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PubMed1982

Handgrip exercise in normal young women: a noninvasive cardiovascular assessment.

Blood pressure, heart rate, and echocardiographic parameters of left ventricular size and shortening were measured both under baseline conditions and during handgrip exercise (50% maximum handgrip effort held to fatigue) in 20 normal women (20 through 29 years of age). As a group, there was a significant increase in heart rate (72 +/- 10 vs 83 +/- 12; P less than .001), systolic blood pressure (111 +/- 8 vs 133 +/- 14 mm Hg; P less than .001), diastolic blood pressure (67 +/- 8 vs 89 +/- 12 mm Hg; P less than .001), and calculated cardiac output (4.3 +/- 1.5 vs 5.2 +/- 1.7 liters/minute; P less than .005). There was no significant change in left ventricular internal dimension in diastole or systole, shortening fraction, or calculated stroke volume. The average group response of an increase in cardiac output secondary to an increase in heart rate is similar to that of male subjects in their second decade. Individual variability in responses was of specific interest since only three of the 20 women demonstrated a totally characteristic response to handgrip exercise. Handgrip exercise in young women may not provide a uniformly characteristic response from which to predict hemodynamic changes in a given individual and may lead to clinical misinterpretation if appropriate caution is not used.

Adult↗
PubMed1998

Functional polymorphism of the human arylamine N-acetyltransferase type 1 gene caused by C190T and G560A mutations.

Human N-acetyltransferase type 1 (NAT1) catalyses the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivate several known carcinogens. Despite wide inter-individual variability in activity, historically, NAT1 was considered to be monomorphic in nature. However, recent reports of allelic variation at the NAT1 locus suggest that it may be a polymorphically expressed enzyme. In the present study, peripheral blood mononuclear cell NAT1 activity in 85 individuals was found to be bimodally distributed with approximately 8% of the population being slow acetylators. Subsequent sequencing of the individuals having slow acetylator status showed all to have either a C190T or G560A base substitution located in the protein encoding region of the NAT1 gene. The C190T base substitution changed a highly conserved Arg64, which others have shown to be essential for fully functional NAT1 protein. The C190T mutation has not been reported previously and we have named it NAT1 x 17. The G560A mutation is associated with the base substitutions previously observed in the NAT1 x 10 allele and this variant (NAT1 x 14) encodes for a protein with reduced acetylation capacity. A novel method using linear PCR and dideoxy terminators was developed for the detection of NAT1 x 14 and NAT1 x 17. Neither of these variants was found in the rapid acetylator population. We conclude that both the C190T (NAT1 x 17) and G560A (NAT1 x 14) NAT1 structural variants are involved in a distinct NAT1 polymorphism. Because NAT1 can bioactivate several carcinogens, this polymorphism may have implications for cancer risk in individual subjects.

4-Aminobenzoic Acid↗
PubMed1988

Changes in QT and Q-aT intervals induced by mental and physical stress with fixed rate and atrial triggered ventricular inhibited cardiac pacing.

We have investigated the influence of mental stress and physical stress, i.e., exercise, on the QT and Q-aT intervals (measured from the pacemaker stimulus to the end or the apex, respectively, of the T wave). The study was made on ten patients with high degree atrioventricular block treated with AV universal (DDD) pacemakers. These were programmed to a fixed rate ventricular (VVI) or an atrial triggered (VDD) function for different parts of the study. An arithmetic mental stress test and a bicycle exercise test were performed with each mode of pacing. In the VVI pacing mode, the atrial rate increased by 11% during mental stress and by 46% during exercise. There was a significant shortening of QT and Q-aT intervals with both types of stress. With VDD pacing, mental stress induced a 12% increase in rate and a significant shortening of QT and Q-aT. The paced rate increased by 50% during the exercise test. This increase in ventricular rate was associated with the most marked changes in QT and Q-aT intervals. Thus, both types of stress cause a significant shortening of the QT and Q-aT interval even in the absence of a simultaneous increase in ventricular rate. When the latter is allowed to increase during VDD pacing, both intervals shorten considerably more. There was a marked inter-individual variability in the response to both types of stress. These findings are of importance with regard to the QT sensing rate responsive pacemaker which can be expected to respond to mental stress in most patients, but that response might be unpredictable in the individual.

