1.
Optimization of Peptide-Based ELISA for Serological Diagnostics: A Retrospective Study of Human Monkeypox Infection.
Source
1 Najít Technologies, Inc. , Portland, Oregon.
Abstract
Abstract Although smallpox has been eradicated, other diseases caused by virulent orthopoxviruses such as monkeypox virus (MPV) remain endemic in remote areas of western and central sub-Saharan Africa, and represent a potential biothreat due to international travel and/or inadvertent exposure. Unfortunately, extensive antigenic cross-reactivity among orthopoxviruses presents a challenge to serological diagnosis. We previously reported a 20mer peptide-based ELISA that identified recent MPV infection with >90% sensitivity and >90% specificity. However, the sensitivity of this approach was not determined with samples obtained at later time points after antibody titers had declined from their peak levels. To improve assay sensitivity for detecting MPV-specific antibodies at later time points, we compared diagnostic 20mer peptides to 30mer peptides. In addition, optimal 30mer peptides were tested in combination or after conjugating selected peptides to a carrier protein (bovine serum albumin) to further improve assay performance. An optimized combination of four unconjugated 30mer peptides provided 100% sensitivity for detecting MPV infection at 2-6 months post-infection, 45% sensitivity for detecting MPV infection at >2 years post-infection, and 99% specificity. However, an optimized combination of two peptide conjugates provided 100% sensitivity for detecting MPV infection at 2-6 months post-infection, 90% sensitivity for detecting MPV infection at >2 years post-infection, and 97% specificity.Peptide-based ELISA tests provide a relatively simple approach for serological detection of MPV infection. Moreover, the systematic approach used here to optimize diagnostic peptide reagents is applicable to developing improved diagnostics to a broad range of other viruses, and may be particularly useful for distinguishing between closely-related viruses within the same genus or family.
- PMID:
- 22217169
- [PubMed - as supplied by publisher]
Isolation of synaptic terminals from Alzheimer's disease cortex.
Source
UCLA School of Nursing, Los Angeles, California 90095; UCLA Center for the Advancement of Gerontological Nursing Sciences, Los Angeles, California 90095; UCLA Brain Research Institute, Los Angeles, California 90095. ssokolow@sonnet.ucla.edu.
Abstract
Amyloid beta (Aβ) oligomers and phosphorylated tau (p-tau) aggregates are increasingly identified as potential toxic intermediates in Alzheimer's disease (AD). In cortical AD synapses, p-tau co-localizes with Aβ, but the Aβ and p-taupeptide species responsible for synaptic dysfunction and demise remains unclear. The present experiments were designed to use high-speed cell sorting techniques to purify synaptosome population based on size, and then extend the method to physically isolate Aβ-positive synaptosomes with the goal of understanding the nature of Aβ and tau pathology in AD synapses. To examine the purity of size-gated synaptosomes, samples were first gated on size; particles with sizes between 0.5 and 1.5 microns were collected. Electron microscopy documented a homogenous population of spherical particles with internal vesicles and synaptic densities. Next, size-gated synaptosomes positive for Aβ were collected by fluorescence activated sorting and then analyzed by immunoblotting techniques. Sorted Aβ-positive synaptosomes were enriched for amyloid precursor protein (APP) and for Aβ oligomers and aggregates; immunolabeling for p-tau showed a striking accumulation of p-tau aggregates compared to the original homogenate and purified synaptosomes. These results confirm co-localization of Aβ and p-tau within individual synaptic terminals and provide proof of concept for the utility of flow sorting synaptosomes. © 2011 International Society for Advancement of Cytometry.
Copyright © 2011 International Society for Advancement of Cytometry.
Growth-Differentiation Factor-15 in the Early Diagnosis and Risk Stratification of Patients with Acute Chest Pain.
Source
Department of Internal Medicine.
Abstract
BACKGROUND:
Growth-differentiation factor-15 (GDF-15) is a stress-responsive marker that might aid in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI).
