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High Interindividual Variability (high + interindividual_variability)
Selected AbstractsORIGINAL ARTICLE: Characteristics of plasma NOx levels in severe sepsis: high interindividual variability and correlation with illness severity, but lack of correlation with cortisol levelsCLINICAL ENDOCRINOLOGY, Issue 3 2010J. T. Ho Summary Objectives, Nitric oxide (NO) concentrations are elevated in sepsis and their vasodilatory action may contribute to the development of hyperdynamic circulatory failure. Hydrocortisone infusion has been reported to reduce nitric oxide metabolite (NOx) concentrations and facilitate vasopressor withdrawal in septic shock. Our aim was to determine whether NOx concentrations relate to (i) protocol-driven vasopressor initiation and withdrawal and (ii) plasma cortisol concentrations, from endogenous and exogenous sources. Demonstration of a relation between NOx, cortisol and vasopressor requirement may provide an impetus towards the study of hydrocortisone-mediated NOx suppression as a tool in sepsis management. Design, A prospective study of 62 patients with severe sepsis admitted to the intensive care unit. Measurements, Plasma NOx, total and free cortisol, and corticosteroid-binding globulin (CBG) concentrations were measured and related to protocol-driven vasopressor use for 7 days following admission. Results, Patients who developed septic shock (n = 35) had higher plasma NOx, total and free cortisol, and lower CBG concentrations than the nonseptic shock group (n = 27). Cortisol, CBG and NOx concentrations correlated with illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx concentrations, predicted septic shock. NOx concentrations were higher in nonsurvivors, and the concentrations were characteristically stable within individuals but marked interindividual differences were only partly accounted for by illness severity or renal dysfunction. NOx concentrations did not correlate with cortisol, did not relate to vasopressor requirement and did not fall after standard dose hydrocortisone, given for clinical indications. Conclusions, Nitric oxide production increased with sepsis severity but did not correlate with plasma cortisol or vasopressor requirement. NOx levels were not suppressed reproducibly by hydrocortisone. High interindividual variability of NOx levels suggests that absolute NOx levels may not be a suitable target for individualized hydrocortisone therapy. [source] Fungal rDNA signatures in coronary atherosclerotic plaquesENVIRONMENTAL MICROBIOLOGY, Issue 12 2007Stephan J. Ott Summary Bacterial DNA has been found in coronary plaques and it has therefore been concluded that bacteria may play a role as trigger factors in the chronic inflammatory process underlying coronary atherosclerosis. However, the microbial spectrum is complex and it is not known whether microorganisms other than bacteria are involved in coronary disease. Fungal 18S rDNA signatures were systematically investigated in atherosclerotic tissue obtained through catheter-based atherectomy of 38 patients and controls (unaffected coronary arteries) using clone libraries, denaturating gradient gel analysis (DGGE), in situ hybridization and fluorescence in situ hybridization (FISH). Fungal DNA was found in 35 of 38 (92.11%) coronary heart disease patients by either polymerase chain reaction (PCR) with universal primers or in situ hybridization analysis (n = 5), but not in any control sample. In a clone library with more than 350 sequenced clones from pooled patient DNA, an overall richness of 19 different fungal phylotypes could be observed. Fungal profiles of coronary heart disease patients obtained by DGGE analysis showed a median richness of fungal species of 5 (range from 2 to 9) with a high interindividual variability (mean similarity 18.83%). For the first time, the presence of fungal components in atherosclerotic plaques has been demonstrated. Coronary atheromatous plaques harbour diverse and variable fungal communities suggesting a polymicrobial contribution to the chronic inflammatory aetiology. [source] Expression of melanoma-associated antigens in melanoma cell culturesEXPERIMENTAL DERMATOLOGY, Issue 7 2005Mirjana Urosevic Abstract:, The efficiency of melanoma immunotherapy appears to depend on both melanoma- and immune system-specific factors. Melanoma-specific factors include melanoma-associated antigen (MAA) expression as well as HLA class I molecule expression. We investigated the expression of five MAA , Melan-A/MART-1, tyrosinase, gp100, MAGE-1 and MAGE-3 , by means of FACS analysis in 50 melanoma cell cultures and compared them to the cultures of human foreskin-derived melanocytes and melanoma cell line UKRV-Mel2. Melan-A, tyrosinase and gp100 expression was frequently reduced in melanoma cell cultures, compared to that in foreskin melanocytes, whereas MAGE-1 and MAGE-3 expression showed variable degree of upregulation, compared to that in foreskin melanocytes. The expression of all tested MAA demonstrated high interindividual variability. We further show that cell cultures derived from the same tissue sample are oligoclonal in nature, by demonstrating the presence of up to three cell populations bearing distinct MAA profile. Analysing samples derived from the same patient but each