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1.
Article in English | MEDLINE | ID: mdl-39306558

ABSTRACT

AIMS: In patients with locally advanced non-small cell lung cancer (LA-NSCLC), curative-intent radiotherapy (RT) or chemoradiotherapy (CRT) is associated with considerable toxicity, and approximately half of the patients die within two years. A better understanding of early mortality is needed to improve patient selection and guide supportive interventions. In this population-based, nationwide cohort study, we investigated the incidence, temporal distribution, and risk factors of early mortality. MATERIALS AND METHODS: Patients with stage II-III NSCLC treated with curative-intent RT/CRT in Denmark from 2010-2017 were included. Patients treated with preoperative or postoperative RT/CRT or stereotactic body radiation therapy were excluded. Early mortality was defined as all-cause death within 180 days from RT/CRT initiation. Multiple logistic regression was used to assess the impact of clinical and demographic variables. RESULTS: We included 1742 patients. The early mortality rate was 10%. The temporal distribution of deaths was uniform across the first year following RT/CRT, indicating the absence of a high-risk period. In multivariable analysis, increasing age and performance status, male sex, and unspecified histology (NSCLC not otherwise specified) were associated with an increased risk. By contrast, the Charlson Comorbidity Index (CCI), TNM stage, and treatment period did not significantly alter the risk of early mortality. Overall survival rates improved throughout the inclusion period but early mortality rates did not. CONCLUSION: No high-risk period for early mortality could be identified. Early mortality was not associated with CCI and other tools should be explored to quantify comorbidity for risk stratification in this setting.

2.
Int J Cardiovasc Imaging ; 40(4): 931-940, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38386192

ABSTRACT

Virtual mono-energetic images (VMI) using dual-layer computed tomography (DLCT) enable substantial contrast medium (CM) reductions. However, the combined impact of patient size, tube voltage, and heart rate (HR) on VMI of coronary CT angiography (CCTA) remains unknown. This phantom study aimed to assess VMI levels achieving comparable contrast-to-noise ratio (CNR) in CCTA at 50% CM dose across varying tube voltages, patient sizes, and HR, compared to the reference protocol (100% CM dose, conventional at 120 kVp). A 5 mm artificial coronary artery with 100% (400 HU) and 50% (200 HU) iodine CM-dose was positioned centrally in an anthropomorphic thorax phantom. Horizontal coronary movement was matched to HR (at 0, < 60, 60-75, > 75 bpm), with varying patient sizes simulated using phantom extension rings. Raw data was acquired using a clinical CCTA protocol at 120 and 140 kVp (five repetitions). VMI images (40-70 keV, 5 keV steps) were then reconstructed; non-overlapping 95% CNR confidence intervals indicated significant differences from the reference. Higher CM-dose, reduced VMI, slower HR, higher tube voltage, and smaller patient sizes demonstrated a trend of higher CNR. Regardless of HR, patient size, and tube voltage, no significant CNR differences were found compared to the reference, with 100% CM dose at 60 keV, or 50% CM dose at 40 keV. DLCT reconstructions at 40 keV from 120 to 140 kVp acquisitions facilitate 50% CM dose reduction for various patient sizes and HR with equivalent CNR to conventional CCTA at 100% CM dose, although clinical validation is needed.


Subject(s)
Computed Tomography Angiography , Contrast Media , Coronary Angiography , Coronary Vessels , Heart Rate , Phantoms, Imaging , Predictive Value of Tests , Radiation Dosage , Humans , Coronary Angiography/instrumentation , Coronary Angiography/methods , Computed Tomography Angiography/instrumentation , Contrast Media/administration & dosage , Coronary Vessels/diagnostic imaging , Radiation Exposure/prevention & control , Radiographic Image Interpretation, Computer-Assisted , Body Size
3.
Radiother Oncol ; 171: 53-61, 2022 06.
Article in English | MEDLINE | ID: mdl-35421513