METHODS:
In a prospective, international multicenter study, GDF-15, high-sensitivity cardiac troponin T (hs-cTnT), and B-type natriuretic peptide (BNP) were measured in 646 unselected patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by 2 independent cardiologists. The primary prognostic end point was all-cause mortality during a median follow-up of 26 months.
RESULTS:
AMI was the adjudicated final diagnosis in 115 patients (18%). GDF-15 concentrations at presentation were significantly higher in AMI patients compared to patients with other diagnoses. The diagnostic accuracy of GDF-15 at presentation for the diagnosis of AMI as quantified by the area under the ROC curve (AUC) was lower (AUC 0.69, 95% CI 0.64-0.74) compared to hs-cTnT (AUC 0.96, 95% CI 0.94-0.98, P < 0.001) and BNP (AUC 0.74, 95% CI 0.69-0.80, P = 0.02). A total of 55 deaths occurred during follow-up. GDF-15 predicted all-cause mortality independently of and more accurately than hs-cTnT [AUC 0.85 (95% CI 0.81-0.90) vs 0.77 (95% CI 0.72-0.83), P = 0.002] and BNP (AUC 0.75, 95% CI 0.68-0.82, P = 0.007). Net reclassification improvement was 0.15 (P = 0.01), and the absolute integrated discrimination improvement was 0.07, yielding a relative integrated discrimination improvement of 0.36 (P = 0.07).
CONCLUSIONS:
GDF-15 predicts all-cause mortality in unselected patients with acute chest pain independently of and more accurately than hs-cTnT and BNP. However, GDF-15 does not seem to help in the early diagnosis of AMI.
Fibrillar Amyloid-β1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase.
Source
Laboratory of Cellular and Molecular Neurosciences, University of Chile and International Center for Biomedicine (ICC), Santiago, Chile.
Abstract
The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer's disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.
Novel Biomarkers in Diagnosing Cardiac Ischemia in the Emergency Department: A Systematic Review.
Source
Division of Emergency Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Rescu, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Health Policy, Management & Evaluation, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND:
: Novel biomarkers of myocardial ischemia and inflammatory processes have the potential to improve diagnostic accuracy of acute coronary syndrome (ACS) within a shorter time interval after symptom onset.
OBJECTIVE:
: The objective was to review the recent literature and evaluate the evidence for use of novel biomarkers in diagnosing ACS in patients presenting with chest pain or symptoms suggestive of cardiac ischemia to the emergency department or chest pain unit.
METHODS:
: A literature search was performed in MEDLINE, EMBASE, Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR, HTA, and NHSEED for studies from 2004-2010. We used the inclusion criteria: 1) Human subjects, 2) Peer-reviewed articles, 3) Enrolled patients with ACS, acute myocardial infarction or undifferentiated signs and symptoms suggestive of ACS, and 4) English language or translated manuscripts. Two reviewers conducted a hierarchical selection and assessment using a scale developed by the International Liaison Committee on Resuscitation.
RESULTS:
: Out of a total 3194 citations, 58 articles evaluating 37 novel biomarkers were included for final review. Forty-one studies did not support the use of their respective biomarkers. Seventeen studies supported the use of 5 biomarkers, particularly when combined with cardiac-specific troponin: heart fatty acid-binding protein, ischemia-modified albumin, B-type natriuretic peptide, copeptin, and matrix metalloproteinase-9.
CONCLUSION:
: In patients presenting to the emergency department with chest pain or symptoms suggestive of cardiac ischemia, there is inadequate evidence to suggest the routine testing of novel biomarkers in isolation. However, several novel biomarkers have the potential to improve the sensitivity of diagnosing ACS when combined with cardiac-specific troponin.
Copyright © 2011. Published by Elsevier Ireland Ltd.
Urocontrin, a novel UT receptor ligand with a unique pharmacological profile.
Source
Laboratoire d'études moléculaires et pharmacologiques des peptides, Université du Québec, INRS - Institut Armand-Frappier, Ville de Laval, Québec, Canada; Laboratoire International Associé Samuel de Champlain (INSERM - INRS - Université de Rouen), Canada.
