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PubMed1998

Relationships among liver and kidney volumes, lean body mass and drug clearance.

AIMS: To determine whether lean body mass (LBM), a possible surrogate of liver and kidney volumes, correlates with hepatic and renal drug clearances. METHODS: Twenty-one disease-free patients with a history of cancer and with normal hepatic and renal function were studied. Salivary pharmacokinetics of oral antipyrine (1200 mg) and 24 h creatinine clearance were determined following the determination of LBM by dual energy X-ray absorptiometry and the determination of liver and kidney volumes by helical CT scanning. RESULTS: Liver volume correlated with LBM (r2=0.21, P=0.04), body surface area (BSA) (r2=0.54, P<0.001), and total body weight (TBW) (r2=0.61, P<0.001). Kidney volume correlated with LBM (r2=0.49, P<0.001), BSA (r2=0.43, P=0.002) and TBW (r2=0.24, P=0.03). Stepwise multiple regression analysis, incorporating the independent variables of age, height, weight, sex, BSA, LBM, alcohol consumption, smoking status and liver volume and the dependent variable antipyrine clearance, indicated that LBM was the only independent correlate of antipyrine clearance. A stepwise multiple regression analysis with kidney volume in the independent variables, and creatinine clearance as dependent variable, showed that kidney volume and age were the only independent correlates of creatinine clearance. A nomogram using serum creatinine and LBM was comparable with the Cockcroft and Gault nomogram in calculating creatinine clearance. CONCLUSIONS: Of the anthropometric variables tested, LBM was the only determinant of antipyrine clearance, but this was not due to a relationship between LBM and liver volume. By contrast, the relationship between creatinine clearance and LBM appeared to be due to a relationship between LBM and kidney volume.

Adult↗

PubMed1997

Evaluation of internal alpha-particle radiation exposure and subsequent fertility among a cohort of women formerly employed in the radium dial industry.

This study examined the effect of internal exposure to alpha-particle radiation on subsequent fertility among women employed in the radium dial industry prior to 1930, when appreciable amounts of radium were often ingested through the practice of pointing the paint brush with the lips. The analysis was limited to women for whom a radium body burden measurement had been obtained and who were married prior to age 45 (n = 603). Internal radiation dose to the ovary was calculated based on initial intakes of radium-226 and radium-228, average ovarian mass, number and energy of alpha particles emitted, fraction of energy absorbed within the ovary, effective retention integrals and estimated photon irradiation. Time between marriage and pregnancy, number of pregnancies and number of live births served as surrogates for fertility. Radiation appeared to have no effect on fertility at estimated cumulative ovarian dose equivalents below 5 Sv; above this dose, however, statistically significant declines in both number of pregnancies and live births were observed. These trends persisted after multivariable adjustment for potential confounding variables and after exclusion of subjects contributing a potential classification or selection bias to the study. Additionally, the high-dose group experienced fewer live births than would have been expected based on population rates. There were no differences in time to first pregnancy between high- and low-dose groups. These results are consistent with earlier studies of gamma-ray exposures and suggest that exposure to high doses of radiation from internally deposited radium reduces fertility rather than inducing sterility.

Abortion, Spontaneous↗

PubMed2006

A statistical rationale for the use of forced expired volume in 6 s.

The purpose of the study was to determine the best surrogate for FVC when performing spirometry to detect obstruction or restriction. Volume-time curves from 3,539 participants in the Family Heart Study with acceptable quality test sessions were analyzed. An index of the variability of each timed volume (FEVx) from 1 to 12 s was determined for each subject. The least within-test session variability was seen for forced expired volume in 6 s (FEV(6)) and forced expired volume in 7 s (for both, mean range was 95 mL). The sensitivity and specificity for detecting obstruction and restriction when substituting the FEV(6) for the FVC were then determined before and after allowing for measurement errors of 50 mL (approximately the lower limit of spirometers ability to detect volume). Sensitivity was 76% before the 50-mL error analysis and 95% after. Specificity was 98% before the 50-mL error analysis and 99.5% after. We conclude that use of FEV(6) to replace the FVC for spirometry testing will result in improved reproducibility, with no significant loss of sensitivity or specificity, after allowing a 50-mL measurement error, for detecting obstruction or restriction.