ABSTRACT

INTRODUCTION: SBRT of central lung tumours implies significant risk of toxicity. We are initiating two phase II trials prescribing 56 Gy/eight fractions to PTV, allowing for dose escalation of GTV. We prioritize organs at risk (OAR) constraints over target coverage, making the treatment plans very sensitive to OAR delineation variations. The aim of this study is to quantify the dosimetric impact of contouring variations and to provide a thorough description of pre-trial quality assurance to be used in upcoming trials to provide consistent clinical care. MATERIALS AND METHODS: Delineation: Seven physicians delineated OAR in three rounds, with evaluations in-between. For each patient case, seven treatment plans, repeatedly using each of the OAR structure sets from the seven physicians, were made and compared to evaluate the dosimetric effect of delineation variability. Treatment planning: Treatment plans for seven cases were made at six departments in two rounds, with discussion in-between. RESULTS: OAR delineation variation between centres resulted in high variabilities in OAR dose for simulated plans and led to potential overdosage of the lobar bronchus (constraint: D0.03cc < 45 Gy), with maximum doses ranging between 58 Gy (first round), and 50 Gy (third round). For mediastinal tissue, the constraint (D0.03cc < 45 Gy) was violated for the majority of the delineations in all three rounds, with maximum doses of 84 Gy (first round), and 72 Gy (third round).For the treatment planning study, the range of the standard deviation for GTV mean dose was 12.8-18.5 Gy (first round) and 2.8-3.5 Gy (second round). CONCLUSIONS: Even small variations in OAR delineation led to high OAR overdosage. The study demonstrates the importance of having extensive QA procedures in place before initiating clinical trials on dose escalation in SBRT.


Subject(s)
Lung Neoplasms , Radiosurgery , Radiotherapy, Intensity-Modulated , Humans , Lung Neoplasms/radiotherapy , Lung Neoplasms/surgery , Organs at Risk , Radiosurgery/adverse effects , Radiosurgery/methods , Radiotherapy Dosage , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy, Intensity-Modulated/methods , Retrospective Studies
5.
Acta Psychiatr Scand ; 132(6): 470-8, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26696384

ABSTRACT

OBJECTIVE: To explore physical health problems and their causes in patients with severe mental illness, as well as possibilities for prevention and treatment from the patients' and staff's perspectives. METHOD: We conducted six focus groups with patients and staff separately, from three out-patient clinics treating patients with schizophrenia or substance-use disorder comorbid to another psychiatric disorder. Focus groups were audio-recorded, transcribed verbatim and analysed using a template approach. RESULTS: Paramount physical health problems are weight issues, cardiovascular diseases and poor physical shape. Main causes are lifestyle, the mental disorder and organisational issues. Patients and staff expressed similar opinions regarding physical health problems and their causes. Possibilities for prevention and treatment includes a case manager and binding communities with like-minded, as well as management support and implementation of physical health into daily psychiatric practice. Although patients and staff suggested different possibilities for prevention and treatment, they support one strategy: less fragmentation of the treatment system and cooperation between psychiatric and somatic healthcare. CONCLUSION: To prevent and treat physical health problems in patients with severe mental illness, support in daily structure and lifestyle changes is needed. Management support is needed to change daily practice and implement routines regarding physical health.


Subject(s)
Attitude of Health Personnel , Health Knowledge, Attitudes, Practice , Health Status , Life Style , Mental Disorders , Adult , Denmark , Female , Focus Groups , Health Promotion , Humans , Male
6.
Acta Psychiatr Scand ; 132(6): 441-50, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26463889

ABSTRACT

OBJECTIVE: The time span between knowledge becoming available and its integration into daily clinical routine is lengthy. This phenomenon is explored in this study. METHOD: We used the outcomes of our activities for investigating and strengthening the research-based activities to improve physical health in the routines of clinical psychiatric wards as examples for our analyses. RESULTS: The time span between new knowledge becoming available and its implementation into general clinical treatment is very long. However, a shortening of this time span is seen through active leadership backup and clinical research experience among psychiatrists and staff in the wards. In particular, the involvement of medical students interested in clinical research activities seems to have a positive impact. CONCLUSION: Academia needs to be re-implemented into clinical psychiatry. Staff with research experience is needed in all professions to increase evidence-based practice. Leaders must take responsibility for implementing new knowledge into the routines of the department and must support staff in these activities on a daily basis.


