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PubMed1987

Methodological aspects of breath hydrogen (H2) analysis. Evaluation of a H2 monitor and interpretation of the breath H2 test.

The reliability of end-expiratory hydrogen (H2) breath tests were assessed and the significance of some important pitfalls were studied, using a compact, rapid H2-monitor with electrochemical cells. The H2 response was shown to be linear and stable. The reproducibility of the breath collection technique was determined in 20 patients following ingestion of lactulose. The increment between consecutive means of duplicate samples indicative of a significant rise of H2 concentration never exceeded 10 p.p.m., the mean coefficient of variation of the duplicate samples was below 5%. Fasting H2 levels were studied in 10 healthy adults during a 4-month period and they showed very marked inter- and intra-individual variability (16% above 40 p.p.m.). Initial peaks (early, short-lived H2 rises unrelated to carbohydrate malabsorption) were identified in 25% of the breath tests (in 4% above 20 p.p.m). It is concluded that the technique used for interval sampling of end-expiratory breath samples for H2 concentration gives reliable results. The biological significance of H2 concentration increments can only be evaluated if the limitations of the technical procedures and the individual ability to produce H2 is known.

Adult↗
PubMedDate not supplied

Non-deterministic individual responses to receptor-selective opioid agonists.

To assess within a single rat strain individual variability of analgesic responses to sub-ED50 doses of receptor-selective opioids, we measured: 1) tail flick latency (TFL) responses after intrathecal (ith) injection of delta, mu, and kappa agonists administered serially; 2) TFL and tail pinch latencies (TPch) after intravenous (iv) mu and kappa agonists; and 3) TFL and TPch after iv agonists of mu or combined mu + delta selectivity. Mean values in each study confirmed an analgesic response, but individual TFL and TPch responses were chaotic and, within each study, rank order correlations between TFL and TPch values within or between drugs were insignificant. Our results suggest a hypothesis that such responses are intrinsically nondeterministic because--resembling other complex dynamic systems--they are generated by stochastic receptor-transmitter interactions that in turn evoke a series of nonlinearly coupled cellular and neural events.

Amino Acid Sequence↗
PubMed2005

Pharmacokinetics and pharmacodynamics of ximelagatran.

Oral anticoagulant therapy with vitamin K antagonists (VKAs) such as warfarin has proven benefits in the treatment and prevention of thromboembolic disorders but has important limitations that result in substantial underuse. In particular, the VKAs have variable and unpredictable pharmacokinetics and pharmacodynamics and a narrow separation between antithrombotic and hemorrhagic effects that necessitates careful dose adjustment based on frequent coagulation monitoring. In contrast, the oral direct thrombin inhibitor ximelagatran has a predictable and reproducible pharmacokinetic/pharmacodynamic profile that allows treatment using fixed-dose regimens without coagulation monitoring. The bioavailability of melagatran, the active form of ximelagatran, after oral administration of ximelagatran is approximately 20% with low inter- and intra-individual variability. Peak plasma melagatran concentrations are reached approximately 2 hours after oral dosing of ximelagatran to healthy volunteers, and melagatran is eliminated with a half-life of approximately 3 hours with clearance predominantly by renal excretion. Hence, a higher melagatran exposure is seen in patients with renal failure; ximelagatran is currently not recommended for patients with severe renal impairment (creatinine clearance of <30 mL/min) as these patients were not included in the clinical trial program. Exposure to melagatran increases linearly with the ximelagatran dose. The pharmacokinetic/pharmacodynamic profile is consistent across a broad range of different patient populations and is unaffected by gender, age, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Any differences in melagatran pharmacokinetics associated with these factors are attributable to differences in renal function.

Administration, Oral↗
PubMed1996

6-Hydroxymelatonin sulfate excretion in human puberty.