Cardiac Pacing, Artificial↗
PubMed1999

The modulatory effect of spermine on the glutamate-NMDA receptor is regionally variable in normal human adult cerebral cortex.

The MK-801, glutamate and polyamine binding sites on the N-methyl-D-aspartate class of glutamate receptors labelled with [3H]MK-801 were characterized in four cortical areas (sensorimotor, superior temporal, mid-frontal and occipital) from seven human adult control cases. Age, post-mortem delay, tissue storage time and sex had no significant effects on any of the parameters measured. Dissociation constants (K(D) values) for MK-801 showed similar mean values in the four cortical areas, whereas receptor densities (B(max) values) showed significant differences between sensorimotor or occipital and superior temporal or mid-frontal cortex. There were marked regional differences in the profiles of the spermine- and glutamate-incremented enhancement of specific [3H]MK-801 binding. The EC(50) for the glutamate enhancement was significantly higher in the occipital than in the mid-frontal and sensorimotor cortex, whereas maximal glutamate-enhanced binding values did not differ. The maximal enhancement of [3H]MK-801 binding by spermine and glutamate varied between the cases, ranging from zero to 40.4+/-9.3 fmol x mg protein(-1) for spermine, and from 85+/-5 to 111+/-10 fmol x mg protein(-1) for glutamate. Maximal spermine enhancement of [3H]MK-801 binding was significantly more variable in superior temporal or mid-frontal than in sensorimotor or occipital cortex. The results suggest that N-methyl-D-aspartate receptor sites, especially the polyamine site, are heterogeneous in human cerebral cortex, and show a high degree of regional and individual variability.

Age Factors↗
PubMed1976

[Radiation injury of the spinal cord].

The literature dealing with radiation myelopathy is reviewed. The following points are to be noticed:radiation myelopathy is a rare complication in the radiation therapy of extraspinal tumors, nevertheless the number of case reports is increasing during the last years; probably this is due to the increasing use of high energy therapy. Already a cord dose of 1000 rad may be dangerous; with an increasing dose the risk of radiation myelopathy is increasing too. Besides the total dose the incidence of radiation myelopathy depends on the rate of delivery, the over-all time of administration, the size of the individual fraction, the field size, the size of the volume irradiated, the type of irradiation, the use of hyperbaric oxygen and some other special conditions of radiation. But the incidence of radiation myelopathy depends not only on radiation technique but also on patients' variables. Individual variations in radiosensitivity are a well known fact; this may be partly due to an inherent biologic variation of response. Moreover the incidence of radiation myelopathy may be intensified by simultaneously existing diseases - above all by hypertension- and probably by some medicaments taken simultaneously. A dependence from age, sex, and the kind of the primary tumor seems not to exist. Radiation lesions of the cervical spinal cord have been reported much more frequently than lesions of the dorsal spinal cord; lesions of the lumbal spinal cord are a very rare event. There exist different conceptions of the pathogenesis: opinions differ as to whether the effect is primarily on the connective tissue and blood vessels or on nerve cells and their axons or if the different tissues are injured simultaneously; moreover an autoimmuno-hypothesis is discussed. The clinical signs of radiation myelopathy can be grouped into two major syndromes: the transient radiation myelopathy and the delayed or chronic radiation myelopathy, which usually develops gradually with a subsequent chronic progressive course but in some cases may occur acutely after the latent period; the course is not always progressive but may be undulating and remissions have been reported in some rare cases...

Adult↗
PubMedDate not supplied

Epidemiology of microalbuminuria in the general population.

Microalbuminuria in the general population is associated with recognized risk factors for cardiovascular disease such as hypertension, hyperglycemia, hyperinsulinemia, and hyperlipidemia; and it is an independent predictor of subsequent cardiovascular mortality in hypertensive, diabetic, and elderly populations. Although different methods have been used for measuring and expressing urinary albumin excretion and a variety of cutoff levels have been used for defining microalbuminuria, prevalence of microalbuminuria appears to be higher in non-Europeans (8%-28%) than in Europeans (2%-10%). However, because of the large within-individual variability of urinary albumin excretion and the relatively low prevalence of microalbuminuria, large studies are required to detect statistically significant associations between albuminuria and cardiovascular risk factors. Evidence presented here supports the proposition that microalbuminuria represents a marker of cardiovascular disease risk in nondiabetic individuals as well as diabetic individuals. Moreover, because of a high sensitivity of the test and because albuminuria is a concomitant of many forms of renal disease, microalbuminuria also has a role in detecting patients with renal involvement associated with essential hypertension, lupus erythematosus, women with pre-eclampsia, and subjects with unsuspected primary and secondary nephropathies.