Abstract
In recent years, several studies have demonstrated that urotensin II (UII) and urotensin II-related peptide (URP) can exhibit differential biological activity. So far, known antagonists of the urotensin II receptor (UT) are of limited usefulness for investigating the specific pathophysiological role of UII or URP. Therefore, identification of new compounds able to discriminate UII- and URP-associated biological activities is crucially needed. In the present study, we report preliminary data regarding the pharmacological properties of a novel UT ligand termed urocontrin, i.e. [Bip(4)]URP, that is able to reduce the ex vivo efficacy of hUII- but not URP-induced vasoconstriction in rat aortic rings. In vivo studies support the pharmacological profile described above. Although urocontrin exert some residual agonist activity, this compound should be useful for the rational design of potent molecules that would allow discriminating specific biological action mediated by UII or URP.
Copyright © 2011. Published by Elsevier Inc.
Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors.
Source
Division of Endocrinology, Molecular Medicine and Metabolism, Department of Internal Medicine, Charles R. Drew University of Medicine & Sciences-David Geffen School of Medicine at UCLA, Los Angeles, CA 90059 College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766.
Abstract
Corticosterone-releasing hormone (CRH) and arginine vasopressin (AVP) are crucial components of the hypothalamic-pituitary-adrenal (HPA) axis that stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary and mediate the stress response. CRH binds to two subtypes of CRH receptors (CRH-R1 and CRH-R2) that are present in both central and peripheral tissues. We used the CRH-R1 specific antagonist, antalarmin (ANT), the CRH-R1 and CRH-R2 peptide antagonist, astressin (AST), and the CRH-R2 specific peptide antagonist, astressin2b (AST2b), to determine which CRH receptor is involved in the nicotine-stimulated secretion of corticosterone. Male C57BL/6 mice were administered ANT (20 mg/kg, i.p.), AST (0.3 mg/kg, i.p.), AST2b (0.3 mg/kg, i.p.) or vehicle prior to administration of nicotine (1.0 mg/kg, s.c.), CRH (10 μg/kg, s.c.), AVP (10 μg/kg, s.c.) or saline (SAL) (s.c.), sacrificed 15 min later and trunk blood collected and assayed for corticosterone plasma levels. We found that CRH enhanced corticosterone release, and this response was blocked by both AST and ANT. Nicotine also increased corticosterone secretion, but this effect persisted in the presence of either CRH antagonist. Furthermore, AST but not ANT or AST2b decreased corticosterone levels associated with stress of handling and injection. We also assessed the role of AVP V(1b) specific receptor antagonist, SSR149415 alone and in combination with AST and AST2b. Although the AVP antagonist did not alter basal or nicotine-stimulated corticosterone secretion, it attenuated the AVP-induced stimulation of corticosterone and its combination with AST but not AST2b completely abolished nicotine-mediated stimulation of corticosterone secretion. Our results demonstrate that the nicotine-induced stimulation of the hypothalamic-pituitary adrenal axis (HPA) is mediated by both the CRH-R and the AVP V(1b) receptor and when the CRH receptor is blocked, nicotine may utilize the AVP V(1b) receptor to mediate secretion of corticosterone. These results argue in favor of the development of specific antagonists that block both AVP and CRH receptors to decrease the pleasurable component of nicotine, which may be mediated by corticosterone © 2011 The Authors Journal of Neurochemistry© 2011 International Society for Neurochemistry.
© 2011 The Authors Journal of Neurochemistry © 2011 International Society for Neurochemistry.
Clinical features of patients with left atrial thrombus undergoing anticoagulant therapy.
Source
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Abstract
PURPOSE:
Left atrial (LA) thrombus was sometimes found by transesophageal echocardiography (TEE) in non-valvular atrial fibrillation (AF), even in the setting of continuous warfarin therapy. A D-dimer cutoff level of 0.50 μg/mL appears to be a useful marker to rule out venous vein thrombosis. This study analyzed the clinical features of patients with LA thrombi who received anticoagulant therapy and whether the D-dimer test is useful to exclude LA thrombus.