We investigated the relationship of urinary excretion rate of 6-hydroxymelatonin sulfate (SM), the main metabolite of melatonin, with pubertal development and determined the day to day variability of SM excretion. Healthy subjects 4-31 years old completed one or multiple timed overnight urine collections. SM excretion rate per body size was significantly higher in 99 prepubertal subjects (35.5 +/- 2.3 ng/h/kg and 0.97 +/- 0.06 microgram/hr/m2) than in 86 pubertal subjects (18.1 +/- 1.1 ng/hr/kg and 0.61 +/- 0.03 microgram/hr/m2) or in 29 adults (15.0 +/- 1.5 ng/hr/kg and 0.59 +/- 0.06 microgram/hr/m2); no significant difference was present in pubertal stages 2 to 5. Among the prepubertal children, SM excretion rate in mid childhood was significantly higher than in late childhood. The variability of SM and creatinine excretion examined in 52 children, adolescents and adults with three or four collections was defined as the mean of the 52 coefficients of variation for the multiple measures in each subject. The variability of total nocturnal SM (25.9 +/- 2.6%) was similar to that of total creatinine (21.7 +/- 2.3%) and neither was significantly correlated with the variability in start time or duration of urine collection. The results suggest that, relative to body size, melatonin secretion rate is higher in mid childhood, decreases during late childhood, and remains stable from pubertal stage 2 to adulthood. The decline in melatonin secretion rate occurs during the developmental phase of disinhibition of the gonadotropin releasing hormone pulse generator. Hence, we infer that melatonin may be a suppressive factor of puberty during childhood. The substantial individual variability observed for SM excretion calls for caution in using single urine collections in longitudinal studies or in studies of drug responses.

Adolescent↗
PubMed1999

Predicting composition of leg sections with anthropometry and bioelectrical impedance analysis, using magnetic resonance imaging as reference.

Magnetic resonance imaging (MRI) was used to evaluate and compare with anthropometry a fundamental bioelectrical impedance analysis (BIA) method for predicting muscle and adipose tissue composition in the lower limb. Healthy volunteers (eight men and eight women), aged 41 to 62 years, with mean (S.D.) body mass indices of 28.6 (5.4) kg/m2 and 25.1 (5.4) kg/m2 respectively, were subjected to MRI leg scans, from which 20-cm sections of thigh and 10-cm sections of lower leg (calf) were analysed for muscle and adipose tissue content, using specifically developed software. Muscle and adipose tissue were also predicted from anthropometric measurements of circumferences and skinfold thicknesses, and by use of fundamental BIA equations involving section impedance at 50 kHz and tissue-specific resistivities. Anthropometric assessments of circumferences, cross-sectional areas and volumes for total constituent tissues matched closely MRI estimates. Muscle volume was substantially overestimated (bias: thigh, -40%; calf, -18%) and adipose tissue underestimated (bias: thigh, 43%; calf, 8%) by anthropometry, in contrast to generally better predictions by the fundamental BIA approach for muscle (bias: thigh, -12%; calf, 5%) and adipose tissue (bias: thigh, 17%; calf, -28%). However, both methods demonstrated considerable individual variability (95% limits of agreement 20-77%). In general, there was similar reproducibility for anthropometric and fundamental BIA methods in the thigh (inter-observer residual coefficient of variation for muscle 3.5% versus 3.8%), but the latter was better in the calf (inter-observer residual coefficient of variation for muscle 8.2% versus 4.5%). This study suggests that the fundamental BIA method has advantages over anthropometry for measuring lower limb tissue composition in healthy individuals.

Adipose Tissue↗
PubMed1988

Short-term risk stratification at admission based on simple clinical data in acute myocardial infarction.

Simple clinical data, available in all coronary care units, were recorded in 1,013 consecutive patients with acute myocardial infarction (AMI). In order to identify the patients at highest and lowest risk of mortality during hospital stay, a prognostic index was established from a stepwise logistic discriminant analysis of 10 clinical variables obtained at admission in a consecutive series of 477 patients hospitalized in 1 of 2 coronary care units admitting new patients on alternate days and treating them similarly. This prognostic index was applied to a comparison group of 536 consecutive patients admitted to the other coronary care unit. In the experimental group, 57 of the 477 patients (12%) died during hospital stay; 60 of the 536 patients (11%) died in the comparison group. As individual variables, age, previous history of AMI, anterior site and left ventricular function on admission were associated with increased mortality. Three variables were selected from the stepwise logistic discriminant analysis of the experimental group: age; site (anterior = 1, other = 0); and grade of left ventricular function (0 to 4). Prognostic index = 5.9019 - 0.8961 function - 0.5708 location - 0.0369 age. This index was validated in the comparison group. Patients were allocated into different classes with increasing index values associated with decreasing risk. Three subgroups of patients were identified: high risk of hospital mortality (index less than or equal to 1; mortality: 51%), intermediate risk (index 1 to 3; mortality: 18%) and low risk (index greater than 3; mortality: 4%). The use of this simple prognostic index may improve clinical management and selection of patients for intervention trials.

