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PubMed2003

In vivo identification of human cortical areas using high-resolution MRI: an approach to cerebral structure-function correlation.

Understanding the relationship between the structural and functional organization of the human brain is one of the most important goals of neuroscience. Individual variability in brain structure means that it is essential to obtain this information from the same subject. To date, this has been almost impossible. Even though noninvasive functional imaging techniques such as functional MRI (fMRI) are now commonplace, there is no complementary noninvasive structural technique. We present an in vivo method of examining the detailed neuroanatomy of any individual, which can then be correlated with that individual's own functional results. This method utilizes high-resolution structural MRI to identify distinct cortical regions based on cortical lamination structure. We demonstrate that the observed MR lamination patterns relate to myeloarchitecture through a correlation of histology with MRI. In vivo high-resolution MRI studies identify striate cortex, as well as visual area V5, in four individuals, as defined by using fMRI. The anatomical identification of a cortical area (V5MT) outside of striate cortex is a significant advance, proving it possible to identify extra-striate cortical areas and demonstrating that in vivo structural mapping of the human cerebral cortex is possible.

Brain↗
PubMed2002

Homeostatic maintenance of neuronal excitability by burst discharges in vivo.

Information in neuronal networks is thought to be represented by the rate of discharge and the temporal relationship between the discharging neurons. The discharge frequency of neurons is affected by their afferents and intrinsic properties, and shows great individual variability. The temporal coordination of neurons is greatly facilitated by network oscillations. In the hippocampus, population synchrony fluctuates during theta and gamma oscillations (10-100 ms scale) and can increase almost 10-fold during sharp wave bursts. Despite these large changes in excitability in the sub-second scale, longer-term (minute-scale) firing rates of individual neurons are relatively constant in an unchanging environment. As a result, mean hippocampal output remains stable over time. To understand the mechanisms responsible for this homeostasis, we address the following issues: (i) Can firing rates of single cells be modified? (ii) Once modified, what mechanism(s) can maintain the changes? We show that firing rates of hippocampal pyramidal cells can be altered in a novel environment and by Hebbian pairing of physiological input patterns with postsynaptic burst discharge. We also illustrate a competition between single spikes and the occurrence of spike bursts. Since spike-inducing (suprathreshold) inputs decrease the ability of strong ('teaching') inputs to induce a burst discharge, we propose that the single spike versus burst competition presents a homeostatic regulatory mechanism to maintain synaptic strength and, consequently, firing rate in pyramidal cells.

Action Potentials↗
PubMed1988

The effects of periodontal therapy on serum antibody (IgG) levels to plaque microorganisms.

The influence of periodontal therapy on serum antibody titers to selected periodontal disease-associated microorganisms was assessed in 23 patients having chronic inflammatory periodontal disease (CIPD). The immunoglobulin G (IgG) titers were determined by the microELISA technique in serum samples obtained prior to treatment; following a hygienic phase which included scaling, root planing, and oral hygiene instruction; following surgical treatment; and one year and two years following hygienic phase (maintenance phase). Considerable individual variability existed in the magnitude of immune response to specific bacterial preparations. Significant reductions in the mean antibody titers were seen to A. viscosus, S. sanguis, F. nucleatum, S. sputigena, B. gingivalis, B. intermedius, B. melaninogenicus, T. vincentii, and T. denticola by the end of the second year of maintenance. There was no consistent response to Capnocytophaga. When individual patient responses were examined, 6 of the 23 were found to have elevated titers to at least one of the microorganisms in the interval between pretreatment and the end of the hygienic phase; however, in all but one case, the titers at the end of the second year of maintenance were below pretreatment levels. Antibody levels to bacteria such as S. sanguis were modified during therapy. This would indicate that immune responses to microbes not generally considered to be "periodontal pathogens" may be modified by adjuvant activity associated with subgingival plaque or changes in the environment of the sulcus and that subsequent changes in titer do not necessarily reflect a role of that microorganism in the disease process.

Adult↗
PubMed1999

Flicker ERG responses to stimuli parametrically modulated in color space.