Airway Obstruction↗

PubMed2006

Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway--a report of the Tumour Angiogenesis Research Group.

PURPOSE: Lactate dehydrogenase 5 (LDH-5) regulates, under hypoxic conditions, the anaerobic transformation of pyruvate to lactate for energy acquisition. Several studies have shown that serum LDH may be an ominous prognostic marker in malignant tumors. The clinical significance of tissue LDH-5, however, remains largely unexplored. PATIENTS AND METHODS: We investigated the immunohistochemical expression of LDH-5 in a series of 128 stage II/III colorectal adenocarcinomas treated with surgery alone. In addition, markers of tumor hypoxia (hypoxia-inducible factor 1 alpha [HIF1alpha]), angiogenesis (vascular endothelial growth factor [VEGF] and phosporylated kinase domain receptor [pKDR]/flk-1 receptor) and the tumor vascular density (CD31 positive standard vascular density [sVD] and pKDR positive activated vascular density [aVD]) were assessed. RESULTS: The expression of LDH-5, together with that of HIF1alpha and pKDR, was both nuclear and cytoplasmic. Assessment, with minimal interobserver variability, was achieved using a previously described scoring system. LDH-5 was significantly associated with HIF1alpha (P = .01), aVD (P = .001) and, particularly, with pKDR expression in cancer cells (P = .0001). Tissue LDH-5 expression was linked with elevated serum LDH levels, but serum levels failed to reflect tissue expression in 71% of LDH-5 positive cases. In univariate analysis tissue LDH-5 was associated with poor survival (P = .0003, HR 15.1), whereas in multivariate analysis this isoenzyme was the strongest independent prognostic factor (P = .0009). VEGF, pKDR, aVD, sVD and vascular invasion were all significantly related to unfavorable prognosis. CONCLUSION: The immunohistochemical assessment of tissue LDH-5 and pKDR provides important prognostic information in operable colorectal cancer. The strong association between LDH-5 and pKDR expression would justify their use as surrogate markers to screen patients for tyrosine kinase inhibitor therapy.

Adenocarcinoma↗

PubMed1995

Estimates of myocardium at risk and collateral flow in acute myocardial infarction using electrocardiographic indexes with comparison to radionuclide and angiographic measures.

OBJECTIVES: This study sought to determine the accuracy of the initial 12-lead electrocardiogram (ECG) in predicting final infarct size after direct coronary angioplasty for myocardial infarction and to examine which physiologic variables known to be determinants of outcome the ST segment changes most closely reflect. BACKGROUND: Myocardium at risk, collateral flow and time to reperfusion have been shown to be independent physiologic predictors of infarct size in animal and clinical models. However, such measurements may be difficult to perform on a routine basis in patients with myocardial infarction. The standard 12-lead ECG is inexpensive and readily available. METHODS: Sixty-seven patients with acute myocardial infarction, ST segment elevation and duration of chest pain < 12 h had an initial injection of technetium-99m sestamibi. Tomographic imaging was performed 1 to 8 h later (after direct coronary angioplasty), and the images were quantified to measure perfusion defect size (myocardium at risk) and severity (a measure of collateral flow). Contrast agent injection and tomographic acquisition were repeated at hospital discharge to measure infarct size. The ST segment elevation score was calculated for each patient according to infarct location and using previously described formulas. RESULTS: ST segment elevation score correlated closest with the radionuclide measure of collateral flow (r = -0.44, p < or = 0.0001), as well as an angiographic measure of collateral flow (r = -0.38, p = 0.05). Although ST segment elevation score correlated weakly with the magnitude of myocardium at risk by technetium-99m sestamibi, it was not as strong as infarct location alone in predicting myocardium at risk ([mean +/- SD] anterior 51 +/- 13% left ventricle vs. inferior 17 +/- 10% left ventricle, p < 0.0001). ST segment elevation score was weakly associated with final infarct size (r = 0.34, p = 0.005). A multivariate ECG model was constructed with infarct location as a surrogate for myocardium at risk, ST segment elevation score as a surrogate for estimated collateral flow, and elapsed time to reperfusion from onset of chest pain. All three variables were independently associated with infarct size. CONCLUSIONS: The initial standard 12-lead ECG can provide insight into myocardium at risk and, to a greater extent, collateral flow and can consequently provide some estimate of subsequent infarct size. However, the confidence limits for such predictors are wide.

