancer tests. None had been administered hCG for dietary, anabolic or fertility reasons. Therefore Familial hCG Syndrome, a genetic defect, was indicated in each of the 10 families. In these cases of Familial hCG Syndrome only biologically inactive variants of hCG were detected. It is inferred that in Familial hCG Syndrome, hCG gene expression does not interfere with fertility.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Routine identity confirmation of recombinant proteins by MALDI-TOF mass spectrometry.
Source
Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR, USA. bsavary@astate.edu
Abstract
Peptide mass fingerprinting (PMF) by matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) provides a simple and direct means to unequivocally confirm identity of recombinant proteins based on predicted peptide profiles. Many universities or research institutions now carry mass spectrometry instrumentation as part of their core bioanalytical facilities or provide public service to outside investigators. This chapter provides methods we have used to generate routinely high quality samples for MALDI-TOF MS analysis. Following resolution of protein preparations by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), we easily process sets of 12 samples manually for MS analysis. Target bands are alkylated and digested in-gel with trypsin, followed by extraction ofpeptides and desalting with a C18 adsorbent resin (e.g., a "ZipTips"). Acquisition of PMF data on MALDI-TOF mass spectrometers is fast, and with on-site instrumentation, the entire process can be completed within 2 days.
Review: The hCG assay or pregnancy test.
Source
USA hCG Reference Service, Department of Obstetrics and Gynecology, University of New Mexico, Albuquerque, NM, USA.
Abstract
Abstract This review examines human chorionic gonadotropin (hCG) or pregnancy tests from multiple perspectives. It first investigates the molecule hCG and shows that the term represents five independent molecules differing in carbohydrate and meric structure that share a common amino acid sequence. The review goes on to show that multiple degradation produces also the need to be tested for an hCG or pregnancy test to be optimally efficient. The review then carefully examines the literature showing the sensitivity and specificity of automated laboratory tests. Point-of-care pregnancy tests are then investigated along with over-the-counter pregnancy tests. Appropriate detection of hyperglycosylated hCG, nicked hCG, nicked hCG missing the β-subunit C-terminal peptide and nicked hyperglycosylated hCG is a limitation on all pregnancy tests. In the opinion of the author, just one automated laboratory test, the Siemen's Immulite, one point-of-care test, the Beckman-Coulter Icon 25, and one brand of over-the-counter device, First Response, are suitable for early pregnancy detection and possibly other applications.
Photocrosslinking between Peptide-Peptide or Peptide-Oligonucleotide by Ru(II) -TAP Complexes.
Source
Service de Chimie Organique et Photochimie, Université Libre de Bruxelles, 50 Av. F. D. Roosevelt, B-1050 Bruxelles (Belgium), Fax: (+32) 26-50-30-18.
Abstract
Ru(II) -TAP complexes have been shown to be very attractive compounds in the frame of developments of new anticancer drugs targeting the genetic material. This increasing interest originates from observations of covalent bond formations, triggered by photo-induced electron transfer (PET) between Ru(II) -TAP complexes and guanine bases of DNA. This photoreaction has recently been extended to the tryptophan (Trp) amino acid for future applications involvingpeptides. Thus, a double photo-addition of Trp residues of peptides on Ru(II) complexes is demonstrated by mass spectrometry with some structural issues. Such bi-adduct formations offer the possibility of photocrosslinking two Trp-containing biomolecules, which is investigated in this study. Thus, photocrosslinking between two complementary oligonucleotides (ODNs) derivatized by Trp-containing tripeptides is demonstrated by polyacrylamide gel electrophoresis (PAGE) in the presence of Ru(II) -TAP complexes. Both PAGE and MS indicate that such photocrosslinkings arise from two reaction pathways: either via the double addition of Trp residues on the Ru complex or from dimerization of Trp radicals. The competition between these two pathways depends on the experimental conditions. Heterobridgings between guanine bases and tryptophan residues mediated by Ru(II) -TAP complexes is also examined, opening the way to ODN-peptide photocrosslinkings.
