Observations In Healthy Subjects Research Articles

Cortical Activation in Mental Rotation and the Role of the Corpus Callosum: Observations in Healthy Subjects and Split-Brain Patients

The mental rotation (MR) is an abstract mental operation thanks to which a person imagines rotating an object or a body part to place it in an other position. The ability to perform MR was belived to belong to the right hemisphere for objects, and to the left for one’s ownbody images. Mental rotation is considered to be basic for imitation with the anatomical perspective, which in turn is needed for social interactions and learning. Altered imitative performances have been reported in patients with resections or microstructure alterations of the corpus callosum (CC). These patients also display a reduced MR ability compared to control subjects, as shown in a recent behavioral study. The difference was statistically significant, leading us to hypothesize a role of the CC to integrate the two hemispheres’ asymmetric functions. The present study was designed to detect, by means of a functional MRI, the cortical activation evoked during an MR task in healthy control subjects and callosotomized patients. The results suggest that performing MR requires activation of opercular cortex and inferior parietal lobule in either hemispheres, and likely the integrity of the CC, thus confirming that the main brain commissure is involved in cognitive functions.

Pharmacokinetics and Pharmacodynamics of Ionis-FXIRx, an Antisense Inhibitor of Factor XI, in Patients with End-Stage Renal Disease on Hemodialysis

BACKGROUNDPatients with end-stage renal disease (ESRD) on hemodialysis are at high risk of both thrombotic and bleeding events. Experimental and clinical data indicate that reducing factor XI (FXI), a key component of the intrinsic pathway, prevents thrombosis without causing bleeding. FXI activity can be lowered with IONIS-FXIRx, a 2nd generation antisense oligonucleotide that specifically reduces human FXI mRNA expression in the liver. This study sought to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-FXIRx in participants with ESRD. METHODSIn this Phase 2 multicenter study, we enrolled a total of 49 ESRD patients: (A) 6 participants receiving chronic in-center hemodialysis (HD) to receive an open-label single-dose of 300 mg IONIS-FXIRx either 5 minutes before or 10 minutes after HD and assessed the effects of HD on peak (Cmax) and the extent of exposure (AUC0-24hr) parameters of IONIS-FXIRx and (B) another 43 participants in a double-blind design to one of two multiple-dose regimens (200 mg or 300 mg) IONIS-FXIRx or placebo for 12 weeks with 12 weeks of additional follow up. In the double-blind portion, IONIS-FXIRx was administered subcutaneously ~10 minutes after HD. For PK, plasma trough concentration and apparent elimination half-life (t1/2λz) were evaluated. The PD parameters including FXI activity and antigen, aPTT, prothrombin time (PT), and INR were evaluated in the per-protocol population (N= 34) that was defined as all participants who received the complete protocol-specified administration of IONIS-FXIRx or placebo through week 8 and who did not have any major protocol violations. The rate and frequency of clotting on the HD filters and circuit were qualitatively measured with a clotting scale as an exploratory PD analysis. RESULTSThe PK cohort included 6 males (5 white) with a mean age of 61 years. The plasma PK profile of IONIS-FXIRx was not significantly altered whether injected before or after HD. After multiple dosing, plasma Cmax values were dose-dependent and similar between Day 1 (first dose) and Day 78 (last dose), suggesting no accumulation of IONIS-FXIRx in ESRD participants after 12-weeks of dosing. After treatment cessation, IONIS-FXIRx had an apparent elimination half-life of approximately 2 weeks. In the double-blind portion of the study, 22 (51.2%) of the participants were male, 24 (55.8%) were white and the mean age was 59 years. Attenuation of FXI activity was associated with a reduction in the incidence of severe clotting events on both the air filter and dialyzer (Table). The reduction in severe clotting events was observed when FXI activity was < 0.4 U/mL. Consistent with prior observations in healthy subjects, IONIS-FXIRx prolonged aPTT in a time and dose-dependent manner with maximum mean percent changes from baseline of 53.3% (p < 0.05) for the 200 mg dose group and 75.6% (p < 0.05) for the 300 mg dose group at Week 14, but had no effect on PT. Treatment emergent adverse events (TEAEs) were mostly mild; participants reporting serious TEAEs were 1 (16.7%) for the PK cohort, 4 (30.8%) for placebo and 3 (20.0%) each for the 200 mg and 300 mg IONIS-FXIRx dose groups. There were no drug-related SAEs and no drug-related major or clinically-relevant non-major bleeding events. Minor bleeds were primarily observed in the 300 mg multiple-dose group at AV fistula/graft sites but did not correlate with reduction of FXI activity. No clinically significant reductions in platelet counts were reported during the study. CONCLUSIONSThis study demonstrated that (i) HD had no effect on IONIS-FXIRx PK, (ii) IONIS-FXIRx was well tolerated and produced sustained, and dose-dependent reductions in FXI antigen and activity, and (iii) IONIS-FXIRx reduced severe dialysis circuit clotting events beyond standard heparin use. Collectively, these data support further evaluation of IONIS-FXIRx as a potentially safe, effective antithrombotic therapy in ESRD patients on HD. [Display omitted] DisclosuresBethune:Ionis Pharmaceuticals: Employment. Walsh:Population Health Research Institute: Employment; Ionis Pharmaceuticals: Consultancy. Jung:Ionis Pharmaceuticals: Employment. Yu:Ionis Pharmaceuticals: Employment. Geary:Ionis Pharmaceuticals: Employment. Bhanot:Ionis Pharmaceuticals: Employment.

