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PubMed2003

Pharmacokinetics of the combination tablet of buprenorphine and naloxone.

The sublingual combination tablet formulation of buprenorphine and naloxone at a fixed dose ratio of 4:1 has been shown to be as effective as the tablet formulation containing only buprenorphine in treating opiate addiction. The addition of naloxone does not affect the efficacy of buprenorphine for two reasons: (1) naloxone is poorly absorbed sublingually relative to buprenorphine and (2) the half-life for buprenorphine is much longer than for naloxone (32 vs. 1 h for naloxone). The sublingual absorption of buprenorphine is rapid and the peak plasma concentration occurs 1 h after dosing. The plasma levels for naloxone are much lower and decline much more rapidly than those for buprenorphine. Increasing dose results in increasing plasma levels of buprenorphine, although this increase is not directly dose-proportional. There is a large inter-subject variability in plasma buprenorphine levels. Due to the large individual variability in opiate dependence level and the large variability in the pharmacokinetics (PK) of buprenorphine, the effective dose or effective plasma concentration is also quite variable. Doses must be titrated to a clinically effective level for individual patients.

Administration, Sublingual↗
PubMed1997

Short-term reproducibility of pressure pain thresholds in masseter and temporalis muscles of symptom-free subjects.

Pressure pain thresholds (PPTs) of the bilateral masseter and temporalis muscles were assessed over a single day and in between 2 days with the aid of an electronic algometer in 11 males and 11 females. Using a mixed model approach, covariance results were controlled for confounding of gender, day, time of the day and the within-session replications of the measurements. For every jaw muscle, the first PPT measurement of a session was markedly higher than the last one of that same session. Except for the right temporalis muscles, no significant systematic PPT differences could be observed between male and female subjects. The differences between morning and afternoon sessions were not significant for any of the muscles tested. Although the PPTs measured on the 1st day were systematically lower than those on the 2nd day for the left masseter and temporalis muscles, no significant difference between the time of the day could be observed when the values of the different muscles were grouped within a subject. Analysis of variance showed that the variability induced by the day or the time of the day was similar to the variability of the measurement itself. The inter-individual variability of PPTs was 2.3 to 9 x higher than the variability observed between trials, sessions or days. The results indicate that the PPT measurement will not be systematically influenced by the time of registration (morning/afternoon) or inbetween consecutive days. In addition, the important inter-individual differences favor the use of longitudinal within-subject studies.

Adult↗
PubMed1992

Depression as a consequence of inadequate neurochemical adaptation in response to stressors.

Stressors induce behavioural disturbances and neurochemical changes in animals, some of which are reminiscent of the symptoms and presumed neurochemical concomitants of depression in humans. Just as in humans, where considerable inter-individual variability is evident in the symptom profile of depression, there is marked inter-individual and inter-strain variability in the behavioural effects of stressors in animals. It is proposed that stressors induce adaptive neurochemical changes, failure of which may engender behavioural disturbances. Variability in the symptoms of depression and in the efficacy of its pharmacological treatment may reflect the biochemical heterogeneity of the illness. Inter-individual differences in vulnerability to stressor-provoked neurochemical changes may contribute to the behavioural profiles observed.

Adjustment Disorders↗
PubMed1987

Variability in hand surface representations in areas 3b and 1 in adult owl and squirrel monkeys.

Detailed microelectrode maps of the hand representation were derived in cortical areas 3b and 1 from a series of normal adult owl and squirrel monkeys. While overlap relationships were maintained, and all maps were internally topographic, many map features varied significantly when examined in detail. Variable features of the hand representations among different monkeys included a) the overall shapes and sizes of hand surface representations; b) the actual and proportional areas of representations of different skin surfaces and the cortical magnifications of representations of specific skin surfaces, which commonly varied severalfold in area 3b and manyfold in area 1; c) the topographic relationships among skin surface representations, with skin surfaces that were represented adjacently in some monkeys represented in locations many hundreds of microns apart in others; d) the internal orderliness of representations; e) the completeness of representations of the dorsal hand surfaces; and f) the skin surfaces represented along the borders of the hand representation. Owl monkey maps were, in general, internally more strictly topographic than squirrel monkey maps. In both species, area 3b was more strictly topographic and less variable than was area 1. The degree of individual variability revealed in these experiments is difficult to reconcile with the hypothesis that details of cortical maps are ontogenetically specified during a period in early life. Instead, we propose that differences in the details of cortical map structure are the consequence of individual differences in lifelong use of the hands. This conclusion is consistent with earlier studies of the consequences of peripheral nerve transection and digital amputation, which revealed that cortical maps are dynamically maintained and are alterable as a function of use or nerve injury in these monkeys (Merzenich et al., '83a,b, '84a; Merzenich, '86; Jenkins et al., '84; Jenkins and Merzenich, '87).

