Young Human Volunteers Research Articles

Event-related Potentials Indicate Target Processing in the Absence of Distractor Suppression during Rapid Serial Visual Presentation.

In our modern world we are exposed to a steady stream of information containing important as well as irrelevant information. Therefore, our brains have to constantly select relevant over distracting items and further process the selected information. Whereas there is good evidence that even in rapid serial streams of presented information relevant targets can be actively selected, it is less clear whether and how distracting information is de-selected and suppressed in such scenarios. To address this issue we recorded electroencephalographic activity during a rapid serial visual presentation paradigm in which healthy, young human volunteers had to encode visual targets into short-term memory while salient visual distractors and neutral filler items needed to be ignored. Event-related potentials were analyzed in 3D source space and compared between stimulus types. A negative wave between around 170 and 230 ms after stimulus onset resembling the N2pc component was identified that dissociated between target stimuli and distractors as well as filler items. This wave appears to reflect target selection processes. However, there was no electrophysiological signature identified that would indicate an active distractor suppression mechanism. The obtained results suggest that unlike in situations where target stimuli and distractors are presented simultaneously, targets can be selected without the need for active suppression of distracting information in serial presentations with a clear and regular temporal structure. It is assumed that temporal expectation supports efficient target selection by the brain.

Alteration in facial skin blood flow during acute exposure to -10 and -30° head-down tilt in young human volunteers.

What is the central question of this study? Facial skin blood flow (SBF) might increase during head-down tilt (HDT). However, the effect of HDT on facial SBF remains controversial. In addition, the changes in facial SBF in the cheek (cheek SBF) during a steeper angle of HDT (>-12° HDT) have not been investigated. What is the main finding and its importance? This study showed that cheek SBF decreased during -30° HDT, alongside increased vascular resistance. Furthermore, vascular impedance was suggested to be elevated, accompanied by an increased hydrostatic pressure gradient caused by HDT. Constriction of the facial skin vascular bed and congestion of venous return owing to the steep angle of HDT can decrease facial SBF. Head-down tilt (HDT) has been used to simulate microgravity in ground-based studies and clinical procedures including the Trendelenburg position or in certain surgical operations. Facial skin blood flow (SBF) might be altered by HDT, but the effect of a steeper angle of HDT (>-12° HDT) on facial SBF remains unclear. We examined alterations in facial SBF in the cheek (cheek SBF) using two different angles (-10 and -30°) of HDT and lying horizontal (0°) in a supine position for 10min, to test the hypothesis that cheek SBF would increase with a steeper angle of HDT. Cheek SBF was measured continuously by laser Doppler flowmetry. Cheek skin vascular resistance and the pulsatility index of cheek SBF were calculated to assess the circulatory effects on the facial skin vascular bed in the cheek. Cheek SBF decreased significantly during -30° HDT. In addition, the resistance in cheek SBF increased significantly during -30° HDT. The pulsatility index of cheek SBF increased during both -10 and -30° HDT. Contrary to our hypothesis, cheek SBF decreased during -30° HDT along with increased skin vascular resistance. Vascular impedance, estimated by the pulsatility index in the cheek SBF, was elevated during both -10 and -30° HDT, and elevated vascular impedance would be related to increased hydrostatic pressure induced by HDT. Skin vascular constriction and venous return congestion would be induced by -30° HDT, leading to deceased cheek SBF. The present study suggested that facial SBF in the cheek decreased during acute exposure to a steep angle of HDT (∼-30° HDT).

Software development to optimize the minimal detectable difference in human airway images captured using optical coherence tomography.

