Contribution of β-adrenergic receptors to exercise-induced bronchodilatation in healthy humans

Exercise in healthy subjects is usually associated with progressive bronchodilatation. Though the decrease in vagal tone is deemed to be the main underlying mechanism, activation of bronchial β(2)-receptors may constitute an additional cause. To examine the contribution of β(2)-adrenergic receptors to bronchodilatation during exercise in healthy humans, we studied 15 healthy male volunteers during maximum exercise test at control conditions and after a non-selective β-adrenergic blocker (carvedilol 12.5mg twice a day until heart rate decreased at least by 10beats/min) and inhaled β(2)-agonist (albuterol 400μg). Airway caliber was estimated from the partial flow at 40% of control forced vital capacity (V˙(part40)) and its changes during exercise from the slope of linear regression analysis of V˙(part40) values against the corresponding minute ventilation during maximal exercise until exhaustion. At control, V˙(part40) increased progressively and significantly with exercise. After albuterol, resting V˙(part40) was significantly larger than at control increased but did not further increase during exercise. After carvedilol, V˙(part40) was similar to control but its increase with exercise was significantly attenuated. These findings suggest that β(2)-adrenergic system plays a major role in exercise-induced bronchodilation in healthy subjects.     

“Dumping” of rebound nystagmus and optokinetic afternystagmus in humans

Rebound nystagmus (RN) is an involuntary movement of the eyes, characterized by slow-phase eye velocity in the direction of previously maintained eccentric gaze. The purpose of this study was to clarify the neural or neuromuscular events that are responsible for the generation of RN. To do so, we examined whether a briefly presented visual stimulus during RN reduces (i.e., dumps) subsequent eye velocity, compared with the velocity of slow-phase eye movements when no visual stimulus was presented. For comparison, dumping was examined also for optokinetic afternystagmus (OKAN), which is generally believed to result from eye-velocity signals stored in a central neural integrator as a consequence of optokinetic stimulation. Results obtained from ten normal observers showed that RN and OKAN both exhibit dumping: average slow-phase eye velocities were reliably slower after fixation of a 0.6 deg stationary target than on trials when no fixation target was presented. Although RN decayed faster than OKAN in darkness, the magnitude of dumping increased similarly with the duration of the visual stimulus (25 ms to 4 s) for both types of eye movement. The results imply that signals from a central velocity-storage mechanism contribute to the generation of RN.     

Does modification of olfacto-gustatory stimulation diminish sensory-specific satiety in humans?

Alimentary sensory pleasure is an important factor in ingestive behavior. Renewal of olfacto-gustatory pleasure by introducing new foods or through seasoning of previously consumed food might increase intake. OBJECTIVES: To explore whether sensory-specific satiety (SSS) for a food could be modulated, either by introducing a novel food or by a modification of sensory stimulation via seasoning the food just eaten. METHODS: 180 out of 242 subjects were distributed over 3 experiments involving ad libitum intake of one of 6 fresh foods (cucumber, tomato, pineapple, banana, peanut, pistachio). Blindfolded subjects reported their sensations for the foods on 3 parameters before and after intake of an olfactorily chosen food: Olfactory pleasure (OP), Specific appetite (SA) and Stimulus-Induced Salivation (SIS). EXP. 1: One chosen food was repeatedly presented orthonasally and rated before and after it was eaten. EXP. 2: A second food was olfactorily chosen and ingested after the first one. EXP. 3: The same food was offered again after seasoning. RESULTS: 2 min after ingestion, food intake was limited by SSS. OP, SA, SIS correlated with each other for eaten and non-eaten foods. OP for non-eaten foods increased (p<0.01) after ingestion of the chosen food to specific satiety. When the food just eaten was seasoned, OP increased (p<0.01) and led to additional intake (80% of first intake). CONCLUSION: A reduction in SSS after introduction of a new flavor or after seasoning an ingested food was observed. Such a reduction has not previously been reported. This could hint at how food sensory variation leads to over-consumption.     