Afferent Pathways↗
PubMed2005

Association of vasopressin 1a receptor levels with a regulatory microsatellite and behavior.

Vasopressin regulates complex behaviors such as anxiety, parenting, social engagement and attachment and aggression in a species-specific manner. The capacity of vasopressin to modulate these behaviors is thought to depend on the species-specific distribution patterns of vasopressin 1a receptors (V1aRs) in the brain. There is considerable individual variation in the pattern of V1aR binding in the brains of the prairie vole species, Microtus ochrogaster. We hypothesize that this individual variability in V1aR expression levels is associated with individual variation in a polymorphic microsatellite in the 5' regulatory region of the prairie vole v1ar gene. Additionally, we hypothesize that individual variation in V1aR expression contributes to individual variation in vasopressin-dependent behaviors. To test these hypotheses, we first screened 20 adult male prairie voles for behavioral variation using tests that measure anxiety-related and social behaviors. We then assessed the brains of those animals for V1aR variability with receptor autoradiography and used polymerase chain reaction to genotype the same animals for the length of their 5' microsatellite polymorphism in the v1ar gene. In this report, we describe the results of this discovery-based experimental approach to identify potential gene, brain and behavior interrelationships. The analysis reveals that V1aR levels, in some but not all brain regions, are associated with microsatellite length and that V1aR levels in those and other brain regions correlate with anxiety-related and social behaviors. These results generate novel hypotheses regarding neural control of anxiety-related and social behaviors and yield insight into potential mechanisms by which non-coding gene polymorphisms may influence behavioral traits.

Animals↗
PubMed2025

Pre-clinical safety and efficacy of human induced pluripotent stem cell-derived products for autologous cell therapy in Parkinson's disease.

Human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic cells (mDACs) represent a promising source for autologous cell therapy in Parkinson's disease (PD), but standardized regulatory criteria are essential for clinical translation. In this pre-clinical study, we generated multiple clinical-grade hiPSC lines from freshly biopsied fibroblasts of four sporadic PD patients using episomal reprogramming and differentiated them into mDACs using a refined 21-day protocol. Rigorous evaluations included whole-genome/exome sequencing, RNA sequencing, and in vivo studies, including a 39-week Good Laboratory Practice-compliant mouse safety study. While mDACs from all lines met safety criteria, mDACs from one patient failed to improve rodent behavioral outcomes, underscoring inter-individual variability. Importantly, in vitro assessments did not reliably predict in vivo efficacy, identifying dopaminergic fiber density as a key efficacy criterion. These findings support comprehensive quality control guidelines for autologous cell therapy and pave the way for a clinical trial with eight sporadic PD patients, scheduled to commence in 2025.

Humans↗
PubMed1997

Discontinuous distribution of senile plaques within striate cortex hypercolumns in Alzheimer's disease.