Optical coherence tomography (OCT) is an imaging methodology that can be used to assess human airways. OCT avoids the harmful effects of ionizing radiation and has a high spatial resolution making it well suited for imaging the structure of small airways. Analysis of OCT airway images has typically been performed manually by tracing the airway with a relatively high coefficient of variation. The purpose of this study was to develop an analysis tool to reduce the inter- and intra-observer reproducibility of OCT and improve the ability to detect differences in airways. OCT images from healthy, young human volunteers were used to develop and test the OCT software. Measurement software was developed to allow the conversion of the original image into a grayscale image and was followed by an enhancement operation to brighten the image, and contour measurement. A total of 140 OCT images, 70 small (<2 mm) and 70 medium (2-4 mm) sized airways were analyzed. The inter- and intraobserver reproducibility of airway measurements ranged for strong to very strong in the small-sized airways. For medium-sized airways the reproducibility was considered moderate. Bland-Altman bias was low between observers and observations for all measures. The minimal detectable differences in the airway measurements with our semi-automated software were lower relative to manual tracing in medium-sized airways. Our software improves the ability to perform quantitative OCT analysis and may help to quantify the extent of airway remodelling in respiratory disease or elite athletes in future studies.

Individual differences in the attentional modulation of the human auditory brainstem response to speech inform on speech-in-noise deficits

People with normal hearing thresholds can nonetheless have difficulty with understanding speech in noisy backgrounds. The origins of such supra-threshold hearing deficits remain largely unclear. Previously we showed that the auditory brainstem response to running speech is modulated by selective attention, evidencing a subcortical mechanism that contributes to speech-in-noise comprehension. We observed, however, significant variation in the magnitude of the brainstem’s attentional modulation between the different volunteers. Here we show that this variability relates to the ability of the subjects to understand speech in background noise. In particular, we assessed 43 young human volunteers with normal hearing thresholds for their speech-in-noise comprehension. We also recorded their auditory brainstem responses to running speech when selectively attending to one of two competing voices. To control for potential peripheral hearing deficits, and in particular for cochlear synaptopathy, we further assessed noise exposure, the temporal sensitivity threshold, the middle-ear muscle reflex, and the auditory-brainstem response to clicks in various levels of background noise. These tests did not show evidence for cochlear synaptopathy amongst the volunteers. Furthermore, we found that only the attentional modulation of the brainstem response to speech was significantly related to speech-in-noise comprehension. Our results therefore evidence an impact of top-down modulation of brainstem activity on the variability in speech-in-noise comprehension amongst the subjects.

Acute administration of roflumilast enhances sensory gating in healthy young humans in a randomized trial

IntroductionSensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer’s disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.MethodsThe current study investigated the effects of the PDE4 inhibitor roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18–30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).ResultsResults show that roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.ConclusionThe PDE4 inhibitor roflumilast has a favorable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.

Analysis of human exhaled breath in a population of young volunteers

Analysis of volatile organic compounds (VOCs) in human breath can provide information about the current physiological state of an individual, such as clinical conditions and exposure to exogenous pollutants. The blood-borne VOCs present in exhaled breath offer the possibility of exploring physiological and pathological processes in a noninvasive way. However, the field of exhaled breath analysis is still in its infancy. We undertook this study in order to define interindividual variation and common compounds in breath VOCs of 48 young human volunteers. Alveolar breath samples were analyzed by automated thermal desorption, gas chromatography with flame ionization detector (FID) and electron capture detector (ECD) using SUPELCO standards with 66 compounds. Predominant compounds in the alveolar breath of analyzed subjects are ethylbenzene, 1-ethyl-4-methylbenzene, 1,2,4-trimethylbenzene and 1,3,5-trimethylbenzene (over 50% of the subjects). Isopropyl alcohol, propylene, acetone, ethanol were found as well. We detected substituted compounds in exhaled breath.

Study of the urinary and faecal excretion of N ε-carboxymethyllysine in young human volunteers

The dietary habits of the adolescent population with a high intake of snack and fast foods mean that they consume a high rate of which in turn leads to the development of different degenerative disorders. There are few studies available on MRP absorption and metabolism. We investigated the effects of a MRP-high and a MRP-low diet on carboxymethyllysine (CML) intake and excretion in 11-14 years adolescent males. In a 2-period crossover trial, 20 healthy subjects were randomly assigned to two groups. The first group consumed the MRP-low diet for 2 weeks, observed a 40-day washout period, and then consumed the MRP-high diet for 2 weeks. The second group received the diets in the reverse order. Subjects collected urine and faeces on the last 3 days of each dietary period. The consumption of the MRP-high diet led to a higher CML input (P < 0.05) (11.28 vs. 5.36 mg/day CML for MRP-high and -low diet, respectively). In parallel, the faecal excretion was also greater (P < 0.05) (3.52 vs. 1.23 mg/day CML, respectively) and proportional to the dietary intake. The urinary elimination of CML was not increased significantly when the MRP-high diet was consumed compared to consumption of the MRP-low diet, and was not proportional to the dietary exposure of CML. In conclusion it was shown that CML absorption and faecal excretion were highly influenced by dietary CML levels. Since the compound has long-term effects on health, an excessive intake deserves attention, especially in a population nutritionally at risk as adolescents.