Female↗
PubMed2002

Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk.

Susceptibility to lung cancer may in part be attributable to inter-individual variability in metabolic activation or detoxification of tobacco carcinogens. The glutathione S-transferase M1 (GSTM1) genetic polymorphism has been extensively studied in this context; two recent meta-analyses of case-control studies suggested an association between GSTM1 deletion and lung cancer. At least 15 studies have been published after these overviews. We undertook a new meta-analysis to summarize the results of 43 published case-control studies including >18 000 individuals. A slight excess of risk of lung cancer for individuals with the GSTM1 null genotype was found (odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.07-1.27). No evidence of publication bias was found (P = 0.4), however, it is not easy to estimate the extent of such bias and we cannot rule out some degree of publication bias in our results. A pooled analysis of the original data of about 9500 subjects involved in 21 case-control studies from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC) data set was performed to assess the role of GSTM1 genotype as a modifier of the effect of smoking on lung cancer risk with adequate power. Analyses revealed no evidence of increased risk of lung cancer among carriers of the GSTM1 null genotype (age-, gender- and center-adjusted OR = 1.08, 95% CI 0.98-1.18) and no evidence of interaction between GSTM1 genotype and either smoking status or cumulative tobacco consumption.

Case-Control Studies↗
PubMed1995

The variable metabolic response to dietary isoflavones in humans.

The aim of this study was to better understand the metabolic fate of dietary estrogenic isoflavones in humans. Twelve volunteers were challenged with soya flour and urinary levels of the isoflavones daidzein (Da), genistein (Gen), and glycitein (Gly), and the isoflavonoid metabolites equol (Eq) and O-desmethylangolensin (O-Dma) determined by GC and GC-MS. Prior to challenge, Da, Gen, and Gly were present in the urine of all participants at low levels and Eq and O-Dma were present in 9/12 and 10/12 participants, respectively. Urinary levels of all five diphenols were increased in each individual on the day following challenge, returning to approximately prechallenge levels on the second or third day post-challenge. Mean post-challenge peak levels of the five diphenols compared with pre-challenge levels were Da (4x), Gen (8x), Gly (5x), Eq (45x), and O-Dma (66x). However, there was considerable individual variation in this metabolic response with peak levels of Eq showing the highest variation (1527x). An inverse relationship between Eq and O-Dma excretion was also found post-challenge suggesting individual variability in the preferred metabolic pathways of dietary isoflavones.

4-Butyrolactone↗
PubMed1998

Cytochrome c oxidase assay in minute amounts of human skeletal muscle using single wavelength spectrophotometers.

Determination of cytochrome c oxidase (COX; EC 1.9.3.1) activity in human mitochondria presents several technical difficulties which result in a large intra- and interlaboratory variability, especially when a single wavelength spectrophotometer (SWS) is used, as is generally done in most laboratories in the context of screening procedures for the detection of respiratory chain deficiencies. We studied the experimental conditions of COX assay in human skeletal muscle mitochondria using a SWS in order to define the optimal conditions for the assay and compared these results with those obtained using a double wavelength spectrophotometer (DWS). We demonstrate that a low intra-individual variability of COX assay can be obtained with SWS by: (1) using manual stirrers to avoid the formation of bubbles in the mixture; (2) preincubating mitochondria and laurylmaltoside before the addition of cytochrome c, which prevents light scattering secondary to mitochondrial swelling; and (3) using low amounts (1-2 microg) of mitochondrial protein to extend and linearize the reaction rate. Under these experimental conditions, the concordance between SWS and DWS was very good (R=0.975).

Electron Transport↗
PubMed2003

Adaptation characteristics of steady-state motion visual evoked potentials.

