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81.
Mahoney TR Luo S Round EK Brauner M Gottschalk A Thomas JH Nonet ML 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(42):16350-16355
The Caenorhabditis elegans defecation motor program (DMP) is a highly coordinated rhythmic behavior that requires two GABAergic neurons that synapse onto the enteric muscles. One class of DMP mutants, called anterior body wall muscle contraction and expulsion defective (aex) mutants, exhibits similar defects to those caused by the loss of these two neurons. Here, we demonstrate that aex-2 encodes a G-protein-coupled receptor (GPCR) and aex-4 encodes an exocytic SNAP25 homologue. We found that aex-2 functions in the nervous system and activates a G(s)alpha signaling pathway to regulate defecation. aex-4, on the other hand, functions in the intestinal epithelial cells. Furthermore, we show that aex-5, which encodes a pro-protein convertase, functions in the intestine to regulate the DMP and that its secretion from the intestine is impaired in aex-4 mutants. Activation of the G(s)alpha GPCR pathway in GABAergic neurons can suppress the defecation defect of the intestinal mutants aex-4 and aex-5. Lastly, we demonstrate that activation of GABAergic neurons using the light-gated cation channel channelrhodopsin-2 is sufficient to suppress the behavioral defects of aex-2, aex-4, and aex-5. These results genetically place intestinal genes aex-4 and aex-5 upstream of GABAergic GPCR signaling. We propose a model whereby the intestinal genes aex-4 and aex-5 control the DMP by regulating the secretion of a signal, which activates the neuronal receptor aex-2. 相似文献
82.
83.
Localization of human factor FVIII inhibitor epitopes to two polypeptide fragments. 总被引:9,自引:3,他引:9 下载免费PDF全文
C A Fulcher S de Graaf Mahoney J R Roberts C K Kasper T S Zimmerman 《Proceedings of the National Academy of Sciences of the United States of America》1985,82(22):7728-7732
Epitopes for 22 alloantibodies that inhibit factor VIII procoagulant protein (FVIII) from multitransfused individuals with severe hemophilia A and three autoantibodies from nonhemophilic individuals appeared to be restricted to two specific regions of the FVIII molecule. Immunoblotting of purified FVIII and purified thrombin-degraded FVIII, followed by reaction with inhibitor plasma samples, monoclonal anti-human IgG3 and IgG4 antibodies, and radiolabeled affinity-purified rabbit anti-mouse IgG, revealed that inhibitor epitopes could be localized to the Mr 72,000 and Mr 44,000 thrombin fragments of FVIII. These two chains are located at the carboxyl terminus and near the amino terminus of the FVIII molecule, respectively. The pattern of reactivity of the inhibitor alloantibodies could be divided into three types: 10 reacted with the Mr 72,000 chain, 3 reacted with the Mr 44,000 chain, and 9 reacted with both of these chains. Among the 3 inhibitor autoantibodies, 1 of each type was found. Ten normal plasmas, as well as 14 plasmas from multitransfused individuals with severe hemophilia A and no inhibitor, were not reactive with the FVIII immunoblots. However, one multitransfused individual with severe hemophilia A and no detectable inhibitor revealed the presence of an antibody reactive with the middle section of the FVIII molecule. The existence of FVIII inhibitor epitopes on both the Mr 72,000 and Mr 44,000 chains raises the possibility that these epitopes might be further restricted to regions of homology between the two chains. These data suggest the possibility of designing inhibitor blocking polypeptides for use as therapeutic agents. 相似文献
84.