Albuminuria↗
PubMed2003

Predictive value of pretransplantation cyclosporine pharmacokinetic studies on initial post-transplantation dosing in pediatric kidney allograft recipients.

Despite the introduction of a variety of new immunosuppressive agents, cyclosporine A (CsA) has maintained a strong position in pediatric transplantation (Tx). Post-Tx dosing with CsA is a challenging task because of the narrow therapeutic window of the drug, the great individual variability of metabolism and the lack of consensus about the optimal dosage and targeted blood concentration. Sufficient administration of CsA may be protective against acute rejections and other early complications after Tx, which is crucial for the long-term survival of the graft. Individual doses based on pre-Tx pharmacokinetic studies might be helpful in achieving optimal early concentrations of CsA. To asses the usefulness of pharmacokinetic studies, we retrospectively compared the post-Tx doses administered with the individually predicted doses between 1988 and 1998. Multiple regression of data on 65 de novo renal transplant recipients, 1.1-15.5 yr old, was used to analyze the significance of the predicted dose, trough blood concentration of CsA (B-CsA), serum creatinine and age at the time of Tx in explaining the doses used during the first three post-Tx weeks. Patients were grouped according to age (<2, 2-8 and >8 yr), according to the predicted dose (within or outside +/-25% of age-group average), and according to the oral formulation of CsA. Standard dosing scheme was simulated by using age-specific average doses in the place of the individual predicted doses. Administered doses of CsA were high [averaging 22.6 (504), 20.7 (484), and 12.4 mg/kg/d (329 mg/m2/d) for patients <2, 2-8, and >8 yr old] but the average B-CsA remained in the target range of 250-450 microg/L. The predicted dose and age were significant parameters in explaining the administered doses during the first 3 wk after Tx. B-CsA and S-creatinine were non-significant. The predicted doses were used to initiate the dosing of CsA after Tx (R2 = 0.70) and adjustments to dosing were made during the next weeks (R2 = 0.59, 0.52). Multiple regression model showed better fit for 60% of our patients, who had atypical predicted doses (R2 = 0.74, 0.60, 0.64 for first, second and third post-Tx weeks, respectively), most remarkably in patients <2 yr of age, than for the study population as a whole. A simulated standard dose was not able to explain the administered doses of CsA. In conclusion, pre-Tx pharmacokinetic studies are valuable for determining individual post-Tx starting doses, especially for those patients who need high or low doses of CsA. Individual dosing led to relatively high initial CsA doses, which could be significant for the long-term survival of the graft.

Adolescent↗
PubMed2000

Assessment of transduction rates of porcine bone marrow.

Although drug resistance is commonly used as an indicator of gene transfer in various cellular contexts, the assessment of drug resistance is often imprecise and over-estimated. To measure accurately transduction efficiencies of the retroviral-mediated transfer of genes encoding the neomycine phosphotransferase (Neo(r)) and porcine major histocompatibility (MHC) class II in pig bone marrow cells (BMC), the fraction of targeted progenitors was evaluated by both colony-forming unit granulocytes/macrophages assays (G418r CFU-GM) and by PCR analysis of the transgenes (Tg). Transduced and untransduced BMC were selected at different concentrations of G418 and revealed high individual variability of drug sensitivity. Comparison of the results obtained by estimating the CFU frequency and the PCR assays on drug-resistant colonies demonstrated a marked overestimation of BM transduction rates when determined by G418 resistance alone, because only approximately one-third of individual colonies were positive for both the Neo(r) and the class II Tg. Because this discrepancy is likely to affect the overall assessment of transduction rates using drug resistance markers, our data attest for the need of a combination of molecular assays to determine transduction efficiencies accurately.