at a different time point, we show that MAA expression profile changes over time either in positive (increase) or in negative (decrease) direction. Finally, we demonstrate that brain metastasis-derived cell cultures significantly overexpress Melan-A and MAGE-3, compared to primary tumours and other metastatic sites (P -value range: 0.05,0.001). Elucidation of the MAA expression patterns and the kinetics within the same patient as well as during the course of the disease may help improve current and develop new immunotherapeutic strategies. [source] The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) scoreJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2008T. GEISLER Summary.,Background:,Recent studies suggest a high interindividual variability of response to clopidogrel associated with adverse cardiovascular outcome. Different clinical factors are considered to influence a persistent residual platelet aggregation (RPA) despite conventional antiplatelet therapy. Objectives:,To investigate clinical factors that affect RPA after 600-mg clopidogrel loading in a large unselected cohort of patients with symptomatic CAD. Methods:,The study population included a consecutive cohort of 1092 patients treated with coronary stenting for stable angina and acute coronary syndromes (ACS). Residual platelet activity was assessed by ADP (20 ,mol L,1)-induced platelet aggregation , 6 h after LD. Eleven clinical factors were included in the primary analysis. Results:,In multivariate regression analysis increased RPA was significantly influenced by ACS, reduced LV-function, diabetes mellitus, renal failure (creatinine > 1.5 mg dL,1), and age > 65 years. In a factor-weighed model the risk for high RPA increased with higher score levels (OR for patients with a score of 1,3, 1.21, 95% CI 0.7,2.1; score 4,6, OR 2.0, 95% CI 1.17,3.5; P = 0.01; score 7,9, OR 3.3, 95% CI 1.8,6.0). During a 30-day follow-up the incidence of major adverse events was higher in patients with RPA in the upper tertile (4.8% vs. 2.5% in the 2nd and 1.5% in the 1st tertile; P < 0.05). Conclusions:,The PREDICT score provides a good tool to estimate residual platelet activity after clopidogrel LD by easily available patient details. Additionally, we demonstrate its association with short-term outcome. Thus, patients with a high score may benefit from intensified antiplatelet therapy by improved platelet inhibition and risk reduction for thromboischemic events. [source] Molecular analysis of the root canal microbiota associated with endodontic treatment failuresMOLECULAR ORAL MICROBIOLOGY, Issue 4 2008M. Sakamoto Introduction:, The failure of endodontic treatment is usually caused by persistent/secondary intraradicular infections and Enterococcus faecalis has been considered to be the main pathogen involved. Nevertheless, the breadth of bacterial diversity involved with endodontic treatment failures remains to be consistently explored by culture-independent approaches. Methods:, This study determined the intraradicular microbiota of root-canal-treated teeth with post-treatment apical periodontitis using 16S ribosomal RNA gene clone library analysis. Results:, Bacteria were present in all cases, confirming the infectious etiology of post-treatment disease. Seventy-four bacterial taxa belonging to six phyla were found in the nine cases investigated. Of these, 55% were identified as as-yet-uncultivated phylotypes, which also made up a significant proportion of the microbiota in many cases. Twenty-five new phylotypes were identified. Most teeth harbored a mixed consortium, with a mean number of 10 taxa per case. Only 11 taxa were found in more than one case, revealing a high interindividual variability in the composition of the microbiota. Conclusion:, The current findings revealed new candidate endodontic pathogens, including as-yet-uncultivated bacteria and taxa other than E. faecalis, which may participate in the mixed infections associated with post-treatment apical periodontitis. [source] Interindividual variability in the concentration,effect relationship of antilymphocyte globulins,a possible influence of Fc,RIIIa genetic polymorphismBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008David Ternant WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ,,There is interindividual variability in the antilymphocyte globulin (ALG) effect, but there is no pharmacokinetic,pharmacodynamic study of this subject. ,,In addition, a time dependence of the pharmacokinetics of some therapeutic antibodies has been described. ,,ALGs may partly act by antibody-dependent cellular cytotoxicity (ADCC), but their mechanism of action in humans is not known. WHAT THIS STUDY ADDS ,,Horse ALG pharmacokinetics can be described using a two-compartment model with time-dependent central volume of distribution. ,,After an initial concentration-independent lymphocyte depletion, the concentration,effect relationship can be described using a physiological indirect response model. ,,The genetic polymorphism of Fc,RIIIa at position 158 may influence the ALG concentration,effect relationship and these polyclonal antibodies may therefore act by ADCC. AIMS Polyclonal antilymphocyte globulins (ALGs) are currently used in transplantation, but the sources of interindividual variability of their effect are poorly understood. No