Mahoney CP Weinberger E Bryant C Ito M Jameson JL Ito M 《The Journal of clinical endocrinology and metabolism》2002,87(2):870-876
Postmortem examinations of the hypothalamus of patients with autosomal dominant neurohypophyseal diabetes insipidus (adNDI), which have been reported only on persons dying between the ages of 37-87 yr, reveal the presence of the arginine vasopressin (AVP)-producing parvocellular neurons but the absence of 95% of the expected AVP-producing magnocellular neurons. To determine whether the clinical course of adNDI is compatible with the hypothesis that the neuropathologic findings are attributable to a progressive loss of magnocellular neurons beginning in early life, we performed posterior pituitary magnetic resonance imaging and water deprivation tests, including plasma ACTH measurements, on 17 affected members of a kindred with the deltaE47 neurophysin mutation whose ages ranged from 3 months to 54 yr. Nine adult nonaffected members (ages, 20-56 yr) underwent these tests as controls. All six children undergoing magnetic resonance imaging demonstrated a posterior pituitary hyperintense signal (PPHS). Eight of nine affected adults showed an absent or barely visible PPHS, whereas eight of nine age-matched nonaffected adults produced a normal size PPHS. During water deprivation tests, infants concentrated their urine normally, and a 3-month-old infant produced a high plasma AVP level of 15.7 pmol/liter. By school age, affected children were no longer able to concentrate their urine or prevent hypernatremia. Affected adults became dehydrated; their median plasma AVP level was less than 1.0 pmol/liter, but their median fasting plasma ACTH was 2-fold greater than the level of nonaffected adults (10.0 vs. 5.0 pmol/liter; P = 0.008). These results suggest that adNDI is a progressive disease associated with chronic loss of the magnocellular neurons that supply AVP to the posterior pituitary but preservation of the parvocellular neurons that supply AVP and CRH to the median eminence and stimulate ACTH production during hypernatremia. 相似文献
85.
Study was made of 95 survivors of aortic valve replacement during the early years of this procedure (1964 to 1970). The average follow-up time was 50.2 months. Survival was not related to hemodynamic parameters, such as cardiac index or left ventricular pressure, and did not appear to be influenced by the type of preoperative valve lesion. A history of angina pectoris and a New York Heart Association Class IV grouping were associated with shorter survival. Associated coronary artery disease was a leading cause of death in those patients surviving less than 2 years and angina pectoris the leading cause of morbidity in the long-term survivors. Sudden death occurred in five patients. Once a patient survived 36 months after the operation, the prognosis was excellent. 相似文献
86.
Colin J. Mahoney Ian B. Malone Gerard R. Ridgway Aisling H. Buckley Laura E. Downey Hannah L. Golden Natalie S. Ryan Sebastien Ourselin Jonathan M. Schott Martin N. Rossor Nick C. Fox Jason D. Warren 《Neurobiology of aging》2013
The primary progressive aphasias (PPA) are a heterogeneous group of language-led neurodegenerative diseases resulting from large-scale brain network degeneration. White matter (WM) pathways bind networks together, and might therefore hold information about PPA pathogenesis. Here we used diffusion tensor imaging and tract-based spatial statistics to compare WM tract changes between PPA syndromes and with respect to Alzheimer's disease and healthy controls in 33 patients with PPA (13 nonfluent/agrammatic PPA); 10 logopenic variant PPA; and 10 semantic variant PPA. Nonfluent/agrammatic PPA was associated with predominantly left-sided and anterior tract alterations including uncinate fasciculus (UF) and subcortical projections; semantic variant PPA with bilateral alterations in inferior longitudinal fasciculus and UF; and logopenic variant PPA with bilateral but predominantly left-sided alterations in inferior longitudinal fasciculus, UF, superior longitudinal fasciculus, and subcortical projections. Tract alterations were more extensive than gray matter alterations, and the extent of alteration across tracts and PPA syndromes varied between diffusivity metrics. These WM signatures of PPA syndromes illustrate the selective vulnerability of brain language networks in these diseases and might have some pathologic specificity. 相似文献
87.