Tangential sections of the primary visual (striate) cerebral cortex from five patients with histopathologically verified Alzheimer's disease were used to study the laminar and tangential disposition of senile plaques. These lesions were visualized with thioflavin S or the modified Bielschowsky method, and classified into four different, purely morphological types: "classical", (predominantly) "neuritic", (primarily amyloid) "core" and "diffuse", which were charted and analyzed using computer-assisted three- and two-dimensional reconstruction and mapping methods. These analyses reveal a tendency for a selective laminar disposition of the lesions (preferentially in layers II/III and V) which is generally consistent with previous reports performed at lower resolution, yet the specific pattern is highly variable among patients, and among plaque subtypes within individual patients. In addition, we observed a clustering of senile plaques in the tangential domain (i.e. parallel to the pial surface) in layers II/III, that suggests a selective involvement of iterated circuits within the "units", "modules", or "hypercolumns" that some believe compose this region of the cortex. These findings also imply an intriguing relative sparing of immediately adjacent components of the modular circuitry of the cerebral cortex, in the same cytoarchitectonic layers. Taken together, these findings indicate that: (1) senile plaques may arise in functionally and anatomically distinct subsets of iterated neuronal circuits that cannot be reduced to schemes based on traditional cytoarchitectonic layers; and (2) that individual variability in the patterns of striate cortex involvement and clinical manifestations must be taken into consideration when addressing the specific mechanisms underlying visual dysfunction in Alzheimer's disease.

Alzheimer Disease↗
PubMed2003

Predicting length of stay on an acute care medical psychiatric inpatient service.

The goal of this study was to identify variables associated with length of stay (LOS) and to incorporate into the authors' routine preadmission assessment the measurement of these variables. A retrospective study of 80 discharged patients explored the association of 25 variables reflecting a mixture of patient/demographic variables, illness variables, and treatment variables with LOS. Multivariate analysis revealed that 10 variables independently accounted for 62% of the variance in LOS. The information used was obtained primarily in the preadmission screening. The predictive power of the variables shrank in the prospective study. However, fewer individual variables were significantly associated with LOS; the summed score of the variables predicted 17% of the LOS variance. Results indicated that factors important for estimating LOS are available at the time of admission, and these variables can be systematically assessed and incorporated into clinical decision making.

Acute Disease↗
PubMed2001

Modified fetal biophysical profile in the assessment of perinatal outcome.

The aim of the study is the evaluation of variables of the biophysical profile in the assessment of perinatal outcome. The prospective study included 87 pregnant women with singleton pregnancy in the 28th to 42nd week of gestation with clinically and ultrasonically verified fetal growth retardation, where the fetal biophysical profile was assessed antenatally. Through the factor analysis of biophysical profile variables we obtained values indicating the contribution of individual variables to the predictability of perinatal outcome. 70% of the patients were examined in 15 minutes according to the principles of modified biophysical profile. The most sensitive variable of the biophysical profile in the prediction of perinatal outcome was the amniotic fluid volume, followed by fetal breathing movements, non-stress test and fetal movements, while the lowest prediction value was assigned to the fetal tone. The modified biophysical profiles need to be perfected on a larger number of pregnant women, which would advance the predictability of this method in detection of hypoxically endangered fetuses.

Female↗
PubMed1994

Relative bioavailability of salbutamol to the lung following inhalation using metered dose inhalation methods and spacer devices.

BACKGROUND: Inhalation aids do not require coordination between actuation of a metered dose inhaler (MDI) with inspiration and reduce oropharyngeal impaction. The delivery of salbutamol to the lung and systemic availability following inhalation with three commonly used spacers and an open mouth technique have been evaluated using a simple noninvasive technique based on urinary excretion 30 minutes and 24 hours after the dose. METHODS: Ten healthy subjects inhaled, on randomised study days, 4 x 100 micrograms from a Ventolin MDI and, subsequently, with the aid of a Volumatic, Bricanyl Spacer, and Nebuhaler spacer device. In addition, an open mouth inhaler technique was evaluated. Urine samples were collected 0-30 minutes and 0.5-24 hours after inhalation. From these samples the relative bioavailability to the lung (urinary salbutamol excretion 30 minutes after dosing) and the systemic bioavailability of the dose (24 hour urinary excretion of salbutamol and its metabolite) for each inhalation method was obtained. RESULTS: The mean (SD) urinary excretion of salbutamol 30 minutes after inhalation using the MDI alone and with the Volumatic, Bricanyl Spacer, Nebuhaler, and open mouth technique was 2.83 (0.78)%, 3.37 (0.69)%, 4.09 (0.91)%, 4.34 (1.60)%, and 3.49 (0.98)%, respectively, expressed as a percentage of the nominal dose. The nebuhaler and Bricanyl Spacer spacer devices were found to increase the relative bioavailability of salbutamol to the lung compared with the MDI alone. Compared with the MDI the inhalation aid increases were much greater than the intra-individual variability of the urinary excretion method. In 11 individuals who each repeated the same inhalation procedure on four separate occasions, the mean (SD) coefficient of variation was 8.24 (2.36)%. The mean (SD) 24 hour urinary excretion of salbutamol and its metabolites was 26.6 (6.79), 27.0 (7.95), and 55.6 (9.74)% of the salbutamol dose for the Volumatic, Nebuhaler, and MDI, respectively. Similar values following the open mouth method and Bricanyl Spacer were 48.9 (10.97)% and 43.8 (11.57)%. These values, representing the systemic availability of the inhaled dose, were lower when inhaling with the aid of the Volumatic and Nebuhaler than inhalation from the MDI alone. CONCLUSIONS: Spacer devices improve pulmonary bioavailability of salbutamol and reduce the systemically available dose.