pharmacokinetic,pharmacodynamic (PK,PD) study of ALG is available. Moreover, the genetic polymorphism of Fc,RIIIa, a receptor for the Fc portion of immunoglobulins involved in antibody-dependent cellular cytotoxicity (ADCC), may influence their concentration,effect relationship. METHODS Fourteen kidney transplant patients treated by horse ALG were included in a prospective, noncomparative study. A population two-compartment PK model including a time dependence of the central volume of distribution was developed. Total lymphocyte count was used as biomarker of effect. Concentration,effect data were described using a physiological indirect response model, combining concentration-dependent and -independent inhibitions of lymphocyte input into the circulation. In addition, six kidney transplant patients in whom ALG concentrations were not available were included retrospectively. All patients were genotyped for FCGR3A. RESULTS Both the PK and the PK,PD model described the data satisfactorily and showed high interindividual variability. Asymptotic T1/2 -, and T1/2 -,-values were 1.3 and 25 days, respectively. The concentration of ALG leading to a 50% inhibition of lymphocyte input (IC50) was lower in FCGR3A- V carriers than in FCGR3A- F/F patients (383 ± 199 vs. 593 ± 209 mg l,1, P = 0.008). CONCLUSIONS This is the first description of the ALG effect on lymphocyte count using PK,PD modelling. Our results show that part of the variability in their concentration,effect relationship may be explained by Fc,RIIIa genetic polymorphism and therefore that horse ALG may deplete lymphocytes by ADCC. [source] The impact of zonisamide on weight.ACTA NEUROLOGICA SCANDINAVICA, Issue 4 2009A clinical study in 103 patients with epilepsy Objective,,, To investigate the impact of zonisamide (ZNS) on body weight in patients with epilepsy. Methods,,, A retrospective chart analysis of weight changes after initiation of ZNS (103 patients; 54 female; age 17,68 years). For 31 patients follow-up data after ZNS-withdrawal were available. Patients were categorized according to body-mass-index (BMI) <20, 20,25, and >25 kg/m2. Results,,, Body weight before ZNS was 78.6 ± 16.0 kg (range 45,120 kg), BMI 26.5 ± 5.2 kg/m2 (range17.6,41.3 kg/m2). Within 13 ± 7.2 months of treatment, mean body weight decreased by ,3.7% ± 9.1%, showing high interindividual variability (,36% to +32%). Weight loss >5% was documented in 35%, weight gain >5% in 14% of patients. Weight loss was more prominent in patients being overweight prior to treatment onset. At the end of follow-up, patients with overweight had decreased by number. Weight changes under ZNS were not correlated to ZNS daily dosage. Following discontinuation of ZNS treatment weight loss proved to be reversible. Conclusion,,, Zonisamide reduced weight in 35% of patients, especially in patients with overweight prior to treatment. Weight loss is reversible following discontinuation of treatment with ZNS. [source] ORIGINAL ARTICLE: Characteristics of plasma NOx levels in severe sepsis: high interindividual variability and correlation with illness severity, but lack of correlation with cortisol levelsCLINICAL ENDOCRINOLOGY, Issue 3 2010J. T. Ho Summary Objectives, Nitric oxide (NO) concentrations are elevated in sepsis and their vasodilatory action may contribute to the development of hyperdynamic circulatory failure. Hydrocortisone infusion has been reported to reduce nitric oxide metabolite (NOx) concentrations and facilitate vasopressor withdrawal in septic shock. Our aim was to determine whether NOx concentrations relate to (i) protocol-driven vasopressor initiation and withdrawal and (ii) plasma cortisol concentrations, from endogenous and exogenous sources. Demonstration of a relation between NOx, cortisol and vasopressor requirement may provide an impetus towards the study of hydrocortisone-mediated NOx suppression as a tool in sepsis management. Design, A prospective study of 62 patients with severe sepsis admitted to the intensive care unit. Measurements, Plasma NOx, total and free cortisol, and corticosteroid-binding globulin (CBG) concentrations were measured and related to protocol-driven vasopressor use for 7 days following admission. Results, Patients who developed septic shock (n = 35) had higher plasma NOx, total and free cortisol, and lower CBG concentrations than the nonseptic shock group (n = 27). Cortisol, CBG and NOx concentrations correlated with illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx concentrations, predicted septic shock. NOx concentrations were higher in nonsurvivors, and the concentrations were characteristically stable within individuals but marked interindividual differences were only partly accounted for by illness severity or renal dysfunction. NOx concentrations did not correlate with cortisol, did not relate to vasopressor requirement and did not fall after standard dose hydrocortisone, given for clinical indications. Conclusions, Nitric oxide production increased with sepsis severity but did not correlate with plasma cortisol or vasopressor requirement. NOx levels were not suppressed reproducibly by hydrocortisone. High interindividual variability of NOx levels suggests that absolute NOx levels may not be a suitable target for individualized hydrocortisone therapy. [source] | ||||||||||