Adult↗

PubMed2005

Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer's disease?

OBJECTIVE: The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression. METHOD: In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups. RESULTS: The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant. CONCLUSIONS: Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.

Aged↗

PubMed2003

Relation of adiposity and body fat distribution to body mass index in Australians of Aboriginal and European ancestry.

OBJECTIVE: To compare the relations of adiposity and body fat distribution to body mass index (BMI) in Australians of Aboriginal and European ancestry. DESIGN: Cross-sectional volunteer samples. SETTING: Australian Aboriginal communities in remote central and northern Australia, urban European Australians resident in Melbourne, Australia. SUBJECTS: Healthy Aboriginal (130 women, 120 men) and European Australians (100 women, 47 men) with a BMI<30 kg/m(2), aged 18-35 y; all women were nonpregnant. INTERVENTIONS: Anthropometric variables and resistance-using a four-terminal impedance plethysmograph-were measured. RESULTS: Aboriginal women and men were significantly shorter and weighed less than European Australians (P<0.05). Aboriginal women had a significantly larger waist circumference and waist-to-hip ratio (WHR, P<0.0005) compared to European Australian women. The sum of four skinfold thicknesses (SFT) (S4) and trunk SFT was higher in Aboriginals as compared to European Australian women (P<0.0005); however, limb SFT tended to be lower (P=0.06). On the other hand, BMI was significantly lower in Aboriginals compared to European Australian men (P=0.011), as was hip circumference (P=0.001); however, WHR was significantly (P=0.007) higher. On regression analysis, Aboriginal women and men were significantly heavier than European Australians for the same height(2)/resistance (surrogate for fat-free mass) and S4 (surrogate for subcutaneous fat); and that Aboriginal men had a significantly higher BMI (by 1.2 kg/m(2); P<0.0005) for any given S4 and height(2)/resistance values, compared to European Australian men. CONCLUSION: Aboriginal and European Australians have a significantly different body fat distribution and fat mass for a given body weight or BMI. Use of the World Health Organization recommended BMI ranges to determine weight status may be inappropriate in Australian Aboriginal people.

Adipose Tissue↗

PubMed2005

Aberrant heteroplasmic transmission of mtDNA in cloned pigs arising from double nuclear transfer.

Double nuclear transfer begins with the transfer of nuclear DNA from a donor cell into an enucleated recipient oocyte. This reconstructed oocyte is allowed to develop to the pronuclear stage, where the pronuclei are transferred into an enucleated zygote. This reconstructed zygote is then transferred to a surrogate sow. The genetic integrity of cloned offspring can be compromised by the transmission of mitochondrial DNA from the donor cell, the recipient oocyte and the recipient zygote. We have verified through the use of sequence analysis, restriction fragment length polymorphism analysis, allele specific PCR and primer extension polymorphism analysis that following double nuclear transfer the donor cell mtDNA is eliminated. However, it is likely that the recipient oocyte and zygote mitochondrial DNA are transmitted to the offspring, indicating bimaternal mitochondrial DNA transmission. This pattern of mtDNA inheritance is similar to that observed following cytoplasmic transfer and violates the strict unimaternal inheritance of mitochondrial DNA to offspring. This form of transmission raises concerns regarding the genetic integrity of cloned offspring and their uses in studies that require metabolic analysis or a stable genetic environment where only one variable is under analysis, such as in knockout technology.