Spatiotemporal Dynamics of Single and Paired Pulse TMS-EEG Responses

For physiological brain function a particular balance between excitation and inhibition is essential. Paired pulse transcranial magnetic stimulation (TMS) can estimate cortical excitability and the relative contribution of inhibitory and excitatory networks. Combining TMS with electroencephalography (EEG) enables additional assessment of the spatiotemporal dynamics of neuronal responses in the stimulated brain. This study aims to evaluate the spatiotemporal dynamics and stability of single and paired pulse TMS-EEG responses, and assess long intracortical inhibition (LICI) at the cortical level. Twenty-five healthy subjects were studied twice, approximately one week apart. Manual coil positioning was applied in sixteen subjects and robot-guided positioning in nine. Both motor cortices were stimulated with 50 single pulses and 50 paired pulses at each of the five interstimulus intervals (ISIs): 100, 150, 200, 250 and 300 ms. To assess stability and LICI, the intraclass correlation coefficient and cluster-based permutation analysis were used. We found great resemblance in the topographical distribution of the characteristic TMS-EEG components for single and paired pulse TMS. Stimulation of the dominant and non-dominant hemisphere resulted in a mirrored spatiotemporal dynamics. No significant effect on the TMS-EEG responses was found for either stimulated hemisphere, time or coil positioning method, indicating the stability of both single and paired pulse TMS-EEG responses. For all ISIs, LICI was characterized by significant suppression of the late N100 and P180 components in the central areas, without affecting the early P30, N45 and P60 components. These observations in healthy subjects can serve as reference values for future neuropsychiatric and pharmacological studies.

Muscle Strength, But Not Muscle Oxidative Capacity, Varies Between the Morning and the Afternoon in Patients with Multiple Sclerosis: A Pilot Study.