METHODS:
Two hundred twenty-five consecutive patients with AF (149 with paroxysmal and 76 with persistent) were enrolled. All patients received continuous warfarin therapy with the prothrombin time-international normalized ratio (PT-INR) between 1.6 and 3.0 for more than 3 months and TEE was performed.
RESULTS:
LA thrombi were present in 23 and absent in 202 patients. Age, gender, and PT-INR (1.96 ± 0.59 vs. 1.98 ± 0.53) were not different between the two groups. Persistent AF (65 vs. 30%; p < 0.005), LA diameter (44 ± 5 vs. 40 ± 7 mm; p < 0.005), ejection fraction (57 ± 13 vs. 65 ± 9%; p < 0.005), brain natriuretic peptide levels (203 ± 209 vs. 105 ± 166 pg/mL; p < 0.05), D-dimer (0.55 ± 0.70 vs. 0.16 ± 0.20 μg/mL; p < 0.001), LA appendage flow velocity (33 ± 15 vs. 54 ± 19 cm/s; p < 0.001), CHADS(2) scores (2 ± 1 vs. 1 ± 1; p < 0.005), and CHA(2)DS(2)-VASc scores (3 ± 2 vs. 2 ± 1; p < 0.005) were significantly different in both groups. Although multivariate analysis showed that D-dimer and LA appendage flow velocity were significant independent predictors of LA thrombus, D-dimer levels below 0.5 μg/mL were found in 19 of 23 patients with LA thrombi.
CONCLUSION:
D-dimer levels below 0.5 μg/mL is not enough to rule out LA thrombus in AF patients with well-controlled anticoagulation.
Neurotherapeutics to inhibit exocytosis from sensory neurons for the control of chronic pain.
Source
International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland.
Abstract
There is a pressing unmet need for long-acting and effective therapeutics to alleviate symptoms of the varied forms of chronic pain. As many sufferers do not respond satisfactorily to non-addictive anti-nociceptives, a new treatment has emerged using inhibitors for the release of pain mediators from peripheral sensory nerves to give prolonged benefit. This strategy relies on proteolytically inactivating intra-neuronal SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptors) proteins which are essential for regulated exocytosis of transmitters, peptides and other pain signalling molecules. Success has been achieved with botulinum neurotoxin A (BoNT/A) which targets neuronal acceptors via its heavy chain, becomes endocytosed and translocated into the cytosol where the long-lived protease of its light chain potently and specifically cleaves SNAP-25 (synaptosomal-associated protease of Mr=25k). Encouragingly, clinical trials have shown that local injections of BOTOX(®) (BoNT/A complex) reduce chronic migraine symptoms including frequency and intensity for many months. Several serotypes of the neurotoxin moiety alone have been prepared recombinantly using Escherichia coli, which exhibit optimal neuroparalysis. Moreover, an engineered chimera of BoNT/E in which its binding domain was replaced with that from /A efficaciously inhibits the TRPV1 (transient receptor potential vanilloid type 1)-triggered release of CGRP (calcitonin gene-related peptide) from cultured sensory neurons, and suppresses the resultant excitatory effects in brain slices. A longer acting composite toxin, containing the protease of type E attached to BoNT/A, displays prolonged amelioration of pain symptoms in an animal model of inflammatory pain. This provides proof of principle that therapeutically advantageous features of /E (most robust inhibitor of CGRP release) and /A (targeting to sensory neurons and dramatic extension of the longevity of E protease) can be incorporated into a single synergistically active anti-nociceptive.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Conference report: the 19th international reid bioanalytical forum.
Source
Huntingdon Life Sciences, Woolley Road, Alconbury, Huntingdon, Cambridgeshire, PE16 5HS, UK. hillh@ukorg.huntingdon.com.
Abstract
The 19th International Reid Bioanalytical Forum was attended by over 120 participants. The Forum divided into approximately eight broad topics, although not always in the same session. The meeting commenced with a discussion on metabolites in safety testing, with emphasis on enabling technologies and philosophies. This was followed by a variety of regulatory-based issues initiated by Brian Booth of the US FDA. The next day started with a review of developing technologies in LC-MS and some anecdotal troubleshooting experiences. Interspersed among the sessions were experiences with bioanalysis in the discovery environment, biomarker-based topics and the rapidly developing field of the quantitation of proteins and peptides using LC-MS. The meeting finished with the best-attended session of the Forum on developing trends in using dried blood spots.
Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance.
Source
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain.
Abstract
Objective:Lipopolysaccharide-binding protein (LBP) is a 65-kDa acute-phase protein present in blood at high concentrations, known to be derived from the liver. We aimed to gain insights into the association of circulating LBP with insulin resistance in humans and mice.Methods, design and measurements:We studied the cross-sectional (n=222) and weight loss-induced (n=34) associations of LBP (enzyme-linked immunosorbent assay) with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity), and the effects of high-fat diet (HFD), metformin and genetic insulin sensitization (glucagon-like peptide 1 receptor knockout model) in mice.Results:Circulating LBP concentration was significantly increased in subjects with type 2 diabetes and dramatically increased in subjects with morbid obesity. LBP was significantly associated with insulin sensitivity and different inflammatory markers and decreased after weight loss (22.2±5.8 vs 16.2±9.3 μg ml(-1), P<0.0001) in association with changes in body mass index and insulin sensitivity. Circulating LBP concentration was increased in HFD mice, whereas decreased in glucagon-like peptide 1 receptor knockout mice (significantly more insulin sensitive than wild-type mice) and after metformin administration.Conclusion:LBP is an inflammatory marker associated with obesity-related insulin resistance.International Journal of Obesity advance online publication, 20 December 2011; doi:10.1038/ijo.2011.256.
The SH2-domain of SHIP1 interacts with the SHIP1 C-terminus: Impact on SHIP1/Ig-α interaction.
Source
RWTH Aachen University, Medical Faculty, Department of Biochemistry and Molecular Immunology, Institute of Biochemistry and Molecular Biology, 52074 Aachen, Germany; International Max Planck Research School, 79108 Freiburg, Germany.
Abstract
The SH2-containing inositol 5'-phosphatase, SHIP1, negatively regulates signal transduction from the B cell antigen receptor (BCR). The mode of coupling between SHIP1 and the BCR has not been elucidated so far. In comparison to wild-type cells, B cells expressing a mutant IgD- or IgM-BCR containing a C-terminally truncated Ig-α respond to pervanadate stimulation with markedly reduced tyrosine phosphorylation of SHIP1 and augmented activation of protein kinase B. This indicates that SHIP1 is capable of interacting with the C-terminus of Ig-α. Employing a system of fluorescence resonance energy transfer in S2 cells, we can clearly demonstrate interaction between the SH2-domain of SHIP1 and Ig-α. Furthermore, a fluorescently labeled SH2-domain of SHIP1 translocates to the plasma membrane in an Ig-α-dependent manner. Interestingly, whereas the SHIP1 SH2-domain can be pulled-down with phospho-peptidescorresponding to the immunoreceptor tyrosine-based activation motif (ITAM) of Ig-α from detergent lysates, no interaction between full-length SHIP1 and the phosphorylated Ig-α ITAM can be observed. Further studies show that the SH2-domain of SHIP1 can bind to the C-terminus of the SHIP1 molecule, most probably by inter- as well as intra-molecular means, and that this interaction regulates the association between different forms of SHIP1 and Ig-α.
Copyright © 2011 Elsevier B.V. All rights reserved.
In Vivo Expression of Salmonella enterica Serotype Typhi Genes in the Blood of Patients with Typhoid Fever in Bangladesh.
Source
International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B), Dhaka, Bangladesh.
Abstract
BACKGROUND:
Salmonella enterica serotype Typhi is the cause of typhoid fever. It is a human-restricted pathogen, and few data exist on S. Typhi gene expression in humans.