OBJECTIVE: Motion visual evoked potentials (motion VEPs) are used in clinical diagnosis and basic research. Employing steady-state rather than the usual transient motion VEPs simplifies statistical evaluation and might drastically reduce examination durations. Protocols for recording transient motion-onset VEPs usually involve fairly long recovery intervals between trials to avoid neural adaptation. This is not feasible for steady-state VEPs. We investigated how adaptation affects the steady-state motion VEP. METHODS: Oscillatory (13.3rev/s) and continuous uni-directional random-dot motion served as adaptation stimuli. Steady-state motion VEPs and, for comparison, transient motion VEPs were recorded. RESULTS: In the first experiment, we investigated how adaptation affects the recordings. Contrary to our expectation, we did not find any sizable effect. However, there was a large inter-individual variability in steady-state amplitude and no correlation across subjects between transient and steady-state amplitude. In the second experiment, we confirmed that the steady-state VEP reflects veridical motion processing by assessing its susceptibility to uni-directional pre-adaptation. CONCLUSIONS: Taken together, the results suggest that steady-state motion VEPs provide a fast method of recording motion responses without suffering from adaptation, but at the expense of inter-individual reproducibility.

Adaptation, Physiological↗
PubMed1993

Rate of progression and prognostic factors in Alzheimer's disease: a prospective study.

OBJECTIVE: To study rate of progression and correlates of cognitive and functional/behavioral deterioration in Alzheimer patients. DESIGN: A 1-year multicenter prospective study. SETTING: Outpatients and inpatients at geriatric institutions. PATIENTS: Fifty-six patients with a clinical diagnosis of Alzheimer's disease according to DSM-III criteria of Primary Degenerative Dementia. MAIN OUTCOME MEASURES: Blessed Dementia Scale (BDS) and Blessed Information-Memory-Concentration test (BIMC) measured at baseline, third, sixth, and twelfth month. RESULTS: The mean annual (+/- SD) rate of progression of our sample was 3.5 (+/- 3.7) points on the BDS and 2.6 (+/- 4.9) on the BIMC, with a wide range of variability. The level of cognitive impairment (BIMC score) at baseline predicted functional and behavioral deterioration: the better the initial BIMC score, the less the rate of negative change of BDS (r = 0.37, P = 0.006). Furthermore, the younger the patients at the disease onset, the faster the progression of cognitive impairment (r = 0.48, P = 0.0003), with men having a slower rate of progression (P = 0.004) than women. CONCLUSIONS: The present study confirms previous findings showing a wide individual variability in rate of progression of cognitive and functional/behavioral impairment as assessed by BIMC and BDS. The cognitive profile may predict the clinical evolution better than the functional and behavioral status, with patients with an earlier onset and women having a faster deterioration.

Age Factors↗
PubMed1993

Handling and diet-induced atherosclerosis in rabbits.

Atherosclerosis was induced in rabbits by feeding them a 2% cholesterol diet (CHOL) during a 5-week period. Twelve rabbits were fed with increasing amounts of CHOL food until the ad libitum level was reached, whereas in 24 other rabbits the food was limited to the amount eaten by the lowest consumer of the group to reduce individual variability in total amount of food consumed. Twice a day, half of the rabbits were handled carefully, the other half had normal laboratory practice contact with their caretaker. Feed intake and amount of atherosclerosis were determined for all experimental animals, while for the handled animals behavioural parameters and changes were recorded daily and per animal. On average the handled and non-handled rabbits took the same amount of food per week, although there were large individual differences. The handled animals showed some behavioural adaptation to being handled. Handling had no influence on atherosclerosis size; this latter measure was only roughly determined by the amount of CHOL food eaten.

Animals↗
PubMed1985

[Drug metabolism in the septic liver: conclusions about the pharmacokinetics of chloramphenicol].