Subject(s)
Biomedical Research/organization & administration , Knowledge , Mental Disorders/therapy , Psychiatric Department, Hospital/organization & administration , Psychiatry/organization & administration , Biomedical Research/standards , Humans , Psychiatric Department, Hospital/standards , Psychiatry/standards , Time Factors
10.
Diabet Med ; 31(5): 615-23, 2014 May.
Article in English | MEDLINE | ID: mdl-24246087

ABSTRACT

AIMS: The Associazione Medici Diabetologi-annals initiative is a physician-led quality-of-care improvement scheme that has been shown to improve HbA1c concentration, blood pressure, lipid profiles and BMI in enrolled people with Type 2 diabetes. The present analysis investigated the long-term cost-effectiveness of enrolling people with Type 2 diabetes in the Associazione Medici Diabetologi-annals initiative compared with conventional management. METHODS: Long-term projections of clinical outcomes and direct costs (in 2010 Euros) were made using a published and validated model of Type 2 diabetes in people with Type 2 diabetes who were either enrolled in the Associazione Medici Diabetologi-annals initiative or who were receiving conventional management. Treatment effects were based on mean changes from baseline seen at 5 years after enrolment in the scheme. Costs and clinical outcomes were discounted at 3% per annum. RESULTS: The Associazione Medici Diabetologi-annals initiative was associated with improvements in mean discounted life expectancy and quality-adjusted life expectancy of 0.55 years (95% CI 0.54-0.57) years and 0.48 quality-adjusted life years (95% CI 0.46-0.49), respectively, compared with conventional management. Whilst treatment costs were higher in the Associazione Medici Diabetologi-annals arm, this was offset by savings as a result of the reduced incidence and treatment of diabetes-related complications. The Associazione Medici Diabetologi-annals initiative was found to be cost-saving over patient lifetimes compared with conventional management [€ 37,289 (95% CI 37,205-37,372) vs € 41,075 (95% CI 40,956-41,155)]. CONCLUSIONS: Long-term projections indicate that the physician-led Associazione Medici Diabetologi-annals initiative represents a cost-saving method of improving long-term clinical outcomes compared with conventional management of people with Type 2 diabetes in Italy.


Subject(s)
Cost-Benefit Analysis/methods , Diabetes Mellitus, Type 2/economics , Diabetes Mellitus, Type 2/therapy , Disease Management , Quality of Health Care/economics , Quality of Health Care/trends , Aged , Diabetes Complications/epidemiology , Female , Health Care Costs/statistics & numerical data , Health Care Costs/trends , Humans , Incidence , Italy , Male , Middle Aged , Outcome Assessment, Health Care/economics , Outcome Assessment, Health Care/trends , Quality-Adjusted Life Years , Time Factors
11.
Eur J Immunol ; 31(5): 1317-23, 2001 May.
Article in English | MEDLINE | ID: mdl-11465088

ABSTRACT

Celiac disease is an HLA-DQ2-associated disorder characterized by intestinal T cell responses to ingested wheat gliadins. Initial studies used gliadin that had been subjected to non-enzymatic deamidation during pepsin/trypsin digestion to enrich for the gliadin-specific T cells in small intestinal celiac biopsies. These T cells recognized synthetic gliadin peptides only after their deamidation in vitro by purified tissue transglutaminase (tTG). However, as these studies used a deamidated antigen for re-stimulation prior to testing for antigen specificity, this raised the possibility that T cells specific for native epitopes had not been expanded in vitro and had thus been overlooked. To address this possibility and to look for more direct evidence that endogenous tTG mediates deamidation of gluten in the celiac lesions, we have here used a minimally deamidated chymotrypsin-digest of gliadin to challenge biopsies and then investigated the specificity of the T cell lines derived from them. Interestingly, these T cell lines only barely responded to the chymotrypsin-digested gliadins, but efficiently recognized the in vitro tTG-treated variants of the same gliadins. Moreover, the addition of a tTG-inhibitor during the gliadin challenge often resulted in T cell lines with abolished or reduced responses to deamidated gliadin. These data demonstrate that DQ2-restricted T cells within adult celiac lesions predominantly recognize deamidated gliadin epitopes that are formed in situ by endogenous tTG.