Despite frequent muscle strength or muscle oxidative capacity (based on exercise-onset oxygen uptake [VO2] kinetics) assessments in patients with multiple sclerosis, the impact of time of day on these parameters is often not taken into account. Based on observations in healthy subjects, it remains to be studied whether muscle strength, and/or exercise-onset VO2 kinetics, varies between the morning and the afternoon in patients with multiple sclerosis. In this prospective observational pilot study, walking capacity, exercise-onset VO2 kinetics, isometric knee extension/flexion strength (dynamometry), and self-reported fatigue were measured in 11 patients with multiple sclerosis (age, 51.8 ± 9.3 yrs; body mass index, 24.7 ± 5.1 kg/m; Expanded Disability Status Scale, 3.5 ± 1.4; 3 men) in the morning and 5 hrs later (afternoon). In the afternoon, self-reported fatigue (1.9 ± 0.9 cm) and muscle strength (knee extension peak torque at 45 degrees, 84 ± 26 Nm) were significantly different (P < 0.05), than in the morning (self-reported fatigue, 1.2 ± 0.9 cm; knee extension peak torque at 45 degrees, 93 ± 32 Nm), but walking capacity and exercise-onset VO2 kinetics were similar at these two time points (P > 0.05). Consistent with observations in healthy subjects, muscle strength varies between the morning and the afternoon in patients with multiple sclerosis, under the conditions of the present study. These findings suggest that muscle strength assessments should be conducted at similar or nearly similar times of the day to minimize diurnal variation in these measures and hence insure correct interpretation.

Quantification and variability in colonic volume with anovel magnetic resonance imaging method.

Segmental distribution of colorectal volume is relevant in a number of diseases, but clinical and experimental use demands robust reliability and validity. Using a novel semi-automatic magnetic resonance imaging-based technique, the aims of this study were to describe: (i) inter-individual and intra-individual variability of segmental colorectal volumes between two observations in healthy subjects and (ii) the change in segmental colorectal volume distribution before and after defecation. The inter-individual and intra-individual variability of four colorectal volumes (cecum/ascending colon, transverse, descending, and rectosigmoid colon) between two observations (separated by 52±10) days was assessed in 25 healthy males and the effect of defecation on segmental colorectal volumes was studied in another seven healthy males. No significant differences between the two observations were detected for any segments (All p>0.05). Inter-individual variability varied across segments from low correlation in cecum/ascending colon (intra-class correlation coefficient [ICC]=0.44) to moderate correlation in the descending colon (ICC=0.61) and high correlation in the transverse (ICC=0.78), rectosigmoid (ICC=0.82), and total volume (ICC=0.85). Overall intra-individual variability was low (coefficient of variance=9%). After defecation the volume of the rectosigmoid decreased by 44% (p=0.003). The change in rectosigmoid volume was associated with the true fecal volume (p=0.02). Imaging of segmental colorectal volume, morphology, and fecal accumulation is advantageous to conventional methods in its low variability, high spatial resolution, and its absence of contrast-enhancing agents and irradiation. Hence, the method is suitable for future clinical and interventional studies and for characterization of defecation physiology.

An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects

Background and ObjectiveChronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug–drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir—a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)—and cyclosporine or tacrolimus in healthy subjects.MethodsHealthy fasted subjects (aged 18–49 years; body mass index 18–32 kg/m2) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4–11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8–19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC–MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC–MS/MS methods.ResultsDaclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration–time curve of daclatasvir but did not affect its maximum observed concentration.ConclusionOn the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.

Touching and feeling: differences in pleasant touch processing between glabrous and hairy skin in humans

Previous functional magnetic resonance imaging studies in two rare patients, together with microneurography and psychophysical observations in healthy subjects, have demonstrated a system of mechanosensitive C-fiber tactile (CT) afferents sensitive to slowly moving stimuli. They project to the posterior insular cortex and signal pleasant aspects of touch. Importantly, CTs have not been found in the glabrous skin of the hand, yet it is commonly observed that glabrous skin touch is also perceived as pleasant. Here we asked if the brain processing of pleasant touch differs between hairy and glabrous skin by stroking the forearm and glabrous skin of the hand during positron emission tomography. The data showed that, when contrasting slow brush stroking on the forearm with slow brush stroking on the palm, there were significant activations of the posterior insular cortex and mid-anterior orbitofrontal cortex. The opposite contrast showed a significant activation of the somatosensory cortices. Although concurrent psychophysical ratings showed no differences in intensity or pleasantness ratings, a subsequent touch questionnaire in which subjects used a newly developed 'touch perception task' showed significant difference for the two body sites. Emotional descriptors received higher ratings on the forearm and sensory descriptors were rated more highly on the palm. The present findings are consistent with the hypothesis that pleasant touch from hairy skin, mediated by CT afferents, is processed in the limbic-related cortex and represents an innate non-learned process. In contrast, pleasant touch from glabrous skin, mediated by A-beta afferents, is processed in the somatosensory cortex and represents an analytical process dependent on previous tactile experiences.