Animals↗
PubMed2004

Pharmacokinetics of rectal tramadol in postoperative paediatric patients.

BACKGROUND: Postoperative analgesia in children may be improved by using tramadol. The pharmacokinetics of rectal tramadol in young children were therefore investigated. METHODS: The pharmacokinetics of rectal tramadol and its active metabolite were studied in 12 young children (age: 1-6 yr) postoperatively. On the basis of these data, a population model was constructed. Using this model, the pharmacokinetics of different doses of tramadol were calculated. RESULTS: The pharmacokinetics of rectal tramadol could be adequately described by a one-compartment model. The pharmacokinetic parameters derived from the model indicate that a low variability was present. Elimination half-life was 4.3 (0.2) h (sem) and the apparent clearance was 16.4 (1.5) litre h(-1) (sem). CONCLUSIONS: The study showed that after rectal administration, tramadol is absorbed at a reasonable rate and with a low inter-individual variability in small children. The data also suggested that a rectal dose of tramadol 1.5-2.0 mg kg(-1) is therapeutic.

Administration, Rectal↗
PubMed2004

Intra-individual variation of serum prostate specific antigen levels in men with benign prostate biopsies.

OBJECTIVE: To determine the intra-individual (physiological) variation of prostate-specific antigen (PSA) measurements in men after a benign prostatic biopsy. PATIENTS AND METHODS: Sixty-four men were prospectively assessed, all of whom had a benign prostatic biopsy within the preceding 13 months. The degree of intra-individual variability was established by calculating the coefficient of variation on four PSA levels obtained from each patient weekly over a month. RESULTS: Six patients were subsequently diagnosed with prostate cancer and their data are presented separately. In the remaining 58 patients the median (range) individual mean PSA value was 6.3 (0.5-34.1) ng/mL. The median (range) coefficient of variation within the group was 9.5 (2.4-76.1)%. There was a clear linear relationship between mean PSA level and the standard deviation. CONCLUSION: In 48 of the 63 patients analysed, the coefficient of variation for serum PSA values in the group as a whole was greater than the variation claimed for the assay technique. The significance of the linear relationship between PSA and the standard deviation is discussed, with particular reference to those men who had a benign prostate biopsy.

Aged↗
PubMed2006

Stereoselective determination of methadone and its main metabolite in serum and urine from methadone maintenance patients.

OBJECTIVES: A stereoselective HPLC method was developed to separate and quantify both enantiomers of methadone and its main metabolite EDDP in serum and urine. The method was used to establish that there is a relationship between the dose of methadone prescribed and its serum concentration as well as urine excretion of methadone and its metabolite enantiomers. METHODS: The chiral alpha1-glycoprotein stationary phase was used for enantioseparation of (R)-methadone, (S)-methadone and (R)-EDDP (S)-EDDP. The enantiomers of methadone and EDDP were extracted from urine and serum by a simple solidphase procedure. RESULTS: The validated method was applied to the analysis of 31 serum and urine samples obtained from methadone-maintained outpatients (65% male, age 28.8+/-4; methadone dose 146+/-47 mg). A significant correlation (Pearson) r=0.67 (p<0.001) between methadone dose and serum concentration of (R)-methadone was found. Due to the large variation in results obtained from analysis of the subjects' urine specimens, no statistically significant relationship between methadone dose and urine excretion of methadone and EDDP enantiomers was established. The rate of R/S methadone (1.38 in serum, 2.43 in urine) and R/S EDDP (0.83 in urine) confirmed stereoselectivity in methadone metabolism with high individual variability. CONCLUSIONS: The enantioselective evaluation of serum methadone concentration might be an interesting tool in methadone maintenance programme. On the other hand, the urinary excretion of methadone and EDDP enantiomers is not reliable as marker of methadone compliance but could be useful for monitoring individual metabolism or for studying the stereoselectivity in pharmacokinetics and metabolism of methadone.

Adult↗
PubMed1998

Fetal mouse NK cell clones are deficient in Ly49 expression, share a common broad lytic specificity, and undergo continuous and extensive diversification in vitro.