Animals↗

PubMed2003

Framingham risk score is related to carotid artery intima-media thickness in both white and black young adults: the Bogalusa Heart Study.

The Framingham risk score (FRS), developed in a white cohort aged 30-74 years, is increasingly used in the early risk identification for coronary artery disease (CAD). This study examines the relationship between FRS and carotid artery intima-media thickness (IMT), a surrogate marker of coronary atherosclerosis, in black and white individuals aged 20-37 years. Five hundred seventeen young adults (aged 20-37 years; 71% white, 39% male) enrolled in the Bogalusa Heart Study had carotid artery ultrasonography. Age, gender, systolic blood pressure, total cholesterol to HDL cholesterol ratio, cigarette smoking habit, type 2 diabetes, and left ventricular hypertrophy (LVH) were used to calculate FRS. Results indicated a significant, positive linear relationship between tertiles of FRS and IMT of the common, bulb, and internal carotid segments in blacks and whites alike. In a multivariate analysis including FRS, race, BMI, parental history of CAD, stroke, type 2 diabetes, or hypertension, logtriglycerides, loginsulin, alcohol consumption (ml/week), and regular physical activity, the FRS was independently associated with all three carotid segments. Further, the FRS as a main predictor variable explained relatively more of the variance in the IMT of the carotid bulb (9%) than in the common (5%) or internal (3%) carotid segments. These results support the use of FRS in both white and black young adults and underscore the importance of prevention and control of multiple risk factors in youth.

Adult↗

PubMed1998

Primary sequence and molecular model of the variable region of a mouse monoclonal anti-Der p 1 antibody showing a similar epitope specificity as human IgE.

BACKGROUND: Der p 1, a major mite allergen, elicits IgE antibody responses in 80% of patients suffering from dust mite allergy. Given the potent IgE eliciting properties of Der p 1, there is considerable interest in studying the molecular architecture of the variable (Fv) region of IgE antibodies specific for this allergen. OBJECTIVES: IgE is present in human serum at extremely low concentrations, and as such it is practically impossible to purify sufficient quantities for structural studies. We have therefore sought to sequence and model a representative murine monoclonal (MoAb) anti-Der p 1 antibody, as a surrogate human IgE. METHODS: The cDNA coding for the Fv region of an anti-Der p 1 MoAb (2C7), that mimics the binding of human IgE to Der p 1, was amplified by PCR, cloned and sequenced. The predicted amino acid sequences were then compared with a directory of human germline V-gene segments. Modelling of the Fv region of MoAb 2C7 was carried out using the extensive database of existing immunoglobulin structures in the Brookhaven PDB. RESULTS: The MoAb 2C7 heavy chain showed greater than 70% homology with three members of the VH3 family, DP-35, DP-53 and DP-54. Similarly, the light chain showed greater than 70% homology with 11 VK sequences, including the VKII sequences DPK18, DPK19 and DPK28. A molecular model of the Fv region of MoAb 2C7 was generated and can be accessed from the EMBL databank. CONCLUSIONS: Antibodies similar to MoAb 2C7 could be generated as part of the human repertoire. The availability of 3-dimensional model of MoAb 2C7, as a surrogate human IgE antibody, combined with further data on its epitope specificity, will facilitate studies into IgE antibody responses to Der p 1.