Dose Titration Regimen Attenuates Bradyarrhythymic Events with BAF312 during Treatment Initiation (P01.131)

Objective: To report effects of BAF312 dose titration on cardiac conduction during treatment initiation in a phase II double-blind, randomised, placebo-controlled study in patients with multiple sclerosis (RRMS). Background A previous study in healthy volunteers indicated that dose titration during treatment initiation can reduce the bradyarrhythymic events typically seen with sphingosine-1-phosphate receptor modulators. 1 Design/Methods: Patients were randomised to two sequential cohorts: Cohort 1 (n=188), once-daily BAF312 0.5mg, 2mg, 10mg, or placebo for 6mos; Cohort 2 (n=109), 0.25mg, 1.25mg or placebo for 3mos. Dose titration was not used in Cohort 1. Patients completing the core study were eligible to participate in an extension study. Following a protocol amendment, all patients in Cohort 2 and the extension study had an initial 10 day dose titration during which, enhanced cardiac monitoring was implemented. Results: Cohort 1: on Day 1, a dose-dependent reduction in mean heart rate was observed and five transient symptomatic 2 nd degree atrioventricular blocks (AVBs) were reported (five patients: three receiving 2mg, two receiving 10mg); two patients received medication for the events, all events resolved within 24 hours. Thirteen asymptomatic events of 2 nd degree AVBs were observed in twelve patients (0.5mg – 2; 2mg – 4; 10mg – 4; placebo – 2 patients, respectively) on 24-hour ambulatory ECGs during the first week of treatment. Cohort 2 and extension: the reduction in mean heart rate was less pronounced with the dose titration regimen. No symptomatic 2 nd degree AVBs were observed. Two patients on placebo and one patient on 2mg experienced asymptomatic 2 nd degree AVBs; all events occurred during the sleeping hours. No episodes of syncope, Mobitz Type II or third degree heart block occurred during the study. Conclusions: In patients with RRMS, a dose-titration regimen with BAF312 attenuates bradyarrhthymic events during treatment initiation, confirming previous observations in healthy subjects. 1 References 1 Legangneux et al. AAN 2011. Supported by: Novartis-sponsored. Disclosure: Dr. DiMarco has received personal compensation for activities with Sanofi, Astellas, Novartis, Medtronic, St. Jude, Tau Therapeutics, Sequel, and Biotronik as a consultant.Dr. DiMarco has received personal compensation in an editorial capacity for Elsevier.Dr. DiMarco has received research support from Boston Scientific. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Jordaan has received personal compensation for activities with Novartis. Dr. Mendzelevski has received personal compensation for activities with Novartis, Teva, Galderma, Astex Pharmaceuticals, MediWould, Mersana Therapeutics, Nabriva Therapeutics, and Xention. Dr. Goncalves has received personal compensation for activities with Novartis as an employee. Dr. Zhang-Auberson has received personal compensation for activities with Novartis as an employee.

Walking speed, unilateral leg loading, and step symmetry in young adults

The purpose of this study was to examine the effects of gait speed and unilateral lower limb loading on step time and step length symmetry in healthy adults. Spatiotemporal gait data were collected from 22 healthy subjects (11 men, 11 women), using the GaitRite walkway, under four randomly sequenced test conditions: self-selected speed (SS), fast speed (F), self-selected speed with the right leg loaded (LSS), and the fastest attainable speed with the right leg loaded (LF). The symmetry index, calculated with the formula [((R−L)/0.5×(R+L))×100], was used to quantify step time and step length symmetry. It was found that over-ground gait speed had no significant effects on the symmetry of step time or step length. Unilateral lower limb loading significantly increased step time asymmetry, with longer step time for the loaded leg. Step symmetry was further compromised and became more asymmetrical when, in addition to unilateral leg loading, subjects maximized their gait speed. This effect of fast speed with unilateral leg loading was particularly prominent in relation to step length, with its shortening in the unloaded leg and lengthening in the loaded leg. These observations in healthy subjects may serve as a reference for the assessment of gait symmetry in patients with unilateral lower limb pathologies.