In nine patients in anaerobic septic shock, five of them with hepatic injury compatible with sepsis liver failure, hematic chloramphenicol concentration was determined at 5 minutes, 1, 2, 3 and 6 hours after intravenous administration of the first of three daily dose (50 mg/k/day); in the hepatic failure group the procedure was repeated with the next dose, previous attempt of haemodynamic compensation with two hours dopamine (3-10 mcg/k/min.) infusion. Starting from experimental data computation adjustment of time-concentration curve and lineal regression with a p = 0.0001 adjustment was done, determining half live (HL), distribution volume (DV), constant of elimination (K) and clearance (CL). In septic shock without hepatic injury patient group, there was noticed a uniform behavior in time-concentration graphic, withdrawn from chloramphenicol bone-marrow depression levels and pharmacokinetics parameters quite near the normal ones, with a reasonable extension of (DV). When attempting hepatic injury patient group, though an individual variability, drug concentration reach bone marrow depression levels and there was a significant lowering of Cl (p = 0.001) and a reasonable one of DV. Dopamine haemodynamic compensation attempt results in an increase of chloramphenicol hematic concentration in the sepsis liver group and the pharmacokinetics levels bear new deterioration. Practical meaning of the methodology used in drug handling in severe hepatic failure is stressed, to allow mathematic valuation of different pathogenic compounds. Though each patient should be individually evaluated, in septic shock without liver injury chloramphenicol dosification should not been any changes but in presence of sepsis liver doses should be diminished to half and administration interval extended to 11.5 hours.

Chloramphenicol↗
PubMedDate not supplied

[Doxorubicin and cisplatin genotoxicity: search for a real indication using the micronucleus test].

Doxorubicin and cisplatin are two major anticancer drugs, and are also known to be mutagen. Using short term mutagenesis tests, the cytokinesis-block micronucleus test and chromosome aberrations test, a study of the cytotoxicity and the mutagenicity of these two drugs has been aimed to determine a genotoxic of reference for these tests. Cisplatin and doxorubicin were genotoxic and gave positive results with the two tests. Since cisplatin was more cytotoxic than doxorubicin for a same genotoxicity, doxorubicin has been selected as a positive control for these two short-term mutagenesis tests. A study of the individual variability in the response to in vitro doxorubicin exposure was made using the cytokinesis-block micronucleus test, applied to cultured T lymphocytes form healthy subjects and cancer patients. Micronucleated cell rate before (T0) and after in vitro exposure to doxorubicin (T1) were determined in the two groups of subjects. Micronucleated cell rates T1 were significantly higher than T0 for healthy subjects and cancer patients. A calculated sensitivity index [(T1)-(T0)] is proposed to evaluate the individual sensitivity to the positive control doxorubicin.

Adult↗
PubMed2003

Nutritional aspects of eating episodes followed by vomiting in Brazilian patients with bulimia nervosa.

BACKGROUND: The clinical aspects of bulimia nervosa (BN) are similar in countries with different sociocultural backgrounds, but less is known about dietary composition in patients from developing countries. Little is also known about the role that nutritional aspects may play in behaviours aimed at counteracting the effects of binge eating. OBJECTIVES: To describe the daily energy intake and eating behaviour of BN patients in Brazil and compare the dietary patterns of the patients who terminated eating episodes by vomiting and those patients who did not. METHODS: Thirty patients from an eating disorders programme in a university-affiliated hospital completed a 14-day dietetic diary; the data were analysed using nutritional software. RESULTS: Mean age and BMI of the patients were respectively 27.2 +/- 9.6 years and 25.5 +/- 6.7 Kg/m2. The patients in the vomiting subgroup ate more irregularly and consumed a more variable number of meals per day than those in the non-vomiting subgroup. The daily energy intake of the patients as a whole was 2,202 kcal, with a macronutrient composition of 53% carbohydrates, 31% fats and 17% proteins. The mean energy intake of the eating episodes followed by vomiting was 1,331 kcal with a macronutrient profile of 51% carbohydrates, 36% fat and 14% protein. Intake and eating patterns were characterised by between- and within- individual variability, and so no significant differences were found in the subgroup comparisons. Foods with a high energy density were preferred during the eating episodes followed by vomiting. CONCLUSIONS: The results indicate that patients who vomit have a more irregular and variable eating pattern than those who do not vomit, but their daily nutrient content is comparable.

Adult↗
PubMed2004

Variability in the resistance of the Nigerian West African Dwarf goat to abbreviated escalating trickle and challenge infections with Haemonchus contortus.