METHODOLOGY/PRINCIPAL FINDINGS:
We applied an RNA capture and amplification technique, Selective Capture of Transcribed Sequences (SCOTS), and microarray hybridization to identify S. Typhi transcripts expressed in the blood of five humans infected with S. Typhi in Bangladesh. In total, we detected the expression of mRNAs for 2,046 S. Typhi genes (44% of the S. Typhi genome) in human blood; expression of 912 genes was detected in all 5 patients, and expression of 1,100 genes was detected in 4 or more patients. Identified transcripts were associated with the virulence-associated PhoP regulon, Salmonella pathogenicity islands, the use of alternative carbon and energy sources, synthesis and transport of iron, thiamine, and biotin, and resistance to antimicrobial peptides and oxidative stress. The most highly represented group were genes currently annotated as encoding proteins designated as hypothetical, unknown, or unclassified. Of the 2,046 detected transcripts, 1,320 (29% of the S. Typhi genome) had significantly different levels of detection in human blood compared to in vitro cultures; detection of 141 transcripts was significantly different in all 5 patients, and detection of 331 transcripts varied in at least 4 patients. These mRNAs encode proteins of unknown function, those involved in energy metabolism, transport and binding, cell envelope, cellular processes, and pathogenesis. We confirmed increased expression of a subset of identified mRNAs by quantitative-PCR.
CONCLUSIONS/SIGNIFICANCE:
We report the first characterization of bacterial transcriptional profiles in the blood of patients with typhoid fever. S. Typhi is an important global pathogen whose restricted host range has greatly inhibited laboratory studies. Our results suggest that S. Typhi uses a largely uncharacterized genetic repertoire to survive within cells and utilize alternate energy sources during infection.
Right ventricular function in AL amyloidosis: characteristics and prognostic implication.
Source
Intensive Cardiac Care Unit, Heart and Vessel Department, Azienda Ospedaliero Universitaria Careggi, University of Florence, Largo Brambilla 3, 50127 Florence, Italy.
Abstract
AimThe importance of right ventricle (RV) dysfunction in AL amyloidosis has been underestimated. This study was designed to comprehensively evaluate RV function and its prognostic role in patients with AL amyloidosis with and without echocardiographic evidence of cardiac involvement.Method and resultsFifty-two biopsy-proven AL amyloidosis patients underwent a thorough echocardiographic evaluation. Twenty-seven patients (CA) met the internationalechocardiographic criteria for cardiac involvement [left ventricular (LV) wall thickness ≥12 mm] and 25 patients had no cardiac amyloidosis features (NCA). Patients were compared with a sex- age-matched control group. Patients and controls underwent traditional, tissue Doppler (TDI), speckle-tracking left and RV echocardiographic evaluation. No difference was observed between groups in RV diastolic diameter, whereas CA patients showed increased RV free wall thickness (P< 0.0001). Compared with controls and NCA patients, traditional echocardiography, TDI, and speckle-tracking evaluation detected significantly (P< 0.0001) depressed RV longitudinal systolic function in CA patients. No difference was observed between groups at Doppler diastolic evaluation, whereas at tricuspidal annulus TDI analysis, CA subject showed significantly lower E' and A' values with increased E/E' ratio (P< 0.0001). Over a 19 months median follow-up period, 18 patients died. Cox multivariate analysis showed that N-terminal pro-Brain natriuretic peptide and RV longitudinal strain were the strongest death predictor. CONCLUSION: Our data show that in patients with AL amyloidosis, RV involvement develops later than LV amyloid deposition but when it occurs, prognosis dramatically worsens. Moreover RV longitudinal strain was the only echocardiographic predictor of prognosis. We suggest that RV function analysis should be performed routinely as a part of echocardiographic evaluation in these patients.
BACE1 Trafficking and Alzheimer's Disease Pathogenesis.
Source
Department of Pathology, and Mental Health Research Institute, The University of Melbourne, Parkville VIC 3010, Australia.