Amino Acid Sequence↗

PubMed2003

Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine responsible for the recruitment of monocytes to sites of inflammation. MCP-1 appears to play a critical role at multiple stages in atherosclerosis, including the initiation of the fatty streak, promotion of plaque instability, and remodeling after myocardial infarction. METHODS AND RESULTS: MCP-1 was measured from frozen plasma specimens in 279 healthy volunteers and 2270 patients with acute coronary syndromes enrolled in the Oral Glycoprotein IIb/IIIa Inhibition with Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI) 16 trial. Median [25th, 75th percentiles] MCP-1 levels were 157 [124, 196] pg/mL in healthy volunteers and 178 [128, 238] pg/mL in the OPUS-TIMI 16 population (P<0.001). In OPUS-TIMI 16, baseline MCP-1 levels were associated with older age, female sex, hypertension, diabetes, prior coronary disease, and renal insufficiency (P<0.01 for each) but not with smoking status, body mass index, ejection fraction, troponin I or C-reactive protein. After adjustment for differences in baseline characteristics, ECG changes, troponin I, and C-reactive protein, an MCP-1 level >75th percentile (corresponding to the 90th percentile in the healthy volunteers) was associated with an increased risk of death or myocardial infarction through 10 months of follow-up (adjusted hazard ratio, 1.53; 95% CI, 1.09 to 2.14; P=0.01). CONCLUSIONS: In a large cohort of patients with acute coronary syndromes, an elevated baseline level of MCP-1 was associated both with traditional risk factors for atherosclerosis as well as an increased risk for death or myocardial infarction, independent of baseline variables. Because it appears to play a crucial role at multiple stages of atherosclerosis, MCP-1 is attractive as a surrogate biomarker and merits further study as a potential therapeutic target.

Acute Disease↗

PubMed2006

Atrial fibrillation and stroke in the general medicare population: a 10-year perspective (1992 to 2002).

BACKGROUND AND PURPOSE: Clinical trials have illustrated warfarin's protective effect on stroke risk in patients with atrial fibrillation (AF). The current study investigated temporal trends in AF prevalence, warfarin use, and its relation to stroke risk in Medicare patients with AF from 1992 to 2002. METHODS: The Medicare 5% sample for 1992 to 2002 was used to create 1-year cohorts of patients with Medicare as primary payer throughout the year. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify AF, ischemic and hemorrhagic stroke, and comorbid conditions. A previously validated surrogate measure, prothrombin/international normalized ratio claims, was used to identify warfarin use. Cox proportional hazards regression was used to examine time to stroke with warfarin use as a time-dependent variable. RESULTS: Among Medicare patients aged > or = 65 years, AF prevalence increased from 3.2% in 1992 to 6.0% in 2002 with higher prevalence in older subsets of the study population. Among patients with AF, warfarin use increased significantly (P< or = 0.001) for each year examined, from 24.5% in 1992 to 56.3% in 2002. Stroke rates per 1000 patient-years declined from 46.7 in 1992 to 19.5 in 2002 for ischemic stroke but remained fairly steady for hemorrhagic stroke (range, 1.6 to 2.9). Time-to-event modeling confirmed a protective association of warfarin against ischemic stroke among Medicare patients with AF. CONCLUSIONS: This analysis represents an observational validation of stroke prevention in AF trials. The significant increase in warfarin use among patients with AF illustrates diffusion of trial evidence into clinical practice.

Aged↗

PubMed2006

Markers of exacerbation severity in chronic obstructive pulmonary disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) can experience 'exacerbations' of their conditions. An exacerbation is an event defined in terms of subjective descriptors or symptoms, namely dyspnoea, cough and sputum that worsen sufficiently to warrant a change in medical management. There is a need for reliable markers that reflect the pathological mechanisms that underlie exacerbation severity and that can be used as a surrogate to assess treatment effects in clinical studies. Little is known as to how existing study variables and suggested markers change in both the stable and exacerbation phases of COPD. In an attempt to find the best surrogates for exacerbations, we have reviewed the literature to identify which of these markers change in a consistent manner with the severity of the exacerbation event. METHODS: We have searched standard databases between 1966 to July 2004 using major keywords and terms. Studies that provided demographics, spirometry, potential markers, and clear eligibility criteria were included in this study. Central tendencies and dispersions for all the variables and markers reported and collected by us were first tabulated according to sample size and ATS/ERS 2004 Exacerbation Severity Levels I to III criteria. Due to the possible similarity of patients in Levels II and III, the data was also redefined into categories of exacerbations, namely out-patient (Level I) and in-patient (Levels II & III combined). For both approaches, we performed a fixed effect meta-analysis on each of the reported variables. RESULTS: We included a total of 268 studies reported between 1979 to July 2004. These studies investigated 142,407 patients with COPD. Arterial carbon dioxide tension and breathing rate were statistically different between all levels of exacerbation severity and between in out- and in-patient settings. Most other measures showed weak relationships with either level or setting, or they had insufficient data to permit meta-analysis. CONCLUSION: Arterial carbon dioxide and breathing rate varied in a consistent manner with exacerbation severity and patient setting. Many other measures showed weak correlations that should be further explored in future longitudinal studies or assessed using suggested mathematical modelling techniques.