Rey Visual Design Learning Test performance correlates with white matter structure.

Studies exploring relation of visual memory to white matter are extensively lacking. The Rey Visual Design Learning Test (RVDLT) is an elementary motion, colour and word independent visual memory test. It avoids a significant contribution from as many additional higher order visual brain functions as possible to visual performance, such as three-dimensional, colour, motion or word-dependent brain operations. Based on previous results, we hypothesised that test performance would be related with white matter of dorsal hippocampal commissure, corpus callosum, posterior cingulate, superior longitudinal fascicle and internal capsule. In 14 healthy subjects, we measured intervoxel coherence (IC) by diffusion tensor imaging as an indication of connectivity and visual memory performance measured by the RVDLT. IC considers the orientation of the adjacent voxels and has a better signal-to-noise ratio than the commonly used fractional anisotropy index. Using voxelwise linear regression analyses of the IC values, we found a significant and direct relationship between 11 clusters and visual memory test performance. The fact that memory performance correlated with white matter structure in left and right dorsal hippocampal commissure, left and right posterior cingulate, right callosal splenium, left and right superior longitudinal fascicle, right medial orbitofrontal region, left anterior cingulate, and left and right anterior limb of internal capsule emphasises our hypothesis. Our observations in healthy subjects suggest that individual differences in brain function related to the performance of a task of higher cognitive demands might partially be associated with structural variation of white matter regions.

A cerebral network model of speech prosody comprehension

Comprehension of information conveyed by the tone of voice is highly important for successful social interactions (Grandjean et al., 2006). Based on lesion data, a superiority of the right hemisphere for cerebral processing of speech prosody has been assumed. According to an early neuroanatomical model, prosodic information is encoded within distinct right-sided perisylvian regions which are organized in complete analogy to the left-sided language areas (Ross, 1981). While the majority of lesion studies are in line with the assumption that the right temporal cortex is highly important for the comprehension of speech melody (Adolphs et al., 2001; Borod et al., 2002; Heilman et al., 1984), some studies indicate a widespread network of partially bilateral cerebral regions to contribute to prosody processing including the frontal cortex (Adolphs et al., 2002; Hornak et al., 2003; Rolls, 1999) and the basal ganglia (Cancellieve & Kertesz, 1990; Pell & Leonard, 2003). More recently, functional imaging experiments have helped to differentiate specific functions of distinct brain areas contributing to recognition of speech prosody (Ackermann et al., 2004; Schirmer & Kotz, 2006; Wildgruber et al., 2006). Observations in healthy subjects indicate a strong association of cerebral responses and acoustic voice properties in some regions (stimulus-driven effects), whereas other areas show modulation of activation linked to the focusing of attention to specific task components (task-dependent effects). Here we present a refined model of prosody processing and cross-modal integration of emotional signals from face and voice which differentiates successive steps of cerebral processing involving auditory analysis and multimodal integration of communicative signals within the temporal cortex and evaluative judgements within the frontal lobes.