The West African Dwarf (WAD) goat is known to be relatively resistant to infection with Haemonchus contortus. An experiment was carried out to assess variability in resistance under escalating trickle and single pulse challenge infection protocols. Thirty two 7-8 month old goats were subjected to trickle infection beginning with a thrice weekly dose of 100 L3 and increasing to 500 L3 by week 5, the last dose being administered on D30. Infection was abbreviated with fenbendazole on D32 and the animals challenged with 4000 L3 (=404-741L3/kg body weight) on D46 and necropsied on D81. The goats exhibited marked individual variability in faecal egg counts (FEC) and worm burdens (Wb). For convenience, we arranged the goats into FEC classes 1, 2 and 3, corresponding to peak counts of <1000, 1000-2500 and >2500 epg and Wb classes 1, 2 and 3, with counts of <50, 50-100 and >100 worms, respectively, broadly reflecting relatively resistant, intermediate and poorly resistant response phenotypes. Wb classes broadly reflected the FEC phenotypes and although there were no significant differences between the Wb of the FEC classes at necropsy, significant differences in FEC were detected when analysis was carried out only on Wb classes. There was also a significant positive correlation between FEC class on each of the days of challenge (D67 to D80) and worm burden at necropsy. In general, the goats showed strong resistance/tolerance to challenge, with more than 80% having Wb not exceeding 5% of the challenge dose, and only in class three goats were weight loss and anaemia detected in some animals. PCV and weight changes also closely reflected the FEC and Wb classes, with a significant negative correlation between each and Wb. Infection level did not significantly affect the sizes of either male or female worms and no significant difference was detected between the levels of circulating eosinophils in any FEC or Wb class. Overall, the data are consistent with the existence of a range of response phenotypes, which reflect variations in resistance of WAD goats to H. contortus infection, the genetic basis of which will be explored in future experiments.

Animals↗
PubMed1982

Febrile infants: predictors of bacteremia.

One hundred and seventy-five infants less than 8 weeks of age, presenting to the pediatric emergency room of the Bronx Municipal Hospital Center with rectal temperature greater than or equal to 38 degrees C (100.4 degrees F), were studied. House officers recorded their impressions of the infants on a number of variables prior to performing a lumbar puncture and obtaining laboratory data. All infants were admitted for parenteral antibiotic therapy pending culture results. Culture-positive bacterial infections occurred in 6.3% (n = 11); the incidence of bacteremia was 3.4% (n = 6). Of special concern were the 134 infants who had no visible source for their fever during the first examination. A major goal was to determine whether there were any early predictors of bacteremia in this group. The individual variables of white blood cell count greater than or equal to 15,000/mm3, band count greater than or equal to 500/mm3, temperature, impression of irritability, tone, cry, and activity level were not related to the presence of bacteremia. An erythrocyte sedimentation rate greater than or equal to 30 and the examiner's impression of sepsis were significantly associated with bacteremia but did not correctly identify all cases. However, the combination of impression of sepsis, white blood count greater than or equal to 15,000/mm3, and erythrocyte sedimentation rate greater than or equal to 30 identified all infants with bacteremia and excluded 82% of the infants who were eventually shown not to have bacteremia.

Blood Sedimentation↗
PubMed1999

The genetics of serum lipid responsiveness to dietary interventions.

CHD is a multifactorial disease that is associated with non-modifiable risk factors, such as age, gender and genetic background, and with modifiable risk factors, including elevated total cholesterol and LDL-cholesterol levels. Lifestyle modification should be the primary treatment for lowering cholesterol values. The modifications recommended include dietary changes, regular aerobic exercise, and normalization of body weight. The recommended dietary changes include restriction in the amount of total fat, saturated fat and cholesterol together with an increase in the consumption of complex carbohydrate and dietary fibre, especially water-soluble fibre. However, nutrition scientists continue to question the value of these universal concepts and the public health benefits of low-fat diets, and an intense debate has been conducted in the literature on whether to focus on reduction of total fat or to aim efforts primarily towards reducing the consumption of saturated and trans fats. Moreover, it is well known that there is a striking variability between subjects in the response of serum cholesterol to diet. Multiple studies have examined the gene-diet interactions in the response of plasma lipid concentrations to changes in dietary fat and/or cholesterol. These studies have focused on candidate genes known to play key roles in lipoprotein metabolism. Among the gene loci examined, APOE has been the most studied, and the current evidence suggests that this locus might be responsible for some of the inter-individual variability in dietary response. Other loci, including APOA4, APOA1, APOB, APOC3, LPL and CETP have also been found to account for some of the variability in the fasting and fed states.

Apolipoprotein C-III↗