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Structural role of counterions adsorbed on self-assembled Peptide nanotubes.
Source
Institut de Biologie et de Technologies de Saclay/Service de Bioénergétique and ‡Institut de Biologie et de Technologies de Saclay/Service de Chimie Bioorganique et Marquage, Biologie Structurale et Mécanismes, Commissariat à l'Énergie Atomique et aux Énergies Alternatives-Saclay , 91191 Gif-sur-Yvette, France.
Abstract
Among noncovalent forces, electrostatic ones are the strongest and possess a rather long-range action. For these reasons, charges and counterions play a prominent role in self-assembly processes in water and therefore in many biological systems. However, the complexity of the biological media often hinders a detailed understanding of all the electrostatic-related events. In this context, we have studied the role of charges and counterions in the self-assembly of lanreotide, a cationic octapeptide. This peptide spontaneously forms monodisperse nanotubes (NTs) above a critical concentration when solubilized in pure water. Free from any screening buffer, we assessed the interactions between the different peptide oligomers and counterions in solutions, above and below the critical assembly concentration. Our results provide explanations for the selection of a dimeric building block instead of a monomeric one. Indeed, the apparent charge of the dimers is lower than that of the monomers because of strong chemisorption. This phenomenon has two consequences: (i) the dimer-dimer interaction is less repulsive than the monomer-monomer one and (ii) the lowered charge of the dimeric building block weakens the electrostatic repulsion from the positively charged NT walls. Moreover, additional counterion condensation (physisorption) occurs on the NT wall. We furthermore show that the counterions interacting with the NTs play a structural role as they tune the NTs diameter. We demonstrate by a simple model that counterions adsorption sites located on the inner face of the NT walls are responsible for this size control.
Are γ-secretase and its associated Alzheimer's disease γ problems?
Source
Clinical Analysis Service, Hospital SVS Vega Baja, Orihuela, Alicante, Spain.
Abstract
Presenilins (PS1 and PS2) and the amyloid-β precursor protein (AβPP) are the only known proteins as causing monogenic Alzheimer's disease. AβPP is not the unique substrate of the γ-secretase complex. Presenilins are also implicated in the processing of Notch, an important developmental protein, which is thought to compete directly with AβPP for cleavage by γ-secretase. In the context of cleavages in alpha, beta and gamma and with the recent three-dimensional models of γ-secretase complex, a kinetic study of the sequential proteolysis of AβPP prompts us to think the possible existence of two entrance sites for substrate with only one exit site, a configuration depicting a lowercase gamma letter. The quantitative distribution of the cleavage products by the γ-secretase, mainly Aβ(40), Aβ(42) and Aβ(43), could be explained in the context of this hypothesis. Based on published results in the literature and the analyses of AβPP C99 fragment, highly abundant in Down's syndrome patients, we propose that β- and γ-secretases can function as a supra-enzyme complex where AβPP substrate might be attached to the γ-secretase complex before β cleavage takes place. Different studies point that a small peptide sequence, showing homology in presenilins and AβPP, plays a pivotal role and that minor alterations in the sequence of AβPP protein limit the formation of C99 and also of Aβ(40) and Aβ(42). The model proposed could be of importance in future studies aimed at understanding the specific events involved in course of Alzheimer disease pathophysiology and also at studying of formation/deterioration of memory.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Brain Natriuretic Peptide Predicts Functional Outcome in Ischemic Stroke.
Source
From the J. Philip Kistler Stroke Research Center, Department of Neurology, and the Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA; the Stroke Service, Mater University Hospital, Dublin, UK; the Department of Neurology, Yale University Medical Center, New Haven CT; and the Division of Cardiology, University of California, San Francisco, CA.
Abstract
BACKGROUND AND PURPOSE:
Elevated serum levels of brain natriuretic peptide (BNP) have been associated with cardioembolic stroke and increased poststroke mortality. We sought to determine whether BNP levels were associated with functional outcome after ischemic stroke.