PURPOSE: To develop methods for recording human electroretinogram (ERG) responses to stimuli that modulate different classes of cones in various ratios, to draw inferences about the combination of cone signal in early retinal processing. METHODS: Subjects viewed large-field temporal modulations presented on a computer-controlled color monitor. A flicker photometric paradigm was used to equate the ERG response elicited by interleaved reference and test modulations. Test modulations were chosen to stimulate the L- and M-cones in various ratios. Results were obtained from color-normal subjects, dichromats, and an anomalous trichromat. RESULTS: Reliable signals were obtained from all subjects to both L- and M-cone-isolating modulations and to intermediate modulations. Signals from color-defective subjects were predominantly determined by the modulation seen by only one cone type, whereas signals from color-normal subjects were sensitive to both L- and M-cone modulations. For most color-normal subjects, the recorded signal was a linear function of the contrasts seen by the L- and M-cones. There was individual variability in how strongly each cone type contributed to the overall signal. CONCLUSIONS: It is straightforward to record signals to color modulations presented on a CRT by using the flicker photometric ERG. For most observers, signals from L- and M-cones combine linearly. The relative contribution of the two cone classes varies across observers, probably because of individual differences in the relative numbers of L- and M-cones.

Adult↗
PubMed2001

Intestinal permeability in newborns with necrotizing enterocolitis and controls: Does the sugar absorption test provide guidelines for the time to (re-)introduce enteral nutrition?

BACKGROUND: In necrotizing enterocolitis (NEC), (sub)mucosal edema, hemorrhage, ulceration, or necrosis will disturb intestinal integrity, as reflected by an increased intestinal permeability. Enteral substrate is therefore withheld for a variable period up to 3 weeks (in many clinics). The authors used the sugar absorption test to measure intestinal permeability changes in surgically treated necrotizing enterocolitis patients and surgical controls to evaluate the usefulness of this test in timing the (re-)introduction of enteral feeding in NEC patients as intestinal integrity recovers. METHODS: Changes in intestinal permeability to lactulose and rhamnose were evaluated prospectively in 13 children with NEC and 10 operated control patients. The patients were given 1 mL/kg body weight lactulose/rhamnose solution at different time intervals after admission. The lactulose to rhamnose (L/R) ratio was determined by gaschromatography in 4-hour urine samples. RESULTS: The L/R ratios in NEC patients were increased for prolonged periods of time with a tendency to decrease in the third week after the start of NEC. However, in some cases, the increased L/R ratios even exceeded the 3-week period of starvation. High peaks in the L/R ratio were seen in patients suffering from bowel perforation or sepsis. Compared with necrotizing enterocolitis patients, L/R ratios of control patients were increased only in the first days after surgery and normalized more rapidly. The results of the L/R tests in this study corroborated the clinical condition of the patients. CONCLUSIONS: The sugar absorption test shows an individual variability in the recovery of intestinal permeability in a group of seriously ill newborns with advanced stages of NEC. An individual approach in restarting enteral nutrition seems to be justified; however, the optimal time-point to restart enteral nutrition cannot be determined by the sugar absorption test alone. Combining parameters of intestinal integrity and function could enable a more accurate determination of this optimal timepoint. J Pediatr Surg 36:587-592.

Capillary Permeability↗
PubMed2004

In vivo biometry in the mouse eye with low coherence interferometry.

PURPOSE: A major drawback of the mouse model of myopia is that the ocular dimensions cannot be measured in vivo, and that histological techniques post-mortem suffer from limited resolution. We have tested the potential of a newly developed technique, optical low coherence interferometry (OLCI), adapted for short measurement distances by Meditec, Carl Zeiss, Jena, Germany (the "ACMaster"). Using this technique, ocular biometry was performed in mice with normal vision and after deprivation of form vision. METHODS: Axial eye length, corneal thickness and anterior chamber depth were measured in 23 mice, aged 25-53 days, and standard deviations from repeated measurements in the same eyes, as well as intra-individual and inter-individual variability were determined in different age groups. The data were compared to those from a preceding study in which biometrical data were obtained from frozen sections [Vision Res. 44 (2004) 1857]. Refractions were measured by automated infrared photorefraction. Mice had either normal visual exposure or were monocularly deprived of form vision for 14 days. RESULTS: Using OLCI, axial length could be determined with an average standard deviation of 8.0 +/- 2.9 microm, corneal thickness with 3.5 +/- 2.1 microm, and anterior chamber depth with 10.6 +/- 12.3 microm. Neither axial length, nor corneal thickness, nor anterior chamber depth were significantly different in left and right eyes of individual mice that had normal visual experience (mean absolute difference between axial lengths: 17 +/- 18 microm, between corneal thickness 5.1 +/- 4.8 microm, and between anterior chamber depths 16.7 +/- 14.8 microm). Compared to the variability that was previously found in frozen sections, the variability of axial length measurements with OLCI was 2.7 times less. After two weeks of form deprivation, OLCI revealed a significant axial elongation in the occluded eyes, compared to the contralateral fellow eyes (+38 +/- 36 microm or 1.16%, p = 0.045, n = 7, paired t-test). In this sample, no accompanying myopic shift was observed in the occluded eyes but this observation is not unexpected given the inherently variable responses of mouse eye growth to visual deprivation. CONCLUSION: OLCI had sufficient resolution in living mice to detect axial length changes in vivo that were equivalent to a dioptric change of 2 D. Using this technique, it was confirmed that mouse eyes respond to form deprivation by axial elongation, similar to the eyes of other animal models. The lack of a myopic shift in this sample, despite the axial elongation, demonstrates that biometric data are particularly important when the mouse eye is used as a model to study myopia.