Administration, Inhalation↗
PubMed2005

Analysis of factors that influence rates of carbon monoxide uptake, distribution, and washout from blood and extravascular tissues using a multicompartment model.

To better understand factors that influence carbon monoxide (CO) washout rates, we utilized a multicompartment mathematical model to predict rates of CO uptake, distribution in vascular and extravascular (muscle vs. other soft tissue) compartments, and washout over a range of exposure and washout conditions with varied subject-specific parameters. We fitted this model to experimental data from 15 human subjects, for whom subject-specific parameters were known, multiple washout carboxyhemoglobin (COHb) levels were available, and CO exposure conditions were identical, to investigate the contributions of exposure conditions and individual variability to CO washout from blood. We found that CO washout from venous blood was biphasic and that postexposure times at which COHb samples were obtained significantly influenced the calculated CO half times (P < 0.0001). The first, more rapid, phase of CO washout from the blood reflected the loss of CO to the expired air and to a slow uptake by the muscle compartment, whereas the second, slower washout phase was attributable to CO flow from the muscle compartment back to the blood and removal from blood via the expired air. When the model was used to predict the effects of varying exposure conditions for these subjects, the CO exposure duration, concentration, peak COHb levels, and subject-specific parameters each influenced washout half times. Blood volume divided by ventilation correlated better with half-time predictions than did cardiac output, muscle mass, or ventilation, but it explained only approximately 50% of half-time variability. Thus exposure conditions, COHb sampling times, and individual parameters should be considered when estimating CO washout rates for poisoning victims.

Carbon Monoxide↗
PubMed1998

Is post-dialysis urea rebound significant with long slow hemodialysis?

BACKGROUND: According to previous studies, postdialysis urea rebound (PDUR) is achieved within 30-90 min, leading to an overestimation of Kt/V of between 15 and 40% in 3- to 5-hour dialysis. The purpose of the study was to assess the impact of PDUR on the urea reduction ratio (URR), Kt/V and normal protein catabolic rate (nPCR) with long 8-hour slow hemodialysis. METHODS: This study was performed in 18 patients (13 males/5 females), 62.5 +/- 11.7 years of age, hemodialyzed for 3-265 months. Initial nephropathies were: 3 diabetes; 2 polycystic kidney disease; 3 interstitial nephritis; 2 nephrosclerosis; 3 chronic glomerulonephritis, and 5 undetermined. Residual renal function was negligible. The dialysis sessions were performed using 1- to 1.8-m2 cellulosic dialyzers during 8 h, 3 times a week. Blood flow was 220 ml/min, dialysate flow 500 ml/min, acetate or bicarbonate buffer was used. Serial measurements of the urea concentration were obtained before dialysis, immediately after dialysis (low flow at t = 0), and at 5, 10, 20, 30, 40, 60, 90 and 120 min, and before the next session. The low-flow method was used to evaluate the access recirculation, second-generation Daugirdas formulas for Kt/V, and Watson formulas for total body water volume estimation. The difference between the expected urea generation (UG) and urea measured after dialysis (global PDUR) defines net PDUR (n-PDUR). RESULTS: The n-PDUR usually became stable after 58 +/- 25 (30-90) min. Its mean value was 17 +/- 10% of the 30-second low-flow postdialysis urea (3.9 +/- 2 mmol/l). This small postdialysis urea value and the importance of UG in comparison with shorter dialysis justify the use of n-PDUR. Ignoring n-PDUR would lead to a significant 4% overestimation (p < 0.001) of the URR (79 +/- 7 vs. 76 +/- 8%), 12% of Kt/V (1.9 +/- 0.4 to 1.7 +/- 0.38) and 4% of the nPCR (1.1 +/- 0.3 to 1.05 +/- 0.3). n-PDUR correlated negatively with postdialysis urea (r = 0.45 p = 0.05), positively with URR (r = 0.31 p = 0.01) and Kt/V (r = 0.3 p = 0.03) but not with K, and negatively with the urea distribution volume (r = 0.33 p = 0.05). Mean total recirculation, ultrafiltration rate, predialysis urea levels and urea clearance did not correlate with n-PDUR. CONCLUSION: We found a significant PDUR in long-slow hemodialysis after a mean of 1 h after dialysis. This PDUR has a less important impact upon dialysis delivery estimation than short 3- to 5-hour hemodialysis, especially for the lower Kt/V or URR ranges. This is explained by the low-flux, high-efficiency, and long-term dialysis. Its inter-individual variability incites us to calculate PDUR on an individual basis.