Immunological evaluation into the bone allograft and selection of experimental animal model on im-munogenicity

Objective To explore the effect of immunogenicity of freeze-dried bone allograft on different in vitro experimental models. Methods The lymphocytes were obtained respectively from 10 healthy young human volunteers, 10 Balb/c and 10 C57 mice and 10 New Zealand rabbits. The experiment was carried out in 6 groups: positive control group (PHA/ConA+lymphocyte), negative control group (Hydroxyapatite powder + lymphocyte), allogeneic bone group A (Freeze-dried bone powder 2. 0 g/L + lym-phocyte), allogeneic bone group B (Freeze-dried bone powder 1.0 g/L + lymphocyte), allogeneic bone group C (Freeze-dried bone powder 0.5 g/L + lymphocyte), and negative control group (culture solution + lym-phocyte). Lymphocyte transformation test (Alamarblue) was conducted to culture the 6 kinds of experimental materials in vitro. After 72 hours, samples were scanned with ELISA muhiscan at wave lengths 570 nm and 600 nm to fetal the light absorption value. Pearson analyses were performed 10 determine the relationships a-mong the 3 animals and 1 human groups and find out which animal would be highly correlated to human. Results In the human and Balb/c mice lymphocyte transformation tests, there was no significant difference (P > 0.05) between allogeneic bone groups A, B, C and negative control group (HA) ; but there was sig-nificant difference (P 0.05). There was no significant difference among the 6 groups of C57 mice and New Zealand rabbits (P > 0.05). The coefficient r between Balb/c mice and human groups was 0.959, P = 0.003, showing a highly positive correlation. The coefficient r between C57 mice and human groups was 0.527, P = 0.283, while the coefficient r between New Zealand rabbits and human groups was 0.866, P =0.026. Conclusions The immunogenicity of freeze-dried bone powder in this experiment may not be sufficient enough to induce significanrt immunologic response. Balb/c mice may be preferable for immunogenicity related experiments. Key words: Lymphocyte activation; Cytotoxi, immunologic; Bone allograft

Insulin at physiological concentrations increases microvascular perfusion in human myocardium

Vascular endothelium regulates vascular tone and tissue perfusion in response to various physiological and pathological stimuli. Insulin and meal feeding increase microvascular perfusion and thus oxygen, nutrient, and hormone delivery to human skeletal muscle. Meal feeding also increases cardiac microvascular perfusion in healthy humans. To examine whether insulin at physiological concentrations increases microvascular perfusion in human myocardium, we studied 13 healthy, overnight-fasted, lean, young human volunteers by using myocardial contrast echocardiography (MCE) and insulin-clamp techniques. We measured cardiac microvascular blood volume (MBV), microvascular flow velocity (MFV), and microvascular blood flow (MBF) at baseline, 60 min, and 120 min after initiating insulin infusion at 1 mU.kg(-1).min(-1). MBF is the product of MBV and MFV and represents microvascular perfusion. Insulin increased myocardial MBV by 23% at 60 min (P < 0.01) and by 41% at 120 min (P = 0.001) without changing MFV. As a result, insulin-mediated myocardial MBF increased significantly at both 60 min (P < 0.01) and 120 min (P < 0.0005). Insulin also significantly increased brachial artery diameter, flow velocity, and total blood flow at 60 and 120 min (P < 0.05 for all). The changes in cardiac MBV correlated positively with quantitative insulin sensitivity check index (QUICKI) and negatively with body mass index but not with the steady-state glucose-infusion rates or the changes in brachial artery parameters. We conclude that insulin, at physiologically relevant concentrations, increases microvascular perfusion in human heart muscle by increasing cardiac MBV in healthy, insulin-sensitive adults. This insulin-mediated cardiac microvascular perfusion may play an important role in normal human myocardial oxygen and substrate physiology.