Subject(s)
Amides/metabolism , Celiac Disease/immunology , Epitopes, T-Lymphocyte/immunology , Epitopes, T-Lymphocyte/metabolism , Gliadin/immunology , T-Lymphocytes/immunology , Transglutaminases/metabolism , Antigen-Presenting Cells/immunology , Biopsy , Celiac Disease/enzymology , Celiac Disease/pathology , Cells, Cultured , Chymotrypsin/metabolism , Cystamine/pharmacology , Epitopes, T-Lymphocyte/chemistry , Gliadin/chemistry , Gliadin/metabolism , Humans , Intestines/immunology , Lymphocyte Activation , T-Lymphocytes/cytology , Transglutaminases/antagonists & inhibitors
12.
Pediatr Hematol Oncol ; 17(8): 651-8, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11127396

ABSTRACT

High-dose methotrexate (HD-MTX) is widely used in combination chemotherapy and can be handled without life-threatening toxicity in combination with leucovorin (LV) rescue. However, in an experimental animal model for testing of short-term HD-MTX effects in anesthetized rats, the authors previously demonstrated intolerable toxicity and death within a few hours in some animals. Serum levels were below levels routinely found in patients on HD-MTX treatment. This study was aimed at disclosure of possible mechanisms for acute toxicity of MTX in rats. The previously determined maximum tolerated dose of 5 g/kg MTX was used as the test dose. The animals that died showed sudden reduction in heart rate and blood pressure. LV, 1 g/kg infused immediately prior to MTX, changed MTX elimination kinetics, but did not change the acute toxicity. The data of this study together with additional evidence obtained in the experimental model, suggest that MTX acute toxicity may not be related to its antiproliferative effect, but rather to perturbation of endothelial cell and platelet function.


Subject(s)
Antimetabolites, Antineoplastic/toxicity , Leucovorin/pharmacology , Maximum Tolerated Dose , Methotrexate/toxicity , Animals , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/blood , Arrhythmias, Cardiac/chemically induced , Kidney/drug effects , Liver/drug effects , Male , Methotrexate/administration & dosage , Methotrexate/blood , Rats , Rats, Wistar , Survival Rate
13.
Ultrastruct Pathol ; 24(5): 325-32, 2000.
Article in English | MEDLINE | ID: mdl-11071571

ABSTRACT

Methotrexate (MTX) is a clinically important cytostatic antifolate. The study describes the acute effects of maximum tolerated doses of MTX or its major metabolite 7-hydroxymethotrexate (7-OH-MTX) on the ultrastructure of rat liver and kidneys. The ultrastructural changes in rats receiving MTX or 7-OH-MTX were, in principle, indistinguishable and their severity and extension increased with time of survival or doses of medication. All lesions were focal, microvascular, or parenchymal. Microvascular changes were more severe in nature when blood cells were present. The endothelial cells were swollen with loss of pinocytotic vesicles, their luminal plasma membrane formed blebs or were disrupted. Partly detached endothelial cells or deendothelialized areas, various types of white blood cells, in particular, neutrophil granulocytes, were observed in the microcirculation. Single platelets or small platelet aggregates were found either in the lumen or adhering to deendothelialized areas of injured endothelial cells. Hepatocytes exhibited steatosis, edema, and manifest single cell necrosis. There were also nuclear changes, marked proliferation of smooth endoplasmatic reticulum, increased amounts of intracellular lipid vacuoles, and a decrease in glycogen particles in hepatocytes. The kidney presented the major changes in the tubules and in the interstitial part. MTX and 7-OH-MTX acute toxicity may primarily be related to microvascular perturbation.