EH Gemmill DJ Humes JA Catton 《Annals of the Royal College of Surgeons of England》2015,97(3):173-179
Introduction
Fast track methodology or enhanced recovery schemes have gained increasing popularity in perioperative care. While evidence is strong for colorectal surgery, its importance in gastric and oesophageal surgery has yet to be established. This article reviews the evidence of enhanced recovery schemes on outcome for this type of surgery.Methods
A systematic literature search was conducted up to March 2014. Studies were retrieved and analysed using predetermined criteria.Results
From 34 articles reviewed, 18 eligible studies were identified: 7 on gastric and 11 on oesophageal resection. Three randomised controlled trials, five case-controlled studies and ten case series were identified. The reported protocols included changes to each stage of the patient journey from pre to postoperative care. The specific focus following oesophageal resections was on early mobilisation, a reduction in intensive care unit stay, early drain removal and early (or no) contrast swallow studies. Following gastric resections, the emphasis was on reducing epidural anaesthesia along with re-establishing oral intake in the first three postoperative days and early removal of nasogastric tubes.In the papers reviewed, mortality rates following fast track surgery were 0.8% (9/1,075) for oesophageal resection and 0% (0/329) for gastric resection. The reported morbidity rate was 16.5% (54/329) following gastric resection and 38.6% (396/1,075) following oesophageal resection. Length of stay was reduced in both groups compared with conventional recovery groups in comparative studies.Conclusions
The evidence for enhanced recovery schemes following gastric and oesophageal resection is weak, with only three (low volume) published randomised controlled trials. However, the enhanced recovery approach appears safe and may be associated with a reduction in length of stay. 相似文献88.
Extracellular matrix of cultured bovine aortic endothelial cells contains functionally active type 1 plasminogen activator inhibitor 总被引:17,自引:0,他引:17
The extracellular matrix (ECM) of cultured bovine aortic endothelial cells (BAEs) was analyzed by immunoblotting and reverse fibrin autography and shown to contain type 1 plasminogen activator inhibitor (PAI-1). Most PAI-1 in the ECM formed complexes with exogenously added tissue-type plasminogen activator (tPA), demonstrating that this PAI-1 was functionally active. The resulting tPA/PAI-1 complexes were recovered in the reaction solution, indicating that the PAI-1 in such complexes no longer bound to ECM. The PAI-1 could not be removed by incubating ECM in high salt (2 mol/L NaCl), sugars (1 mol/L galactose, 1 mol/L mannose), glycosaminoglycans (10 mmol/L heparin, 10 mmol/L dermatan sulfate), or epsilon-aminocaproic acid (0.1 mol/L). However, PAI-1 could be extracted from ECM by treatment with either arginine (0.5 mol/L) or potassium thiocyanate (2 mol/L), or by incubation under acidic conditions (pH 2.5). ECM depleted of PAI-1 by acid extraction was able to bind both the active and latent forms of PAI-1. In this instance, most of the bound PAI-1 did not form complexes with tPA, indicating that the latent form was not activated as a consequence of binding to ECM. Although the PAI-1 activity in conditioned medium decayed with a half-life (t 1/2) of less than 3 hours, the t 1/2 of ECM- associated PAI-1 was greater than 24 hours. These data suggest that PAI- 1 is produced by cultured BAEs in an active form and is then either released into the medium where it is rapidly inactivated or into the subendothelium where it binds to ECM. The specific binding of PAI-1 to ECM protects it from this inactivation. 相似文献
89.
We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl- GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma. 相似文献
90.
PURPOSE: We determine the main outcome effects of a 12-month computer-mediated automated interactive voice response (IVR) intervention designed to assist family caregivers managing persons with disruptive behaviors related to Alzheimer's disease (AD). DESIGN AND METHODS: We conducted a randomized controlled study of 100 caregivers, 51 in the usual care control group and 49 in the technology intervention group, who received yearlong access to an IVR-mediated system. The system provided caregiver stress monitoring and counseling information, personal voice-mail linkage to AD experts, a voice-mail telephone support group, and a distraction call for care recipients. We conducted analyses by using a repeated measures approach for longitudinal data and an intention-to-treat analytic approach. Outcomes included the caregiver's appraisal of the bothersome nature of caregiving, anxiety, depression, and mastery at baseline, 6, 12, and 18 months. RESULTS: There was a significant intervention effect as hypothesized for participants with lower mastery at baseline on all three outcomes: bother (p =.04), anxiety (p =.01), and depression (p =.007). Additionally, wives exhibited a significant intervention effect in the reduction of the bothersome nature of caregiving (p =.02). IMPLICATIONS: Wives who exhibited low mastery and high anxiety benefited the most from the automated telecare intervention. Findings suggest that, to optimize outcome effects, similar interventions should be tailored to match the users' characteristics and preferences. 相似文献