Is there a circadian rhythm of interleukin 15 in humans?

Nine healthy young men were studied under strict conditions for 48 h. The subjects were selected after a clinical examination and exploration of their rest-activity rhythm by actometry. The circadian rhythms of cortisol (peak at 8 AM) and melatonin (peak at 4 AM) were confirmed. The interleukin 15 (IL-15) was detected in the plasma samples with an Elisa kit (R&D System), but no reproducible variation could be observed during day 1 and day 2. In conclusion, in the conditions of our study, no rhythm was observed for IL-15. Our population will be completed with the inclusion of 6 additional subjects. These results will be specified.     

Does autoimmunity of endogenous vasoactive neuropeptides cause retinopathy in humans?

Immune privilege is a physiologic mechanism within the eye which protects it against pathogens, while also protecting it from inflammation. Immunological mechanisms in the eye must be tightly regulated to ensure externally mediated injury and infection or internally mediated autoimmunity do not exceed self-defence tolerance. Vasoactive neuropeptides (VNs) including vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase polypeptide (PACAP) and their receptors exist in the mammalian eye including the sclera, cornea, iris, ciliary body, ciliary process and the retina and may have a role in protecting these normally immune privileged sites. VN receptors are class II G protein-coupled receptors (GPCRs) which couple primarily to the adenylate cyclase (AC)-cyclic AMP pathway. A sound blood supply is essential for retinal survival hence vascular compromise will have serious consequences. Retinal vasculitis is a potentially blinding condition with a strong association with systemic inflammatory diseases. Compromise of the endothelial barriers and the blood retina barrier (BRB) may instigate inflammatory responses setting up a chain of events involving VNs in a manner which provokes autoimmunity to them. Protection from BRB breakdown may be linked to nitric oxide (NO) effects and actions of phosphodiesterase inhibitors and cAMP production. Induced NO expressed under influences of inflammatory mediators evokes neurodegeneration and cell apoptosis and may lead to serious ocular disease including retinal injury. Other inflammatory mediators also play a role in retinal pathology. PACAP and glutamate are co-stored in the retinohypothalamic tract and PACAP attenuates glutamate induced neurotoxicity in cultured retinal neurons suggesting that compromise of this VN would have significant detrimental impact on retinal viability though glutamate toxicity. Additional effects of VN compromise would possibly occur through unopposed vasoconstriction and inflammation. Proof of this hypothesis has important implications for treatment and prevention of autoimmune retinopathy and blindness as a number of therapeutic pathways may be opened. Importantly for therapeutic contexts cAMP effects are maintained by phosphodiesterase (PDE) inhibitors which could be used in VN autoimmune disorders. A compelling case may exist to undertake a therapeutic trial of VN replacement, PDE inhibitors and other agents in autoimmune retinopathies resulting from possible VN autoimmunity.     

Ex-vivo α-galactosylceramide activation of NKT cells in humans and macaques

NKT cells are key mediators of antiviral and anticancer immunity. Experiments in mice have demonstrated that activation of NKT cells in vivo induces the expression of multiple effector molecules critical to successful immunity. Human clinical trials have shown similar responses, although in vivo activation of NKT cells in humans or primate models are far more limited in number and scope. Measuring ex vivo activation of NKT cells by the CD1d-restricted glycolipid ligand α-Galactosylceramide (α-GalCer) through cytokine expression profiles is a useful marker of NKT cell function, but for reasons that are unclear, this approach does not appear to work as well in humans and non-human primate macaque models in comparison to mice. We performed a series of experiments on human and macaque (Macaca nemestrina) fresh whole blood samples to define optimal conditions to detect NKT cell cytokine (TNF, IFNγ, IL-2) and degranulation marker (CD107a) expression by flow cytometry. We found that conditions previously described for mouse splenocyte NKT cell activation were suboptimal on human or macaque blood NKT cells. In contrast, a 6h incubation with brefeldin A added for the last 4h, in a 96-well plate based assay, and using an α-GalCer concentration of 1 μg/ml were optimal methods to stimulate NKT cells in fresh blood from both humans and macaques. Unexpectedly, we noted that blood NKT cells from macaques infected with SIV were more readily activated by α-GalCer than NKT cells from uninfected macaques, suggesting that SIV infection may have primed the NKT cells. In conclusion, we describe optimized methods for the ex vivo antigen-specific activation of human and macaque blood NKT cells. These assays should be useful in monitoring NKT cells in disease and in immunotherapy studies.     