Animals↗
PubMed2000

Cortisol secretion throughout the day, perceptions of the work environment, and negative affect.

The effects of explanatory variables derived from a work stress model (the effort-reward imbalance model) on salivary cortisol were assessed. A multilevel analysis was used to distinguish the effects of single occasion and multiple occasion measurements of work stress and effect on cortisol. The single (or cross-sectional) factors include Effort-Reward Imbalance (ERI), need for control, negative affect, and other enduring factors (type of occupation, gender, and smoking). The multiple occasion measurements include momentary negative mood, Momentary Demand-Satisfaction Ratio (MD-SR), sleep quality, work load (workday versus day off), at work (versus not being at the workplace), and lunch. The effect of time of day on cortisol was controlled for before the effects of these variables were determined. Momentary negative mood but not trait negative affect was positively associated with ambulatory measured cortisol. The variables from the work stress model--effort, reward, need for control, and the multiple occasion measurements of demand and satisfaction--did not affect cortisol. As could be expected, time of day had an effect on cortisol, but a hypothesised interaction with momentary negative mood was not found. Additionally, the results show that the time course of cortisol differs between individuals and that the effect of sleep quality on cortisol can vary from person to person. This points to the necessity of continued efforts to single out sources of individual variability. The finding that variables derived from the effort-reward imbalance model are not related with cortisol does not support the hypothesis that ERI leads to short-term changes in cortisol, indicating no relation with hypothalamic-pituitary-adrenal (HPA) axis activity. On the other hand, the present results invite further qualification of negative affect as a potential determinant of HPA activity, at least, as far as can be deduced from cortisol measurements.

Adult↗
PubMedDate not supplied

Risk factors for high diarrhoea frequency: a study in rural Zimbabwe.

Diarrhoea morbidity data were collected prospectively over 22 months from a cohort of young children living in a deprived community in rural Zimbabwe. Despite the general high prevalence of diarrhoeal disease, there was considerable individual variability in attack rates. Risk factors associated with high diarrhoea frequency were therefore sought by a questionnaire study on feeding, environmental, educational and socio-economic factors. This was supported by observation of living conditions, and water and sanitation facilities. Surprisingly, no association was found between diarrhoeal morbidity and any of these factors, suggesting that other factors such as individual hygiene behaviour or individual susceptibility to diarrhoea may play a role in determining the observed differences in diarrhoea rates in this community.

Diarrhea, Infantile↗
PubMed1998

One-year follow-up of quality of life in adults with untreated growth hormone deficiency.

OBJECTIVE: The aim of the study was to evaluate the impact on health-related quality of life (HRQoL) in untreated GHD patients using the disease-specific Assessment of Growth Hormone Deficiency in Adults (AGHDA) questionnaire. DESIGN AND PATIENTS: A cohort of 356 consecutive adult GHD patients, diagnosed after the age of 18 years, from the endocrinology units of 37 Spanish hospitals were included over a 6-month period in a longitudinal observational quality-of-life study. In addition, patients' HRQoL scores were compared to those obtained from a random sample of 963 subjects from the general population recruited by trained interviewers in a 6-month period and matched by age and sex to figures of the 1991 Spanish census. MEASUREMENTS: Patients were evaluated at baseline and after 12-months. Socio-demographic and health variables such as age, sex, level of education, income level, number of chronic diseases and self-reported health status were recorded at baseline and follow-up visits. Patients underwent physical and analytical examination and completed the AGHDA questionnaire. A survey including socio-demographic, self-reported health status and the AGHDA questionnaire was administered at the individuals' homes. RESULTS: Mean score for patients at baseline was 9.4 (CI = 8.4-10.4) and at 12 months 10 (CI = 8.8-11). HRQoL was worse in the case of older patients with a low level of education, lower income levels, reporting having an associated chronic disease and poor self-reported health status (P < 0.01). Untreated GHD patients maintain or slightly worsen their HRQoL after 12 months of follow-up, with high individual variability. Although AGHDA scores worsened during the observation period, differences were not statistically significant. AGHDA mean score in controls was 5.49 (CI = 5.27-5.71). Comparison of the mean AGHDA scores between patients and controls previously standardized by level of education and age were statistically different (P < 0.01), indicating that patients declared a worse HRQoL than the general population except for those aged 60-69 years. GHD patients presented a deterioration in HRQoL almost double that of the general population. CONCLUSIONS: These results permit comparison of patients' scores against reference scores with regard to the desirable effect of treatment. Future use of the AGHDA questionnaire in clinical trials should try to establish a relationship between biological and HRQoL changes.