Arteries↗

PubMed1994

Stochastic versus deterministic variability in simple neuronal circuits: I. Monosynaptic spinal cord reflexes.

Long time series of monosynaptic Ia-afferent to alpha-motoneuron reflexes were recorded in the L7 or S1 ventral roots in the cat. Time series were collected before and after spinalization at T13 during constant amplitude stimulations of group Ia muscle afferents in the triceps surae muscle nerves. Using autocorrelation to analyze the linear correlation in the time series demonstrated oscillations in the decerebrate state (4/4) that were eliminated after spinalization (5/5). Three tests for determinism were applied to these series: 1) local flow, 2) local dispersion, and 3) nonlinear prediction. These algorithms were validated with time series generated from known deterministic equations. For each experimental and theoretical time series used, matched time-series of stochastic surrogate data were generated to serve as mathematical and statistical controls. Two of the time series collected in the decerebrate state (2/4) demonstrated evidence for deterministic structure. This structure could not be accounted for by the autocorrelation in the data, and was abolished following spinalization. None of the time series collected in the spinalized state (0/5) demonstrated evidence of determinism. Although monosynaptic reflex variability is generally stochastic in the spinalized state, this simple driven system may display deterministic behavior in the decerebrate state.

Afferent Pathways↗

PubMedDate not supplied

Dynamic contrast-enhanced MR imaging evaluation of osteosarcoma response to neoadjuvant chemotherapy.

Assessment of osteosarcoma response to neoadjuvant chemotherapy has prognostic implications, but conventional imaging techniques have been unable to provide an accurate quantitative measure of tumor response. We developed an analysis of dynamic contrast-enhanced MR imaging (DEMRI) to render an image of dynamic vector magnitudes (DVM) and to summarize the result in a quantitative parameter, mean DVM for the lesion (mu DVM). We compared the mu DVM from the examination before surgery with histologic results from an en bloc resection of the tumor in 19 cases. The final mu DVM value provided an accurate (89.5%) measure of tumor necrosis in osteosarcoma. Further, we analyzed the findings in 17 patients with osteosarcoma who completed three DEMRI examinations during the course of therapy. Tumors with higher mu DVM values at presentation had greater decreases in the parameter over the course of therapy. These results are consistent with the distribution of DVM values in these lesions serving as an indicator of tumor perfusion and a possible surrogate variable for drug delivery.

Adolescent↗

PubMed2006

PR interval: a comparison of electrical and mechanical methods in the fetus.