NK cells obtained by exposing mouse fetal thymocytes to appropriate combinations of IL-4, IL-2, and PMA are phenotypically indistinguishable from cultured adult splenic NK cells with the exception that they generally lack measurable expression of all of the inhibitory Ly49 molecules that can currently be detected with Abs (Ly49A, -C, -G, and -I) and of the activating molecule Ly49D. Despite this deficiency, fetal NK cells have a similar specificity to Ly49-expressing adult splenic NK cells. Individual fetal NK cell clones display an essentially invariant and broad specificity similar to that of polyclonal populations of fetal or adult NK cells, although significant differences in the fine specificity of clones can occasionally be detected. Most remarkably, cloned fetal NK cell lines display heterogeneous expression of a restricted set of surface molecules that includes 10A7, Ly6C, 3C2, CD8, certain isoforms of CD45, and also, occasionally, Ly49 molecules. This heterogeneity is not related to the cell cycle or activation status of the cells, and micromanipulation recloning demonstrates unambiguously that it is not due to a lack of a single cell origin. Diversity is generated rapidly and the capacity for diversification appears to persist indefinitely in vitro. The expression of individual variable Ags is independent and stochastic, resulting in fetal NK "clones" being potentially composed of hundreds of phenotypically distinct cells. We hypothesize that fetal NK cells behave as progenitor cells that are undergoing a process of rapid, extensive, and continuous diversification and that are individually capable of generating and regenerating a complex NK cell repertoire.

Animals↗
PubMed2003

Variability in position of the subthalamic nucleus targeted by magnetic resonance imaging and microelectrode recordings as compared to atlas co-ordinates.

BACKGROUND: Traditional methods for localisation of target nuclei for deep brain stimulation (DBS) have used brain atlas co-ordinates for initial targeting. It is now possible to visualise the subthalamic nucleus (STN) on magnetic resonance imaging (MRI) and determine the individual variability of its position. METHODS: The present study was performed in patients undergoing STN DBS for Parkinson's disease. The STN was directly targeted from axially obtained MRI and verified with microelectrode recordings. Postoperatively, the most effective contact was identified for each patient, and its position was calculated. RESULTS: Fifty electrodes were inserted in 25 patients. The target position varied considerably in relation to the mid-commissural point. The mean effective contact position lies just dorsal to the location of the STN in a standard brain atlas. CONCLUSION: The STN varies in position, and can be accurately targeted from MRI alone.

Adult↗
PubMed1998

Forecasting generalized epileptic seizures from the EEG signal by wavelet analysis and dynamic unsupervised fuzzy clustering.

Dynamic state recognition and event-prediction are fundamental tasks in biomedical signal processing. We present a new, electroencephalogram (EEG)-based, brain-state identification method which could form the basis for forecasting a generalized epileptic seizure. The method relies on the existence in the EEG of a preseizure state, with extractable unique features, a priori undefined. We exposed 25 rats to hyperbaric oxygen until the appearance of a generalized EEG seizure. EEG segments from the preexposure, early exposure, and the period up to and including the seizure were processed by the fast wavelet transform. Features extracted from the wavelet coefficients were imputed to the unsupervised optimal fuzzy clustering (UOFC) algorithm. The UOFC is useful for classifying similar discontinuous temporal patterns in the semistationary EEG to a set of clusters which may represent brain-states. The unsupervised selection of the number of cluster overcomes the a priori unknown and variable number of states. The usually vague brain state transitions are naturally treated by assigning each temporal pattern to one or more fuzzy clusters. The classification succeeded in identifying several, behavior-backed, EEG states such as sleep, resting, alert and active wakefulness, as well as the seizure. In 16 instances a preseizure state, lasting between 0.7 and 4 min was defined. Considerable individual variability in the number and characteristics of the clusters may postpone the realization of an early universal epilepsy warning. University may not be crucial if using a dynamic version of the UOFC which has been taught the individual's normal vocabulary of EEG states and can be expected to detect unspecified new states.

Algorithms↗
PubMed1995

Calcium antagonist use in congestive heart failure: still a bridge too far?