Abstract
BACE1 cleaves the amyloid precursor protein (APP) at the β-secretase site to initiate the production of Aβ peptides. These accumulate to form toxic oligomers and the amyloid plaques associated with Alzheimer's disease (AD). An increase of BACE1 levels in the brain of AD patients has been mostly attributed to alterations of its intracellular trafficking. Golgi-associated adaptor proteins, GGA sort BACE1 for export to the endosomal compartment, which is its major cellular site of BACE1 activity. BACE1 undergoes recycling between endosome, trans-Golgi network (TGN), and the plasma membrane, from where it is endocytosed and either further recycled or retrieved to the endosome. Phosphorylation of Ser498 facilitates BACE1 recognition by GGA1 for retrieval to the endosome. Ubiquitination of BACE1 C-terminal Lys501 signals GGA3 for exporting BACE1 to the lysosome for degradation. In addition, the retromer mediates the retrograde transport of BACE1 from endosome to TGN. Decreased levels of GGA proteins and increased levels of retromer-associated sortilin have been associated with AD. Both would promote the co-localization of BACE1 and APP in the TGN and endosomes. Decreased levels of GGA3 also impair BACE1 degradation. Further understanding of BACE1 trafficking and its regulation may offer new therapeutic approaches for the treatment of Alzheimer's disease. © 2011 The Authors Journal of Neurochemistry© 2011 International Society for Neurochemistry.
© 2011 The Authors Journal of Neurochemistry © 2011 International Society for Neurochemistry.
Evaluation of Kisspeptin Levels in Obese Pregnancy as a Biomarker for Pre-Eclampsia.
Source
Clinical Biochemistry, Wishaw General Hospital, Wishaw, Lanarkshire, ML2 0DP Tommy's Centre for Fetal and Maternal Health, MRC Centre for Reproductive Health Endocrinology Unit, University/BHF Centre for Cardiovascular Sciences, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ.
Abstract
Objective(s): Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre-eclampsia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay, and to determine sensitivity and specificity of the test for pre-eclampsia. Design: Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic. Patients: Severely obese (body mass index, BMI>40kg/m(2) , n=194) and lean (BMI<25kg/m(2) , n=78) pregnant women. Measurements: A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery, and stability in maternal plasma samples at 16, 28 and 36 weeks gestation. Pre-eclampsia, defined using International Society for the Study of Hypertension in Pregnancy guidelines; blood pressure; delivery gestation; birthweight. Results: Kisspeptin concentrations were lower in early pregnancy in obese women (p<0.001), and in women who later developed pre-eclampsia (p<0.05), compared with women with uncomplicated pregnancies. For 16 week plasma kisspeptin in prediction of pre-eclampsia, area under the ROC curve was 0.80 (p<0.01), positive and negative likelihood ratios were 3.0 and 0.2, and test sensitivity and specificity were 85.7% and 71.4% respectively. In regression analyses kisspeptin (16 weeks) associated positively with delivery gestation (p<0.05), and birthweight (p<0.0001), and negatively with 28 and 36 week blood pressure (p<0.0001). Conclusions: Kisspeptin concentration in early pregnancy is a promising biomarker for pre-eclampsia and low birthweight but cannot be recommended, in isolation, for universal screening due to inadequate test sensitivity and specificity. Large-scale studies are required to assess its potential in a panel of biomarkers. © 2011 Blackwell Publishing Ltd.
© 2011 Blackwell Publishing Ltd.
Early cardiac abnormalities and serum N-terminal pro B-type natriuretic peptidelevels in obese children.
Source
Department of Pediatrics, Karaelmas University, Zonguldak, Turkey.
Abstract
OBJECTIVE:
The aim of this study was to evaluate early cardiac abnormalities in obese children by the conventional echocardiography and to verify whether N-terminal pro B-type natriuretic peptide (NT-proBNP) differ between obese and healthy children.
METHODS:
We started this study with 68 obese children and 35 healthy controls matched for age and sex. Body mass index (BMI) was calculated. Children with a BMI > or = 95th percentile were considered obese. Thirty children in the obese group were also diagnosed with metabolic syndrome, according to the International Diabetes Federation criteria. Standard echocardiographic study was performed on each patient and control subject. Diastolic filling parameters were evaluated using pulsed-wave tissue Doppler method. Blood samples were taken at 8 a.m. to study blood biochemistry tests, including insulin, lipids, glucose, and NT-proBNP. Serum NT-proBNP levels were measured by a solid-phase, enzyme-labeled chemiluminescent immunometric assay. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. Children with HOMA-IR > 3.16 were considered insulin-resistant.