Subject(s)
Antineoplastic Agents/toxicity , Endothelium, Vascular/drug effects , Kidney/blood supply , Liver/blood supply , Methotrexate/toxicity , Animals , Dose-Response Relationship, Drug , Endothelium, Vascular/ultrastructure , Hepatocytes/drug effects , Hepatocytes/ultrastructure , Kidney/ultrastructure , Liver/ultrastructure , Male , Maximum Tolerated Dose , Methotrexate/analogs & derivatives , Microcirculation/drug effects , Microcirculation/ultrastructure , Rats , Rats, Wistar
14.
Ugeskr Laeger ; 162(37): 4927-30, 2000 Sep 11.
Article in Danish | MEDLINE | ID: mdl-11002741

ABSTRACT

The trial included ninety-five consecutive outpatients admitted with symptoms and signs suggesting deep venous thrombosis. Blood samples were collected on admission and analysed when the trial was ended. The three different D-dimer methods were BC D-dimer, Tinaquant D-dimer (both quantitative latex agglutination methods) and VIDAS D-dimer, based on the ELISA principle. Ultrasound was used as the reference method, but the outcome evaluated at three month follow up was the gold standard. The sensitivities of the three different methods were 66% (95% confidence interval 55-75%), 93% (88-98%) and 98% (94-100%) respectively. The negative predictive values were respectively 71% (62-80%), 88% (81-95%) and 95% (91-99%). This trial confirms that VIDAS D-dimer has a high sensitivity and negative predictive value that makes it suitable for clinical use. The same conclusion can be drawn for the Tinaquant D-dimer. The trial also emphasizes the importance of testing new methods under routine clinical conditions.


Subject(s)
Blood Coagulation Tests , Fibrin/analysis , Venous Thrombosis/diagnosis , Adult , Biomarkers/analysis , Female , Fibrin Fibrinogen Degradation Products/analysis , Hemagglutination Tests , Humans , Male , Middle Aged , Sensitivity and Specificity , Venous Thrombosis/blood
15.
Cancer Chemother Pharmacol ; 46(1): 69-73, 2000.
Article in English | MEDLINE | ID: mdl-10912581

ABSTRACT

PURPOSE: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD(50) for reasons of animal welfare. METHODS: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8 11.3 g/kg MTX and 0.1-1.2 g/kg 7-OH-MTX. RESULTS: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. CONCLUSIONS: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.


Subject(s)
Methotrexate/analogs & derivatives , Methotrexate/toxicity , Animals , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Electrocardiography/drug effects , Heart Rate/drug effects , Male , Methotrexate/administration & dosage , Methotrexate/pharmacokinetics , Models, Biological , Rats , Rats, Wistar
16.
Thromb Res ; 98(2): 157-63, 2000 Apr 15.
Article in English | MEDLINE | ID: mdl-10713317

ABSTRACT

Phenprocoumon, whose elimination half-time is 144 hours, has been the traditional oral anticoagulant of choice in Europe. However, today's most widely used drug is warfarin, whose elimination half-time is 40 hours. This study aims to evaluate a method for safe transition from phenprocoumon to warfarin, which is sometimes required. Hence, the large difference in their elimination rates may on occasion lead to serious overdosage upon transition from one drug to the other. According to average equipotent doses, a stepwise increase in warfarin dose was calculated based on the elimination half-times of the two drugs. The dosage scheme was subsequently tested in a pilot study including 35 patients. The conversion scheme was then adjusted based on the results from the pilot study. The new scheme was tested in 69 patients. The transition factor was 2.3, which implies that equipotency was achieved when the warfarin dose was 2.3 times larger than the phenprocoumon dose (in mg). This scheme proved optimal for 75% of the patients. However, the dose had to be adjusted individually in the remaining 25% of the patients to a level corresponding to the measured international normalised ratios. No patients experienced haemorrhages or thromboembolic complications during the period of changeover. In conclusion, the proposed scheme for changing medication from phenprocoumon to warfarin is safe and convenient.