Biophysical parameters of skin: map of human face, regional, and age‐related differences

The face showed anatomical variation on reaction to chemicals, which could be related to differences in biophysical specificities of the skin. The aim of this study was to establish a map of the face for 6 biophysical parameters.10 young human volunteers (24-34 years) and 10 old volunteers (66-83 years) were studied to prepare a map of the human face based on regional variations and age-related differences by measuring various biophysical parameters. 7 locations on the face, neck, and forearm were investigated. Skin blood flow, transepidermal water loss (TEWL), stratum corneum hydration (capacitance), temperature, pH, and sebum content of the skin surface were measured. In both groups, skin blood flow in the nose showed the highest value. Perioral and nasolabial areas showed the highest TEWL values. The neck showed the highest capacitance value. The highest skin temperature was detected in the neck in the young group and in the nasolabial area in the old group. The chin showed the most alkaline pH in both groups. Nasolabial area showed the highest sebum content in the young group, as did the chin in the old group. These baseline values provide a framework to build on for ascertaining disease and intervention-related effects.

Human photopic response to circulating glucose.

Circulating glucose was manipulated in young human volunteers with clinically normal vision. Fasting achieved a concentration range of 45-91 mg/dl. And sugar loading produced a range of 79-108 mg/dl. Glucose increased in all subjects. A nonparametric ANOVA provided a p=0.0005 for the significance of the concentration differences between group glucose concentrations under the two conditions in the sample. Each volunteer participated in each condition of the repeated-measures design. Clinical tests were completed before electroretinograms were recorded under photopic and scotopic adaptation conditions. Measures were made from 12 eyes. Only photopic adaptation conditions with maximal stimuli produced significant results. Inter-individual differences were robust and constrained to reduced implicit times for b-wave peaks and 30 Hz flicker implicit times. Under the elevated glucose conditions. Other variables showed very strong trends. These results confirm and extend other human indications of photopic retinal sensitivity to variations within the normal range of circulating glucose concentrations.

Comparison of the pharmacokinetics of parenteral parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in healthy young humans.

The amino-terminal fragments of human PTH [hPTH-(1-34)] and PTH-related peptide [PTHrP-(1-34)] appear to be equipotent in several rodent models. However, continuous i.v. infusions of these peptides to young human volunteers suggested that a 10-fold higher molar dose of PTHrP was required to produce comparable circulating levels of the peptide and biochemical responses similar to PTH. As PTHrP has a wide variety of target tissues in mammalian species and may, therefore, play a paracrine, rather than an endocrine, hormonal role in vivo, we evaluated whether enhanced metabolic clearance of injected PTHrP might explain its apparently reduced potency as a PTH-like hormone. Ten healthy subjects [age, 25 +/- 9 (+/- SD) yr] received in random order either hPTH-(1-34) or hPTHrP-(1-34) given by bolus i.v. injections in a dose of 10.7 nmol. Measurements of plasma immunoreactive peptide indicated a comparable volume of distribution for each, but the apparent t1/2 (8.3 +/- 1.6 min) and plasma clearance (4.0 +/- 1.4 L/min) for hPTHrP were significantly (P < 0.05) accelerated compared to those of hPTH (t1/2, 10.2 +/- 0.5 min; clearance, 2.0 +/- 0.4 L/min). Peak plasma cAMP levels were 9-fold lower in response to hPTHrP (29.5 +/- 19 vs. 190 +/- 63 pmol/L; P < 0.01), and increases in urinary cAMP excretion were 5-fold lower (2.1 +/- 1.1 vs. 11.2 +/- 3.7 nmol/mmol creatinine; P < 0.01). No major differences were observed in the urinary excretion of phosphate, calcium, or sodium between the two peptides. Although hPTHrP-(1-34) has a 2-fold higher MCR than hPTH-(1-34), this may not explain the more than 5-fold lower plasma or urinary cAMP response to PTHrP in humans. The comparable effects of PTH and PTHrP on urinary phosphate, calcium, and sodium may indicate a non-cAMP-dependent pathway for these responses, although the intracellular pool of cAMP generated to either peptide, and thus the local target tissue response, could not be estimated in the present study.