Leptin and energy metabolism in pulmonary tuberculosis

Pulmonary tuberculosis is the classic cause of "consumption," but the pathogenesis of such wasting is largely unknown. Animal studies in other conditions suggest that leptin may be a mediator between proinflammatory cytokine activity and wasting. We tested whether the leptin concentration, after control for body fat mass, is higher during active pulmonary tuberculosis than after recovery and whether it correlates with energy metabolism and proinflammatory cytokine activity. Nondiabetic adults with pulmonary tuberculosis (n = 32) were recruited into a prospective observational study. Patients found to be antibody positive for human immunodeficiency virus were excluded from the study. Dual-energy X-ray absorptiometry, indirect calorimetry, and food intake protocols were performed at baseline and after 1 and 6 mo of tuberculosis treatment. Fasting plasma leptin, tumor necrosis factor alpha and its soluble receptor, and interleukin 6 were measured by enzyme-linked immunosorbent assay. Resting energy expenditure was close to Harris-Benedict predictions and did not change significantly during treatment, but energy intake increased. Leptin concentration was correlated in a log-linear fashion with percentage body fat but was independent of cytokines and energy intake. There was no significant difference in leptin, corrected for energy balance and fat mass, at baseline and after 1 and 6 mo of treatment. These data are compatible with recovery from anorexia or starvation without discernible hyper- or hypometabolism. The close correlation of leptin with body fat mass is similar to observations in healthy subjects. No additional influence of disease state or proinflammatory cytokine activity was found. Leptin does not appear to be a component of the immune response to human pulmonary tuberculosis, and thus it cannot account for the weight loss and anorexia associated with tuberculosis.

Thin-Section CT in Obstructive Pulmonary Disease: Discriminatory Value

To use thin-section computed tomography (CT) to distinguish between causes of obstructive pulmonary disease, to determine which distinctions give rise to diagnostic imprecision, and to identify the most useful CT features. Thin-section CT scans of 105 patients with obstructive pulmonary disease (asthma, n = 35; centrilobular emphysema, n = 30; panlobular emphysema, n = 21; and obliterative bronchiolitis, n = 19) and 33 healthy subjects were assessed independently by two observers. The most likely diagnosis and a confidence rating were assigned. Individual thin-section CT features were recorded. Accuracy, sensitivity, specificity, negative predictive value, and positive predictive value for first-choice diagnoses were calculated. The prevalence of CT features between pairs of conditions was compared with the chi(2) or Fisher exact test as appropriate. A correct first-choice diagnosis was made in 199 of 276 (72%) observations. A correct first-choice diagnosis was made in 35 of 38 (92%) observations in patients with obliterative bronchiolitis, in 53 of 60 (88%) observations in patients with centrilobular emphysema, in 53 of 66 (80%) observations in healthy subjects, in 37 of 70 (53%) observations in patients with asthma, and in 20 of 42 (48%) observations in patients with panlobular emphysema. The major sources of diagnostic inaccuracy were differentiation between panlobular and centrilobular emphysema, asthma and normality, and asthma and obliterative bronchiolitis. There were significant increases in prevalence of (a) bronchial wall thickening and vascular attenuation in patients with asthma when compared with healthy subjects and (b) vascular attenuation and decreased attenuation in patients with obliterative bronchiolitis when compared with patients with asthma (P <.001). CT helps to distinguish diseases that cause airflow obstruction. Thin-section CT is particularly accurate in the identification of obliterative bronchiolitis.

New criteria for estimating baroreflex sensitivity using the transfer function method.