Subject(s)
Anticoagulants/administration & dosage , Phenprocoumon/administration & dosage , Warfarin/administration & dosage , Administration, Oral , Adult , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Anticoagulants/pharmacokinetics , Half-Life , Humans , Middle Aged , Phenprocoumon/adverse effects , Phenprocoumon/pharmacokinetics , Pilot Projects , Prothrombin Time , Safety , Warfarin/adverse effects , Warfarin/pharmacokinetics
17.
Gut ; 46(1): 46-51, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10601054

ABSTRACT

BACKGROUND/AIMS: Coeliac disease is a chronic intestinal disorder most probably caused by an abnormal immune reaction to wheat gliadin. The identification of the HLA-DQ2 and HLA-DQ8 as the molecules responsible for the HLA association in coeliac disease strongly implicates a role for CD4 T cells in disease pathogenesis. Indeed, CD4 T cells specific for gliadin have been isolated from the small intestine of patients with coeliac disease. However, identification of T cell epitopes within gliadin has been hampered by the heterogeneous nature of the gliadin antigen. To aid the characterisation of gliadin T cell epitopes, multiple recombinant gliadins have been produced from a commercial Nordic wheat cultivar. METHODS: The alpha-gliadin and gamma-gliadin genes were amplified by polymerase chain reaction from cDNA and genomic DNA, cloned into a pET expression vector, and sequenced. Genes encoding mature gliadins were expressed in Escherichia coli and tested for recognition by T cells. RESULTS: In total, 16 alpha-gliadin genes with complete open reading frames were sequenced. These genes encoded 11 distinct gliadin proteins, only one of which was found in the Swiss-Prot database. Expression of these gliadin genes produced a panel of recombinant alpha-gliadin proteins of purity suitable for use as an antigen for T cell stimulation. CONCLUSION: This study provides an insight into the complexity of the gliadin antigen present in a wheat strain and has defined a panel of pure gliadin antigens that should prove invaluable for the future mapping of epitopes recognised by intestinal T cells in coeliac disease.


Subject(s)
Celiac Disease/immunology , Gliadin/biosynthesis , T-Lymphocyte Subsets/immunology , Amino Acid Sequence , Electrophoresis, Polyacrylamide Gel , Epitope Mapping/methods , Gliadin/genetics , Gliadin/immunology , Humans , Intestine, Small/immunology , Molecular Sequence Data , Polymerase Chain Reaction , Recombinant Proteins/biosynthesis
18.
Nat Med ; 4(6): 713-7, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9623982

ABSTRACT

The action of tissue Transglutaminase (TGase) on specific protein-bound glutamine residues plays a critical role in numerous biological processes. Here we provide evidence for a new role of this enzyme in the common, HLA-DQ2 (and DQ8) associated enteropathy, celiac disease (CD). The intestinal inflammation in CD is precipitated by exposure to wheat gliadin in the diet and is associated with increased mucosal activity of TGase. This enzyme has also been identified as the main target for CD-associated anti-endomysium autoantibodies, and is known to accept gliadin as one of its few substrates. We have examined the possibility that TGase could be involved in modulating the reactivity of gliadin specific T cells. This could establish a link between previous reports of the role of TGase in CD and the prevailing view of CD as a T-cell mediated disorder. We found a specific effect of TGase on T-cell recognition of gliadin. This effect was limited to gliadin-specific T cells isolated from intestinal CD lesions. We demonstrate that TGase mediates its effect through an ordered and specific deamidation of gliadins. This deamidation creates an epitope that binds efficiently to DQ2 and is recognized by gut-derived T cells. Generation of epitopes by enzymatic modification is a new mechanism that may be relevant for breaking of tolerance and initiation of autoimmune disease.


Subject(s)
Celiac Disease/enzymology , Coagulants/pharmacology , Gliadin/drug effects , T-Lymphocytes/drug effects , Transglutaminases/pharmacology , Amino Acid Sequence , Binding Sites , Celiac Disease/immunology , Cells, Cultured , Chromatography, Ion Exchange , Epitopes/chemistry , Epitopes/drug effects , Epitopes/metabolism , Gliadin/chemistry , Gliadin/immunology , HLA-DQ Antigens/metabolism , Humans , Intestines/cytology , Molecular Sequence Data , Oligopeptides/chemistry , Oligopeptides/drug effects , Oligopeptides/metabolism , Protein Binding , Sequence Homology, Amino Acid , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Transglutaminases/metabolism
19.
Res Nurs Health ; 18(1): 17-26, 1995 Feb.
Article in English | MEDLINE | ID: mdl-7831491