Adolescent↗
PubMed1998

Reliability of the transient hyperemic response test in detecting changes in cerebral autoregulation induced by the graded variations in end-tidal carbon dioxide.

UNLABELLED: The transient hyperemic response (THR) in the middle cerebral artery (MCA) after the release of brief compression of the ipsilateral common carotid artery has been used to study cerebral autoregulation. We conducted the present study to evaluate the reliability of THR to detect changes in cerebral autoregulation induced by graded variations in PETCO2. Seven healthy adult volunteers were recruited. Fifteen THR tests were performed on every volunteer: three at baseline PETCO2, three each at PETCO2 of 7.5 mm Hg and 15 mm Hg above the baseline, and then three each at PETCO2 of 7.5 mm Hg and 15 mm Hg below the baseline. Transient hyperemic response ratio (THRR) and strength of autoregulation (SA) were calculated using established formulae. Both THRR and SA were highly sensitive (96%) in detecting the changes in cerebral autoregulation induced by graded changes in PETCO2. The within-individual variability of SA was significantly smaller than that of THRR at all levels of PETCO2. IMPLICATIONS: This study demonstrates the reliability of the THR test, when used for repetitive measurements, in detecting changes in cerebral autoregulation induced by graded changes in PETCO2. This test may provide a simple and noninvasive method of evaluating changes in cerebral autoregulation within an individual.

Adult↗
PubMed1990

[Dynamics of changes of anteroposterior jaw positions relative to the cranial base during the second trimester of normal intrauterine growth].

The aim of this investigation was to estimate dynamics of changes of maxillary (SNAns) and mandibular (SNMe) prognathism relative of the cranial base from 14th to 24th week of normal intrauterine growth. Investigation was performed on lateral cephalometric radiographs of 50 fetuses, both sexes, derived from artificial abortions in advanced uncomplicated pregnancies, due to social indication. Estimation of gestational ages was made according to contemporary ultrasonic standards of the normal fetal growth. The results obtained from this study showed that enlargement of the SNAns angle was relatively more rapid and regular (2.806 degrees +/- 0.483 degrees per week). The average change of this angle was from 61.047 degrees (in 14th week) to 89.107 degrees (in 24th week), with total change of 28.060 degrees during the period investigated. On the other hand, enlargement of the SNMe angle was, relatively, moderate an variably of 1.678 degrees +/- 0.597 degrees per week. Changes of this angle were ranged, in average from 46.295 degrees (in 14th week) to 63.074 degrees (in 24th week), with the total change of the 16.780 degrees during the same period. Rhythm of enlargement of SNAns angle was 76.222% more rapid than in SNMe angle (p less than 0.05). However, individual variability of SNMe angle enlargement was 23.602% higher compared with SNAns angle (p greater than 0.05). The author concluded that changes of anteroposterior position of the upper jaw relative to the cranial base ranged from marked retrognathism to mild prognathism. During the period investigated, changes of anteroposterior position of the lower jaw relative to the cranial base ranged from marked to moderate retrognathism.

Cephalometry↗
PubMed1997

Pharmacokinetic and pharmacodynamic interaction of single oral doses of valsartan and furosemide.