Aged↗
PubMed1995

Stool composition in factitial diarrhea: a 6-year experience with stool analysis.

OBJECTIVE: To evaluate the utility of stool water analysis in the management of patients with chronic diarrhea. DESIGN: Retrospective analysis of 6 years of experience. SETTING: A specialized laboratory in a major referral center. PATIENTS: 325 patients with diarrhea who were referred for stool chemistry analysis. Fecal analysis was requested by many internists and gastroenterologists. Patient records were reviewed to establish the final and most likely cause of diarrhea. RESULTS: One third of patients provided samples that were inappropriate for analysis, but data from 202 persons were available. The usefulness of the general separation of cases of chronic diarrhea into those in which patients had predominantly osmotic pathophysiologies and those in which patients had predominantly secretory pathophysiologies was confirmed, but overlap and intra-individual variability limited the usefulness of this approach in individual patients. Thirty-five patients (17%) had a diagnosis of factitial diarrhea (30 because of laxative use and 5 because of fluid added to stools). CONCLUSIONS: Among selected subpopulations, the chemical analysis of fresh stools has a role in the evaluation of obscure examples of chronic diarrhea. It is especially useful in identifying factitial diarrhea.

Adolescent↗
PubMed2001

[Pharmacology of mycophenolate mofetil: recent data and clinical consequences].

New insights have been recently obtained about pharmacokinetic and pharmacodynamic characteristics of mycophénolate mofetil (MMF). One of the already described MPA metabolite, the acylglucuronide of MPA may be both active and responsible for some side-effects. Glucuronidation is mediated by at least two uridine diphosphate glucuronosyltransferase (UGT) forms, namely UGT1A8 and UGT1A10 whose variability could explain the inter- and intra-individual variability of MMF metabolism. MPA pharmacokinetic data in dialyzed patients or in patients with chronic renal failure are now available. After renal transplantation, MPA levels vary between immediate post-transplant period, at three months and at two years. The target enzyme is inosine monophosphate dehydrogenase (IMPDH). The genes of the two IMPDH isoforms have been cloned. The bicyclic ring system of MPA packs underneath the hypoxanthine ring of IMPDH, thereby trapping this covalent intermediate of the enzymatic reaction. After renal transplantation, a randomized trial has shown that clinical efficacy is correlated with MPA AUC but side effects are correlated with MMF dosage. When associated with cyclosporine, there is a significant decrease of MPA level. Better knowledge of MMF metabolism, of variability factors and target levels to reach in clinical practice should allow a better use of MMF.

Animals↗
PubMed2004

Multivariate approach to evaluating the fatty acid composition of seed oil in a doubled haploid population of winter oilseed rape (Brassica napus L.).