Calcium antagonists continue to be used to treat congestive heart failure (CHF), despite clinical evidence that they may exacerbate the disease. The systemic vasodilatory actions of these drugs make them potentially attractive for use as afterload reducing agents in patients with CHF. Newer calcium antagonists of the 1,4-dihydropyridine class, with claims of little or no negative inotropic properties and minimal effects on the sympathetic nervous system, seem a promising treatment of this disease. All calcium antagonists, however, consistent with their ability to block transmembrane calcium transport in cardiac muscle cells, are intrinsically negative inotropes. Moreover, clinical trial data are inconclusive about the ability of these newer calcium antagonists to activate the sympathetic nervous system. The relatively small numbers of patients with CHF, the differing degrees of CHF in different patient groups, and the variation in route of administration, dosage, and schedule of hemodynamic measurements make analyses of published data difficult. Although some patients with CHF respond positively to treatment with calcium antagonists, there is great individual variability of response, and the majority of patients show deterioration of myocardial function when taking calcium antagonists. Until conclusive clinical evidence of the safety and effectiveness of calcium antagonists in the treatment CHF is available, they should not be used to treat this disease unless individual patient characteristics clearly indicate a positive benefit/risk ratio.

Animals↗
PubMed2000

Nutritional implications of the cephalic-phase salivary response.

The rapid release of saliva following cognitive or sensory stimulation is termed the cephalic phase salivary response. Optimal methods and conditions for measuring the cephalic phase salivary response have not been established. Consequently, determination of the extent to which the large inter and intra-individual variability reflect biological or procedural influences is not possible. The nutritional significance of the response may be great due to the multiple roles played by saliva in food selection and digestion. The cephalic phase salivary response has been proposed as an objective index of various individual states (e.g. hunger) and characteristics (e.g. dietary restraint, extroversion), but its value for such purposes requires further verification.

Appetite Stimulants↗
PubMed2002

Metastable epialleles in mammals.

There are some mammalian alleles that display the unusual characteristic of variable expressivity in the absence of genetic heterogeneity. It has recently become evident that this is because the activity of these alleles is dependent on their epigenetic state. Interestingly, the epigenetic state is somewhat labile, resulting in phenotypic mosaicism between cells (variegation) and also between individuals (variable expressivity). The establishment of the epigenetic state occurs during early embryogenesis and is a probabilistic event that is influenced by whether the allele is carried on the paternal or maternal alleles. In addition, the epigenetic state determines whether these alleles are dominant. We propose that mammalian alleles with such characteristics should be termed metastable epialleles to distinguish them from traditional alleles. At this stage, it is unclear how common these alleles are, but an appreciation of their existence will aid in their identification.

Alleles↗
PubMed2003

Pharmacokinetics of mycophenolate mofetil in patients with autoimmune diseases compared renal transplant recipients.

Mycophenolate mofetil (MMF), being effectively used as immunosuppressant in transplant medicine, has recently attracted interest as therapeutic agent for autoimmune diseases (AID). For these patients, no pharmacokinetic (PK) data are available. This study is an investigation of single-dose concentration-time profiles of 1 g off MMF in 16 patients with AID, including 10 patients with ANCA-associated vasculitis and 6 patients with systemic lupus erythematosus, and compares them with profiles of 16 renal transplant recipients (RTX). Mycophenolic acid (MPA) blood levels were measured by both HPLC and EMIT, and MPA-glucuronide was determined by HPLC. In AID, mean MPA concentrations at 12 h were significantly higher compared with RTX (4.1 +/- 3.27 versus 1.8 +/- 1.15 mg/L; P = 0.018), whereas peak concentrations were lower (P = 0.017). However, mean MPA-AUC at 12 h as well as at 24 h were comparable between both groups. In contrast to RTX, there was an association in AID between MPA trough levels at 12 h and at 24 h with AUC(0-12) (P < 0.05 and P < 0.01). MPA trough concentrations at 24 h provided an estimation of AUC(0-24 h) in both patient groups (P < 0.001 and P < 0.01; AID and RTX, respectively). Compared with RTX, MPA-PK seems to be less affected in AID by renal function. Inter-individual variability of PK parameters was high in both groups. These data indicate that there are differences of MPA-PK between RTX and AID. The use of therapeutic drug monitoring in patients with AID appears to be clinically practicable and may be valuable to optimize individual immunosuppressive therapy.

Adult↗