OBJECTIVE: Pharmacokinetic and pharmacodynamic interactions between single oral doses of valsartan (160 mg) and furosemide (40 mg) were investigated in an open, randomized, three-period crossover study in twelve healthy male subjects. METHODS: A washout period of one week was observed between treatments. Pharmacokinetic measurements included plasma concentrations of valsartan and furosemide, and urinary excretion of the latter. Plasma renin activity (PRA), plasma angiotensin II, blood pressure, heart rate, as well as urinary water and electrolyte excretion were determined as pharmacodynamic variables. Efficiency of furosemide for sodium and water excretion was calculated as the ratio of the measured pharmacodynamic effect and the urinary excretion of furosemide. RESULTS: Simultaneous administration of valsartan and furosemide did not modify the pharmacokinetics of valsartan. In contrast, Cmax, AUC, and urinary excretion of furosemide were significantly reduced following simultaneous treatment with valsartan. Inter- and intra-individual variability of the pharmacokinetic variables was high for both furosemide and valsartan. PRA and angiotensin II increased, and blood pressure decreased after all treatments. These effects were most pronounced after the combined treatment. The decrease in blood pressure was additive, at most, while the increase in PRA and angiotensin II appeared to exceed simple addition. No relevant effects on heart rate were observed. The diuretic effect of furosemide, as assessed by urinary water and electrolyte excretion, was unchanged after co-administration of valsartan, despite the lower bioavailability of furosemide after the combined treatment.

Administration, Oral↗
PubMed2000

The IgG subclass profile of anti-HBs response in vaccinated children and children seroconverted after natural infection.

The IgG subclass profiles of anti-HBs antibodies were investigated in 30 children who had recovered from acute hepatitis B and 40 children vaccinated against hepatitis B virus (HBV) with Engerix B. After natural seroconversion the mean geometric value of anti-HBs titres was ca 41-fold lower than at the peak of response in vaccinees, and specific antibodies were highly restricted to IgG1 subclass followed by IgG3 with only a minor contribution of IgG2 and IgG4. Conversely, in children immunized with recombinant HBsAg, IgG1 and IgG3 dominated after two doses of vaccine and 1 month after the third injection but the response was less selective and more variable. One year after vaccination IgG4 anti-HBs antibodies became the second dominating isotype. Significant statistical differences in the profiles of IgG anti-HBs were observed when the age and maturity of humoral response were considered. While children vaccinated below 5 years of age responded mainly with IgG1 and IgG3 subclasses, older children (> 5 years) showed a high individual variability in the specific profiles with a high contribution of IgG4. We concluded that vaccination at a younger age leads to the production of antibody subclasses which are more effective for virus neutralization.

Adolescent↗
PubMed1979

[Variations in blood pressure measurement during systematic screening tests and their effects on public health].

The variability of blood pressure measurements is studied, in a standardized screening, by comparing the measures obtained during a medical examen and those made by technicians under different circumstances. This variability is important. A systematic bias is due to the digit preference for the zero value by the doctors. Besides, strong subject/obser interaction accounts partly for higher values measured in the medical exam. The mean blood pressures and the prevalence of hypertension are increased under some circumstances close to those of everyday life and labile hypertension is very frequent. The individual variability of the measure and the prevalence of hypertension are reduced by a standardized technique when applied under favorable circumstances by technicians. The reproductibility of this measure is good but the simultaneous taking into account of two successive measures still reduces much this prevalence. In these conditions it is very difficult to estimate the prevalence of hypertension in the population: an example is given where this frequency varies in the proportion of 1 to 6 according to the measures considered. The implications of this variability on the screening of hypertension are discussed.

Adult↗
PubMed1987

Acute and chronic pain in hemophilia.

The present study compared acute vs. chronic pain in hemophiliac subjects who suffer both types of pain. Characteristics of the acute pain produced by a hemorrhage into a joint and the chronic arthritic pain that results from repeated bleeding episodes were assessed with the McGill Pain Questionnaire and a visual analogue pain intensity scale. The results showed a high degree of similarity in the sensory, affective and evaluative properties of the two types of pain. The main difference between the acute and chronic pains was one of overall intensity, with the acute pain generally being described as more intense. A comparison of the arthritic pain in hemophilia with the pain of other arthritic disorders revealed no major differences. Sources of inter-individual variability were also explored and the results showed that the pain scores in hemophiliac subjects were largely unrelated to demographic and pain history variables. However, significant differences were observed in the way French- and English-speaking subjects described and rated their pain. Irrespective of the origin of their pain, French-speaking subjects characteristically rated their pain as more intense and more affectively laden than the English group. These results demonstrate that ethnocultural factors associated with language affiliation may contribute to inter-individual variation in pain perception.

Acute Disease↗
PubMedDate not supplied

Neurobehavioral mechanisms of nicotine action: role in the initiation and maintenance of tobacco dependence.