Computer simulations were carried out to appraise three new criteria for the estimation of baroreflex sensitivity (BRS) using the transfer function method. The major goal was to identify a computation procedure able to overcome the intrinsic limitations of the classical coherence criterion. Four representative shapes of the gain function and three different average gains (2, 5 and 8 ms(mmHg)(-1) in the low-frequency (LF) band (0.04-0.15Hz) were considered. The signal-to-noise ratio was made to vary so that the peak coherence in the LF band changed from 0.15 to 0.9. All simulation parameters were derived from previous observations in healthy subjects and heart disease patients. The error of the estimated gain function was obtained from its confidence interval. BRS was computed as average gain in the LF band: (a) including in the average only those points having error < or = threshold (criterion 1, C1); (b) calculating the mean error in the band and accepting BRS measurements only when this error was < or = threshold (criterion 2, C2); (c) including in the average all points, regardless of the error (criterion 3, C3). The three criteria were compared in terms of measurability (percentage of measured BRS) and accuracy (bias and SD of BRS). Using C1 and C2, measurability dropped to 10% when the peak coherence in the LF band decreased, respectively, to 0.18-0.41 and to 0.26-0.53, depending on the shape and strength of the gain. In this condition (lower bound of measurability), worst bias and SD (average gain: 8 ms(mmHg)(-1)) were, respectively, 0.8 ms(mmHg)(-1) and 3.3ms(mmHg)(-1) (C1), and 0.1 ms(mmHg)(-1) and 1.0 ms(mmHg)(-1) (C2). C3, by definition, always ensured 100% measurability and showed bias and SD comparable with, or even lower than, C1 and C2, within the common range of measurable BRS. In the extreme condition of 0.15 coherence, bias and SD were, respectively, 1.7 ms(mmHg)(-1) and 2.3ms(mmHg)(-1) (average gain: 8ms(mmHg)(-1)). Hence, error checking (C1 and C2) dramatically reduced measurability and did not improve accuracy of BRS measurements compared with performing no error check (C3). In conditions of low signal-to-noise ratio and/or impaired baroreflex gain, leading to markedly reduced coherence, the simple average of the gain function in the LF band allows BRS to be estimated with accuracy adequate for clinical purposes.

Validation and steady-state analysis of a power-law model of purine metabolism in man.

The paper introduces a model of human purine metabolism in situ. Chosen from among several alternative system descriptions, the model is formulated as a Generalized Mass Action system within Biochemical Systems Theory and validated with analyses of steady-state and dynamic characteristics. Eigenvalue and sensitivity analyses indicate that the model has a stable and robust steady-state. The model quite accurately reproduces numerous biochemical and clinical observations in healthy subjects as well as in patients with disorders of purine metabolism. These results suggest that the model can be used to assess biochemical and clinical aspects of human purine metabolism. It provides a means of exploring effects of enzyme deficiencies and is a potential tool for identifying steps of the pathway that could be the target of therapeutical intervention. Numerous quantitative comparisons with data are given. The model can be used for biomathematical exploration of relationships between enzymic deficiencies and clinically manifested diseases.

Effects of Hemodialysis on Plasma Protein Binding of Bepridil

The effects of end-stage renal disease (ESRD) and hemodialysis on the in vitro plasma protein binding of bepridil hydrochloride were investigated. The possible influence of bepridil metabolites on bepridil-protein binding in ESRD patients was also examined. Plasma samples were obtained from six patients with ESRD. Bepridil-plasma protein binding was measured by microequilibrium dialysis after addition of freshly prepared bepridil-14C (239 microCi/mg) at a final concentration of 2 micrograms/mL. The percentage of free bepridil in peripheral venous samples drawn on a nondialysis day was lower (i.e., binding was greater) in the patients with ESRD relative to previous observations in healthy subjects (0.15% +/- 0.04% versus 0.31% +/- 0.05% (mean +/- SD). The plasma concentrations of alpha-1-acid glycoprotein (AAG), the principal bepridil binding protein, were also higher in ESRD patients (110 +/- 32 mg/dL) than previously reported in healthy subjects. Although hemodialysis resulted in significant increases in AAG, total protein, and albumin concentrations, no significant difference in bepridil-plasma protein binding was detected between predialysis and postdialysis peripheral venous samples in the presence (0.16 versus 0.18) or absence (0.20 versus 0.17) of bepridil metabolites. The percentage of free bepridil in plasma from both the arterial and venous limbs of the dialyzer during hemodialysis (means of free bepridil ranged from 0.24-0.28%) was higher than in samples drawn from a peripheral vein. This displacement of bepridil from its binding sites as blood passes through the dialyzer may have been owing to the presence of high local concentrations of plasticizers. Confirmation of this hypothesis will require further investigation.

Gemfibrozil reduces postprandial lipemia in non-insulin-dependent diabetes mellitus.