Do mosquito-associated bacteria of the genus Asaia circulate in humans?

Symbiotic bacteria of the genus Asaia have been proposed as tools for control of mosquito-borne diseases, specifically malaria. However, safety issues are a major concern for paratransgenesis strategies. The aim of this study is to investigate, with immunofluorescence assays and quantitative PCR experiments, whether Asaia spp. is circulating among humans. All human sera and whole blood samples analyzed were negative for Asaia spp., thus suggesting that this organism could be utilized, in the future, as a malaria control tool.     

Changes in the elastic properties of tendon structures following 20 days bed-rest in humans

The purpose of this study was to investigate the effects of 20 days bed-rest on the elastic properties of tendon structures of the human knee extensor muscles in vivo. Six healthy men carried out a 6° head-down bed-rest for 20 days. Muscle volume and maximal voluntary contraction (MVC) torque of the quadriceps femoris muscle significantly decreased by an average of 7.8 (SD 2.7)% and 14.9 (SD 6.9)%, respectively. Before and after bed-rest, the elongation (l) of the tendon and aponeurosis of vastus lateralis muscle was measured directly by ultrasonography, while the subjects performed ramp isometric knee extension up to MVC. The extent of l tended to be greater after bed-rest. The l above 110 N was significantly greater after bed-rest. Furthermore, the mean stiffness after bed-rest [35.5 (SD 7.8) N · mm⁻¹] was significantly lower than that before bed-rest [52.6 (SD 19.2) N · mm⁻¹]. The rate of torque development significantly reduced after bed-rest by an average of 47%, and the bed-rest induced a lengthening in the electromechanical delay (mean 21%). These results suggest that bed-rest results in a decrease in the stiffness of tendon structures with a reduction of muscle strength and volume. These adaptations of the tendon structures to bed-rest would bring about the changes in electromechanical delay and rate of torque development. Accepted: 28 July 2000     

Physical activity and plasma interleukin-6 in humans – effect of intensity of exercise

The present study included data from three marathon races to investigate the hypothesis that a relationship exists between running intensity and elevated concentrations of interleukin (IL)-6 in plasma. The study included a total of 53 subjects whose mean age was 30.6 [95% confidence interval (CI) 1.4] years, mean body mass 77.7 (95%CI 2.0) kg, mean maximal oxygen uptake (V˙O_2max) 59.3 (95%CI 1.4) ml · min⁻¹ · kg⁻¹, and who had participated in the Copenhagen Marathons of 1996, 1997 or 1998, achieving a mean running time of 206 (95%CI 7) min. Running intensity was calculated as running speed divided by V˙O_2max. The concentration of IL-6 in plasma peaked immediately after the run. There was a negative correlation between peak IL-6 concentration and running time (r=−0.30, P < 0.05) and a positive correlation between peak IL-6 concentration and running intensity (r=0.32, P < 0.05). The IL-1 receptor antagonist (IL-1ra) plasma concentration peaked 1.5 h after the run and there was a positive correlation between the peak plasma concentrations of IL-6 and IL-1ra (r=0.39, P < 0.01). Creatine kinase (CK) plasma concentration peaked on the 1st day after the run, but no association was found between peak concentrations of IL-6 and CK. In conclusion, the results confirmed the hypothesized association between plasma IL-6 concentration and running intensity, but did not confirm the previous finding of a connection between IL-6 plasma concentration and muscle damage. Accepted: 6 August 2000     

Examination of the law of grotthus-draper: does ultrasound penetrate subcutaneous fat in humans?