METHODS:
We measured BNP in consecutive patients aged ≥18 years admitted to our stroke unit between 2002 to 2005. BNP quintiles were used for analysis. Stroke subtypes were assigned using Trial of ORG 10172 in Acute Stroke Treatment criteria. Outcomes were measured as 6-month modified Rankin Scale score ("good outcome"=0-2 versus "poor") as well as mortality. Multivariate logistic regression was used to assess association between the quintiles of BNP and outcomes. Predictive performance of BNP as compared with clinical model alone was assessed by comparing receiver operating characteristic curves.
RESULTS:
Of 569 patients with ischemic stroke, 46% were female; mean age was 67.9±15 years. In age- and gender-adjusted analysis, elevated BNP was associated with lower ejection fraction (P<0.0001) and left atrial dilatation (P<0.001). In multivariate analysis, elevated BNP decreased the odds of good functional outcome (OR, 0.64; 95% CI, 0.41-0.98) and increased the odds of death (OR, 1.75; 95% CI, 1.36-2.24) in these patients. Addition of BNP to multivariate models increased their predictive performance for functional outcome (P=0.013) and mortality (P<0.03) after cardioembolic stroke.
CONCLUSIONS:
Serum BNP levels are strongly associated with cardioembolic stroke and functional outcome at 6 months after ischemic stroke. Inclusion of BNP improved prediction of mortality in patients with cardioembolic stroke.
A Role for ADAP in Collagen-Induced Platelet Activation Mediated via Integrin α2β1.
Source
School of Pharmacy, Queen's University Belfast, Belfast, BT9 7BL Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, CB2 1QW Department of Pathology, University of Cambridge, Downing Site, Cambridge, CB2 1QP Department of Haematology, University of Cambridge, National Blood Service Centre, Long Road, Cambridge, CB2 0PT Centre for Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, U.K. University of Arkansas for Medical Sciences, Department of Physiology and Biophysics, 4301 West Markham, Slot 505, Little Rock, AR 72205, U.S.A.
Abstract
Background: Collagen-induced platelet activation is a key step in the development of arterial thrombosis via its interaction with receptors glycoprotein VI (GpVI) and integrin α2β1. ADAP (adhesion and degranulation-promoting adapter protein) regulates αIIbβ3 in platelets and αLβ2 in T cells and is phosphorylated in GpVI-deficient platelets activated by collagen. Objectives: To determine whether ADAP plays a role in collagen-induced platelet activation and in the regulation and function of α2β1. Methods: Using ADAP(-/-) mice and synthetic collagen peptides, we investigated the role of ADAP in platelet aggregation, adhesion, spreading, thromboxane synthesis and tyrosine phosphorylation. Results & Conclusions: Platelet aggregation and phosphorylation of PLCγ2 induced by collagen was attenuated in ADAP(-/-) platelets. However, aggregation and signalling induced by CRP, a GpVI selective agonist, was largely unaffected. Platelet adhesion to CRP was also unaffected by ADAP deficiency. Adhesion to the α2β1 selective ligand, GFOGER, and to a peptide (III-04) which supports adhesion dependent on both GpVI and α2β1 was reduced in ADAP(-/-) platelets. An impedance-based label-free detection technique, which measures adhesion and spreading of platelets, indicated that in the absence of ADAP, spreading on GFOGER was also reduced. This was confirmed using non-fluorescent differential-interference contrast microscopy which revealed reduced filpodia formation in ADAP(-/-) platelets adherent to GFOGER. This indicates that ADAP plays a role in mediating platelet activation via the collagen-binding integrin α2β1. In addition, we found that ADAP(-/-) mice, which are mildly thrombocytopenic, have enlarged spleens compared to wild type animals. This may reflect an increased removal of platelets from the circulation.
Copyright © 2011 International Society on Thrombosis and Haemostasis.
No comments:
Post a Comment