RESULTS:
There were diastolic filling abnormalities in obese children, as shown by a decreased mitral valve early filling (E) wave/late filling (A) ratio and a prolongation in E-wave deceleration time. The levels of NT-proBNP were not statistically different among the groups. The levels of NT-proBNP were not different between obese children with and without metabolic syndrome, those with and without hypertension, and those with and without insulin resistance, respectively.
CONCLUSION:
Although there were diastolic filling abnormalities in obese children, their NT-proBNP levels were not different from healthy controls. It seems that there is no diagnostic value in NT-proBNP levels between obese children and healthy controls.
- PMID:
- 22145463
- [PubMed - indexed for MEDLINE]
The 10th International Symposium on VIP-PACAP and Related PeptidesDecember 13-16, 2011 Eilat, Israel.
Influence of age, race, sex, and body mass index on interpretation of midregional pro atrial natriuretic peptide for the diagnosis of acute heart failure: results from the BACH multinational study.
Source
University of California, San Diego, La Jolla, CA, USA.
Abstract
AIMS:
Midregional pro atrial natriuretic peptide (MR-proANP) is useful for diagnosing acute heart failure (HF) in patients presenting to the Emergency Department with dyspnoea. Optimal interpretation of MR-proANP requires understanding of how various demographic variables influence its levels and performance as a diagnostic marker. We sought to determine how age, race, sex, and body mass index (BMI) affect the levels and interpretation of MR-proANP for the diagnosis of acute HF.
METHODS AND RESULTS:
The Biomarkers in Acute Heart Failure (BACH) study was an international 15-centre study of 1641 patients presenting to the Emergency Department with acute dyspnoea. Of these, 1352 had complete information on age, race, sex, and BMI. MR-proANP levels increased with age and were higher in men and in patients with lower BMI. MR-proANP performed better as a diagnostic marker in younger individuals and in blacks compared with whites. Despite this, MR-proANP at the recommended cut-off point of 120 pmol/L was >90 % sensitive in ruling out the diagnosis of acute HF in all subgroups of patients except white subjects <50 years old.
CONCLUSION:
Age, race, sex, and BMI affect MR-proANP levels to various degrees. However, the diagnostic performance of the recommended cut-off point of 120 pmol/L to rule out acute HF was robust across most subgroups. Although both sex and BMI affected MR-proANP levels, they did not alter its overall diagnostic performance. Lower cut-off points for MR-proANP could be considered in younger patients and in patients with a higher BMI, to optimize diagnostic sensitivity.
CD4+ T cell derived novel peptide Thp5 induces IL-4 production in CD4+ T cells to direct T helper 2 cell differentiation.
Source
International Center for Genetic Engineering and Biotechnology, India;
Abstract
The differentiation of naive CD4+ T cells into T helper 2 (Th2) cells requires production of the cytokine IL-4 in the local microenvironment. It is evident that naive/quiescently activated CD4+ T cells produce the IL-4 that drives Th2 cell differentiation. Because early production of IL-4 in naive T cells leads to preferential Th2 cell differentiation, this process needs to be tightly regulated so as to avoid catastrophic and misdirected Th2 cell differentiation. Here, we show that Thp5, a novel peptide with structural similarity to vasoactive intestinal peptide (VIP), regulates production of early IL-4 in newly activated CD4+ T cells. Induction of IL-4 in CD4+ T cells by Thp5 is independent of the transcription factor STAT6 but dependent on Erk-1/2 signaling. Furthermore, cytokines (IL-12 and TGF-β) that promote the differentiation of Th1 or Th17 cells inhibit Thp5 induction, thus suppressing Th2 cell differentiation. We further showed that Thp5 enhances Th2 responses and exacerbates allergic airway inflammation (AAI) in mice. Taken together, our findings reveal that early-activated CD4+ T cells produce Thp5, which plays a critical role as a molecular switch in the differentiation of Th cells, biasing the response towards the Th2 cell phenotype.
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