Pharmacological separation of mechanisms contributing to human contrast sensitivity

Two basic types of cholinergic receptor have been identified in nervous systems: nicotinic and muscarinic. In the mammalian visual system, the balance of evidence suggests that nicotinic activity is associated primarily with transmission and processing of information while muscarinic activity reflects modulatory influences arising in the brainstem and basal forebrain. We have measured contrast sensitivity functions using a two-alternative forced-choice procedure in young human volunteers with and without administration of nicotine (1.5 mg by buccal absorption) or the muscarinic antagonist scopolamine (1.2 mg orally). Scopolamine elevates contrast-detection thresholds uniformly at all spatial frequencies, consistent with blocking of a nonspecific arousal system. Nicotine, in contrast, improves sensitivity at low spatial frequencies (below about 4 cycle/deg); at higher spatial frequencies sensitivity is, if anything, impaired. Using counterphase gratings, we find that scopolamine elevates thresholds uniformly at all temporal frequencies. Nicotine lowers thresholds at high but not low temporal frequencies. The results obtained with nicotine suggest that contrast sensitivity reflects the activity of two mechanisms, or sets of spatiotemporal filters, that are pharmacologically distinct, the contrast sensitivity function reflecting the envelope of their sensitivities.

Stereoselectivity in the urinary excretion of the mercapturates of (R-) and (S-) alpha-bromoisovalerylurea in man.

1. alpha-Bromoisovalerylurea (BIU) is a racemic drug that is metabolized by glutathione conjugation. The urinary excretion of the separate diastereomeric mercapturates formed from (S)- and (R)-BIU in healthy young human volunteers was investigated. 2. A pronounced stereoselectivity was observed: the mercapturate formed from R-BIU was excreted with a t1/2 of 1.5 +/- 0.4 h, while that from S-BIU showed a t1/2 of 3.1 +/- 1.3 h. Moreover, 22.5 +/- 4.3 and 5.7 +/- 1.6% of the dose, respectively, was excreted as each mercapturate diastereomer in 24 h. 3. This is the first example of stereoselectivity in the elimination of a substrate for glutathione conjugation in man.

Assessment by antipyrine test of bupropion enzymic induction in elderly depressed patients

AbstractBupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism‐inducer in rodents at high doses but not in young human volunteers. Eleven elderly depressed patients (mean age 76·9 ± 8·7 years) entered in the study and received 100 mg of bupropion t.i.d. for 28 days. An antipyrine test was performed before and at day 28 of therapy. Antipyrine was taken orally (15 mg/kg) at 8 a.m. and blood samples were drawn at 11 a.m., 2, 5, and 8 p.m. Plasma levels were assayed using a GLC method. Results show a slight but significant increase of apparent clearance (+30 per cent) and decrease in the half‐life (–14 per cent) of antipyrine. Difference between these results and previous results in young volunteers might be explained by the usual decrease of hepatic function described in elderly patients. Bupropion can be considered in elderly people as a slight hepatic enzyme‐inducer.

Mutagenic effects of ozone on human cells exposed in vivo and in vitro based on sister chromatid exchange analysis

A sister chromatid exchange (SCE) analysis was performed on circulating lymphocytes collected from young human volunteers exposed to 0.5 ppm ozone for 2 hr, an exposure simulating conditions in severe air pollution episodes. SCE analysis was also performed on diploid human fetal lung cells (WI-38) exposed to 0, 0.25, 0.50, 0.75, and 1.00 ppm ozone for 1 hr in vitro. No increase in SCEs over controls was demonstrated in the lymphocyte chromosomes. However, a clear dose-related increase in SCEs was observed in the WI-38 cells exposed in vitro.