The effect of gemfibrozil on postprandial lipoprotein metabolism was investigated in a 12-week, randomized, double-blind, placebo-controlled trial in 20 non-insulin-dependent diabetic patients with moderate hypertriglyceridemia. The patients were given a meal containing 78 g of fat and 345,000 units of vitamin A to label chylomicrons and their remnants. Plasma obtained at various times during the fat-load test was separated into six fractions by gradient-density ultracentrifugation. Gemfibrozil reduced the postprandial triglyceride response, measured as the area under the time-dependent concentration curve, on average by 32% in whole plasma, by 38% in the Svedberg flotation unit (Sf) 1,100-3,200 chylomicron fraction, by 36% in Sf 400-1,100 chylomicrons, and by 38% in the Sf 60-400 lipoproteins. Retinyl palmitate, a measure of intestinally derived particles, was reduced in plasma by 34%, in Sf 1,100-3,200 by 46%, in Sf 400-1,100 by 44%, and in Sf 60-400 by 37%. All these reductions were significant in comparison with the placebo group. Particles with Sf < 60 were not significantly affected. In contrast to earlier observations in healthy subjects, no significant negative correlations existed between postprandial lipemia and high density lipoprotein cholesterol or the postheparin lipoprotein lipase activity. The reduction of the potentially atherogenic chylomicron remnants may decrease the risk of atherosclerosis in non-insulin-dependent diabetes mellitus, a hypothesis that awaits testing in prospective studies.

Conduction velocity and refractory period of single motor nerve fibres in antecedent poliomyelitis.

The axonal conduction velocity and the axonal refractory period were determined using electromyographic techniques for 60 single motor units in 11 patients with antecedent poliomyelitis. The results were compared with previous observations in healthy subjects as well as subjects with motor neuron disease. In antecedent poliomyelitis there was a reduced proportion of nerve fibres with low conduction velocity as compared with the findings in healthy subjects. The mean value of the axonal conduction velocities in antecedent poliomyelitis (42.4 +/- 3.7 m/s, M +/- SD) was significantly higher (p less than 0.01) while in motor neuron disease the corresponding value (35.2 +/- 7.8 m/s) was significantly lower (p less than 0.005) than in healthy subjects (39.8 +/- 4.9 m/s). In antecedent poliomyelitis the conduction velocity and refractory period were related as in healthy subjects while abnormally long refractory periods were observed in motor neuron disease.

Effect of somatostatin infusion on VIP-induced transport changes in the human jejunum

This study was designed to elucidate the mechanism by which somatostatin administration ameliorates or abolishes diarrhea in pancreatic cholera syndrome (PCS). Absorption (or secretion) of water and electrolytes was measured in 30-cm segments of jejunum of 18 healthy volunteers in whom PCS was mimicked by intravenous infusion of VIP. Using the triple-lumen tube technique, the intestine was perfused with a plasma-like electrolyte solution while administering intravenous saline (control), VIP (400 pmol/kg/hr), somatostatin (5000 pmol/kg/hr), or VIP plus somatostatin. VIP infusion abolished water and electrolyte absorption and somtostatin had no effect on these VIP-induced transport changes regardless of whether somatostatin infusion was started before or after VIP infusion. Somatostatin infusion had no effect on VIP plasma concentration when elevated by intravenous VIP infusion (control: 10±1 pmol/l ; during VIP infusion: 108±6). In a patient with pancreatic cholera syndrome identical perfusion experiments showed jejunal water secretion (93 ml/30 cm/hr) which changed to absorption (65 ml/30 cm/hr) when somatostatin was infused (5000 pmol/kg/hr). Plasma VIP concentration fell from 145 to 74 pmol/l (normal<50) during somatostatin infusion. Stool weight fell from 3722 g to 819 g per 24 hours when somatostatin was given at a dose of 2500 pmol/kg/hr for two days. Our observations in healthy subjects show that somatostatin has no effect on intestinal transport at the mucosal level when circulating VIP concentration is elevated. The findings in the patient with pancreatic cholera syndrome indicate that the effect of somatostatin on secretion (and diarrhea) is due to a decrease in circulating levels of VIP presumably due to reduced release of VIP from a tumor.