BACKGROUND: Mechanical surrogates are used to assess fetal cardiac electrical activity. AIMS: To compare electrical PR interval measured using non-invasive fetal electrocardiography (fECG) with mechanical atrioventricular (AV) interval using Doppler. STUDY DESIGN AND SUBJECTS: Prospective study of 55 recordings made in 50 human fetuses. Those with structural heart defects, second degree or complete heart block were excluded. OUTCOME MEASURES: Mechanical AV interval was measured from the onset of mitral A wave to onset of aortic ejection. Electrical PR interval was measured from a coherent averaged signal obtained using non-invasive fECG recorded from the maternal abdomen. Wilcoxon signed rank test was used to compare both methods. Agreement between AV and PR intervals was assessed using linear regression and by Bland-Altman plots. Bland-Altman analysis assessed inter-observer and intra-observer variability. RESULTS: There was no significant difference in the heart rates of the 55 paired traces measured consecutively using both methods (p<0.35). AV interval was longer than PR (median [range] 116 [96-169] vs. 102 [75-143] ms; p<0.001), with mean difference -16.47 ms (95% Confidence Interval -43.43, 10.44), reflecting the increased proportion of the cardiac cycle measured. Using fECG, PR inter-observer and intra-observer mean differences were 0.4 ms (CI -7.29, 8.09) and 0.7 ms (CI -3.22, 4.62) respectively. R values for inter and intra-observer studies were 0.95 and 0.99 respectively. Using Doppler methods, AV inter-observer and intra-observer mean differences were -2.69 ms, (CI -15.33, 9.95) and 0.92 ms, (CI -9.41, 11.26) respectively. R values for AV measurements were 0.93 for inter-observer and 0.96 for intra-observer variation. CONCLUSIONS: Non-invasive fECG is a robust tool to measure the PR interval with narrow limits of agreement.

Adult↗

PubMed2003

Gln-Arg192 polymorphism of paraoxonase 1 is associated with carotid intima-media thickness in patients of type 2 diabetes mellitus of Chinese.

Serum paraoxonase (PON) is a high-density lipoprotein-bound enzyme that can prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides and thus exert an anti-atherogenic effect. Recent studies have suggested that glutamine(Q isoform)/arginine(R isoform) polymorphism at position 192 of PON(1) gene is associated with macrovascular disease of type 2 diabetes mellitus (T2DM). We re-investigated this relationship using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. The genotype and allele frequency of PON(1) 192 Q/R polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism in 152 type 2 diabetic patients and 128 healthy subjects from a population of Chinese Han nationality in ChengDu area. The carotid IMT was measured by B-mode ultrasonography in type 2 diabetic patients. No differences were found in PON(1) gene Q/R polymorphism in the type 2 diabetic patients when compared with the control group. The mean carotid IMT in type 2 diabetic subjects with the QQ, QR and RR genotype was 0.65+/-0.27, 0.83+/-0.27 and 1.05+/-0.32 mm, respectively. One-way ANOVA showed that IMT was significantly greater in the RR subgroup than in both QR and QQ subgroups (P<0.01). Multivariate logistic regression analysis showed R allele to be the main determinant of IMT variability (OR 4.0 95% CI 2.10-7.40 P=0.005). Our data support the view that 192 R allele of PON(1) gene is a risk factor for macrovascular disease of T2DM in Chinese.

Amino Acid Substitution↗

PubMed2003

High variation of tioguanine absorption in patients with chronic active Crohn's disease.

BACKGROUND: Tioguanine (thioguanine) has been suggested as a therapeutic alternative for patients with Crohn's disease resistant or intolerant to azathioprine or mercaptopurine. However, pharmacokinetic data on tioguanine in inflammatory bowel disease are missing. AIM: To determine the disposition of three different 40 mg tablet preparations of tioguanine in patients with Crohn's disease. METHODS: Six patients with chronic active Crohn's disease were included in a randomized, cross-over, single-dose study. Pharmacokinetic analysis was based on plasma concentrations of tioguanine during 6 h after dosing. Tioguanine was measured by a validated high-pressure liquid chromatographic method. RESULTS: The areas under the curve (AUC) varied 4-7-fold between patients. In two patients, tioguanine was not detected in plasma following the intake of one of the three tablets; another patient did not absorb tioguanine in two of the three different preparations. No significant differences were found in the AUC and Cmax values between the three tablets. In all patients, there was a second peak in plasma concentration following a meal 3 h after drug administration. CONCLUSIONS: The absorption of tioguanine is highly variable in patients with Crohn's disease, which may be responsible for treatment failure. Therapy with tioguanine may be improved by monitoring tioguanine nucleotides as a surrogate parameter of efficacy.

Adult↗