ABSTRACT

Combined mother-infant postnatal nursing care was compared with traditional, separate postpartum and newborn care in two studies. In Study I, self-administered questionnaires were completed by 408 mothers and 63 staff nurses. Data were collected both before and after mother-infant care was implemented. Benefits of the new system included increased maternal competence and satisfaction with parent education, parent-infant contact, and the nurse-client relationship, increased staff satisfaction, with no increase in operational cost. There were no breastfeeding differences, but ways to improve duration were implied by reasons for stopping. These findings were replicated in a separate setting with similar sample sizes. However, in the latter case, low staff ratios appeared to limit the benefits of mother-infant care to multiparas rather than primiparas.


Subject(s)
Maternal-Child Nursing/methods , Postnatal Care/methods , Adult , Analysis of Variance , Breast Feeding/statistics & numerical data , Chi-Square Distribution , Costs and Cost Analysis , Female , Humans , Infant, Newborn , Maternal-Child Nursing/economics , Maternal-Child Nursing/statistics & numerical data , Nursing Evaluation Research/statistics & numerical data , Ontario , Postnatal Care/economics , Postnatal Care/statistics & numerical data , Program Evaluation/statistics & numerical data , Surveys and Questionnaires
20.
Biochim Biophys Acta ; 1209(2): 191-202, 1994 Dec 14.
Article in English | MEDLINE | ID: mdl-7811690

ABSTRACT

Two different techniques have been used to study the complex formation of recombinant human plasminogen activator inhibitor type-1, PAI-1, with either recombinant human two-chain tissue plasminogen activator, tc tPA (EC 3.4.21.68), or the tPA deletion variants tc K2P, containing the kringle 2 domain and the proteinase domain, and P, containing only the proteinase domain. The same value for Kon, 2.10(7) M-1s-1 for binding of PAI-1 was found for the three tPA forms by direct detection of the complex formation in real time by surface plasmon resonance, BIAcore, or indirectly by monitoring the time course of the inhibition of tPA using the chromogenic substrate N-methylsulfonyl-D-Phe-Gly-Arg-4-pNA-acetate. Apparently, no conformational change is involved in the rate-limiting step, since the kon value was found to be independent of the temperature from 20 to 35 degrees C. By the BIAcore technique, it was found that the complex between PAI-1 and tPA covalently coupled to the surface, was stable at 25 degrees C, since no dissociation was seen in buffer. However, extended treatment with 1 M NH4OH destroyed the complex with t 1/2 = 5 h. The same kon values and complex composition were found by measuring either the binding of tPA to PAI-1 captured on the monoclonal antibody MAI-11 or the binding of PAI-1 to tPA captured on the monoclonal antibody 2:2 B10. Quantification of the complex composition between PAI-1 captured on the monoclonal antibody MAI-11 with either tPA, K2P or P gave a one-to-one ratio with the fraction of active PAI-1, consistent with the results from SDS-PAGE and the specific activity of PAI-1. The complexes of the three tPA forms with PAI-1 captured on a large surface of MAI-11 dissociated more rapidly from MAI-11, with the same apparent koff, kdis, = 2.10(-3) s-1, compared with 0.7-10(-3) s-1 for the dissociation of PAI-1 alone. In consistance, the Kd, calculated from the direct determination of the kon and koff for the association of different form of PAI-1 to a small surface of MAI-11, was found to be higher for PAI-1 in complex with tPA than for free active PAI-1. Apparently, upon complex formation, a change is induced in PAI-1 at the binding epitope for MAI-11.(ABSTRACT TRUNCATED AT 400 WORDS)


Subject(s)
Endopeptidases/chemistry , Plasminogen Activator Inhibitor 1/pharmacology , Tissue Plasminogen Activator/chemistry , Amino Acid Sequence , Chromogenic Compounds/chemistry , Kinetics , Molecular Sequence Data , Oligopeptides/chemistry
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