Basic neuroscience research conducted over the last quarter century has provided us with much information concerning potential biobehavioral and neuromolecular mechanisms involved in the initiation and maintenance of tobacco dependence. Nicotinic-acetylcholinergic receptors (AChRs), in addition to having a primary locus on cholinergic neurons, appear to be also located on a variety of noncholinergic neurons (presynaptic and/or postsynaptic sites). Nicotine therefore appears to be able to affect a variety of neuronal pathways involved in behavioral reward and arousal processes, which appear paramount to tobacco dependence. Nicotine appears to have several unique properties at the cellular level that allow it to act both as an agonist and as a potential antagonist at select AChRs. Nicotine's ability to act as an agonist appears to be contingent on an action at nAChRs, which initially open a receptor-linked cation channel, eliciting the entrance of CA++ (or other cations) into the cell. Cation entrance into the cell, therefore, may be the cellular transducer of nicotine's behavioral and dependence-producing effects. Subsequent to this initial agonist effect, the nicotinic receptor is believed to undergo a refractory period, via a desensitization process, during which Ca++ is prevented from further entrance into the cell. It is this ability to induce receptor desensitization which seems central to nicotine's ability to act as an antagonist. The duration of nAChR desensitization may also be useful in explaining individual variability to nicotine's behavioral effects and may be related to the induction of acute and/or chronic tolerance in both animals and man. Nicotine-induced desensitization may also be important to relapse in the smoker if conditioned stimuli are able to provoke such mechanisms, which could lead to the need to smoke. Finally, a model is presented to account for individual smoking patterns and level of tobacco dependence which is partially based on the proposed cellular mechanisms of nicotine action and desensitization at the nAChR.

Animals↗
PubMed1992

Analysis of the clinical variables driving decision in an artificial neural network trained to identify the presence of myocardial infarction.

STUDY OBJECTIVE: To determine which clinical variables drive the output of an artificial neural network trained to identify the presence of myocardial infarction. DESIGN: Partial output analysis. SETTING: Tertiary university teaching center. PARTICIPANTS: Seven hundred six patients more than 18 years old presenting with anterior chest pain. MEASUREMENTS: Differential network output analysis. MAIN RESULTS: A methodology was developed as the first step in measuring the impact input clinical variables have on the output (diagnosis) of an artificial neural network trained to identify the presence of acute myocardial infarction. The methodology revealed that the network used the presence of ECG findings, as well as the presence of rales, syncope, jugular venous distension, response to trinitroglycerin, and nausea and vomiting, as major predictive sources. Although this first-step analysis studied individual variables, it must be stated that the network comes to clinical closure based on the settings of all variables in a pattern and that the impact of a single variable cannot be taken out of the context of a pattern. CONCLUSION: An artificial neural network trained to recognize the presence of myocardial infarction appears to place diagnostic importance on clinical variables that have not been shown previously to be highly predictive for infarction.

Adolescent↗
PubMed2004

The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients.

Cyclosporine and tacrolimus are immunosuppressive drugs largely used in renal transplantation. They are characterized by a wide inter-individual variability in their pharmacokinetics with a potential impact on their therapeutic efficacy or induced toxicity. CYP3A5 and P-glycoprotein appear as important determinants of the metabolism of these drugs. The objective of this study was to investigate the effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood concentrations in stable transplant patients. Stable renal transplant recipients receiving cyclosporine (n = 50) or tacrolimus (n = 50) were genotyped for CYP3A5*3 and *6, and MDR1 C1236T, G2677T/A and C3435T. Dose-adjusted trough blood levels (ng/ml per mg/kg body weight) as well as doses (mg/kg body weight) required to achieve target blood concentrations were compared among patients according to allelic status for CYP3A5 and MDR1. Dose-adjusted trough concentrations were three-fold and 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5*1/*3 patients for tacrolimus and cyclosporine, respectively. In the case of tacrolimus, the difference was even more striking when considering CYP3A5*1/*1 patients showing dose-adjusted trough concentrations 5.8-fold lower than CYP3A5*3/*3 patients. For both drugs, no association was found between trough blood concentrations or dose requirement and MDR1 genotype. Multiple regression analyses showed that CYP3A5*1/*3 polymorphism explained up to 45% of the variability in dose requirement in relation to tacrolimus use. Given the importance of rapidly achieving target blood concentrations after transplantation, further prospective studies should consider the immediate post-graft period and assess the influence of this specific polymorphism. Beside non-genetic factors (e.g. steroids dosing, drugs interactions), CYP3A5 pharmacogenetic testing performed just before transplantation could contribute to a better individualization of immunosuppressive therapy.

Cohort Studies↗