The fatty acid composition of oil of the zero erucic acid commercial Brassica napus L. is typical for this species. It is rich in oleic acid and contains moderate levels of linoleic and linolenic acid. For human nutrition, it is advantageous primarily to obtain the highest possible content of oleic acid and to maintain the 2:1 ratio of linoleic to linolenic acid, while preserving the average total content of saturated acids. Uni- and multivariate analyses of variance were used for evaluation of doubled haploid lines of winter oilseed rape in respect of five fatty acids: palmitic (C16:0), stearic (C18:0) oleic (C18:1), linoleic (C18:2) and linolenic (C18:3). Some proposals of studying doubled haploid (DH) lines with the use of canonical transformation were also given. In MANOVA, the five original variables (individual fatty acids) were replaced by three 'new' variables (combinations of these acids) and used to evaluate DH lines with respect to the requirements concerning the nutritional role of fatty acids. The first variable was the total content of the saturated acids (C16:0 + C18:0), the second (unchanging) was the content of the monounsaturated acid C18:1, and the third was the difference between polyunsaturated acids, i.e. between linoleic acid, and the doubled content of linolenic acid (C18:2 - 2 x C18:3).

Brassica napus↗
PubMed1991

Sleep and epileptic activity.

Thirteen patients suffering from severe partial epilepsy and potential candidates for surgical treatment were investigated with stereotactically implanted intracerebral electrodes during nocturnal physiological sleep. The recorded electrocerebral activity was automatically analyzed to gain information on interictal epileptic events during wakefulness and the phases of sleep. The interictal epileptic activity shows: (1) great variability in the different subjects, and intra-individually, variability according to the explored cerebral regions; (2) is not influenced by the location of the recorded epileptic events; and (3) is affected by the local level of epileptogenicity. The latter was determined by the assessment of the capacity to give origin to ictal discharges and the disappearance of seizures following surgical removal. The interictal rate of spiking from the most epileptogenic cerebral zone is characterized by a relative stability during the night and by a relatively high degree during REM sleep.

Adolescent↗
PubMed1984

Methods for comparing groups of growth curves when patterns of observation times vary among subjects.

A variety of statistical techniques is available if growth is to be compared for two groups followed up over a certain period. In practice straightforward application of such techniques may be hampered if patterns of observation times vary among subjects. Different approaches to deal with such variation are illustrated by analysing data from infants (0-18 months) living in Lesotho, Southern Africa. Data comprises 236 individual series of multiple measurements on five anthropometric variables. Individual patterns of observation times differ because of variation in a) age at entry, b) length of follow-up, and c) observation intervals (nominally 4 weeks). First an ad hoc approach is followed by taking a few summary measures for each individual series, e.g. 'growth velocity'. By contrast two other approaches hinge on preliminary data transformation required to make standard techniques applicable. The pros and cons of the different approaches are discussed.

Anthropometry↗
PubMedDate not supplied

Coat color genetics of Peromyscus: IV. Variable white, a new dominant mutation in the deer mouse.

The variable white mutation arose spontaneously in 1983 within a laboratory stock of wild-type deer mice (Peromyscus maniculatus). The original mutant animal was born to a wild-type pair that had previously produced several entirely wild-type litters. Other variable white animals were bred from the initial individual. Variable white deer mice exhibit extensive areas of white on the head, sides, and tail. Usually a portion of pigmented pelage occurs dorsally and on the shoulders, but the extent of white varies from nearly all white to patches of white on the muzzle, tip of tail, and sides. The pattern is irregular, but not entirely asymmetrical. Eyes are pigmented, but histologically reveal a decrease in thickness and pigmentation of the choroid layer. Many variable white animals do not respond to auditory stimuli, an effect that is particularly evident in animals in which the head is entirely white. Ataxic behavior is also prevalent. Pigment distribution, together with auditory and retinal deficiencies, suggests a neural crest cell migration defect. Breeding data are consistent with an autosomal semidominant, lethal mode of inheritance. The trait differs from two somewhat similar variants in Peromyscus: from dominant spot (S) in extent and pattern of pigmentation and from whiteside (ws), an autosomal recessive trait, in the mode of inheritance and viability. Evidence for possible homology with the Va (varitint-waddler) locus in house mouse (Mus) is presented. The symbol Vw is tentatively assigned for the variable white locus in Peromyscus.

Animals↗