One benefit of ultrasound over infrared modalities is its ability to penetrate subcutaneous fat. The purpose of this study was to compare tissue temperature rise during ultrasound treatments in humans with various thicknesses of subcutaneous fat in the medial gastrocnemius. Twenty males served as subjects. A 23-gauge hypodermic needle microprobe was inserted 3-cm deep into the medial portion of the anesthetized gastrocnemius, and connected to a thermocouple temperature gauge. We applied 15 ml of ultrasound gel, preheated to body temperature (37°C), to a 10-cm-diameter target area. Continuous ultrasound was delivered topically at 1.5 W/cm² for 10 minutes. During this time, the soundhead was moved at a speed of 4 cm per second, and the temperature was recorded every 30 seconds. The mean baseline temperature for all subjects was 35.4°C. The mean temperature increase was 4.9°C. We performed a regression analysis to test for correlation between fat thickness and tissue temperature rise of subjects. There was a small positive but insignificant correlation (r=.128). This supports the claim of Grotthus and Draper. Since subcutaneous fat does not serve as a barrier to therapeutic ultrasound, athletic trainers and physical therapists can expect comparable increases in muscle temperature when using this modality on people with varying thicknesses of adipose tissue.     

Genetic variation of αENaC influences lung diffusion during exercise in humans

Exercise, decompensated heart failure, and exposure to high altitude have been shown to cause symptoms of pulmonary edema in some, but not all, subjects, suggesting a genetic component to this response. Epithelial Na(+) Channels (ENaC) regulate Na(+) and fluid reabsorption in the alveolar airspace in the lung. An increase in number and/or activity of ENaC has been shown to increase lung fluid clearance. Previous work has demonstrated common functional genetic variants of the α-subunit of ENaC, including an A→T substitution at amino acid 663 (αA663T). We sought to determine the influence of the T663 variant of αENaC on lung diffusion at rest and at peak exercise in healthy humans. Thirty healthy subjects were recruited for study and grouped according to their SCNN1A genotype [n=17 vs. 13, age=25±7 years vs. 30±10 years, BMI=23±4 kg/m(2) vs. 25±4 kg/m(2), V(O2 peak) = 95±30%pred. vs. 100±31%pred., mean±SD, for AA (homozygous for αA663) vs. AT/TT groups (at least one αT663), respectively]. Measures of the diffusing capacity of the lungs for carbon monoxide (DL(CO)), the diffusing capacity of the lungs for nitric oxide (DL(NO)), alveolar volume (V(A)), and alveolar-capillary membrane conductance (D(M)) were taken at rest and at peak exercise. Subjects expressing the AA polymorphism of ENaC showed a significantly greater percent increase in DL(CO) and DL(NO), and a significantly greater decrease in systemic vascular resistance from rest to peak exercise than those with the AT/TT variant (DL(CO)=51±12% vs. 36±17%, DL(NO)=51±24% vs. 32±25%, SVR=-67±3 vs. -50±8%, p<0.05). The AA ENaC group also tended to have a greater percent increase in DL(CO)/VA from rest to peak exercise, although this did not reach statistical significance (49±26% vs. 33±26%, p=0.08). These results demonstrate that genetic variation of the α-subunit of ENaC at amino acid 663 influences lung diffusion at peak exercise in healthy humans, suggesting differences in alveolar Na(+) and, therefore, fluid handling. These findings could be important in determining who may be susceptible to pulmonary edema in response to various clinical or environmental conditions.     

“Proprioceptive signature” of cursive writing in humans: a multi-population coding

The goal of the present study was to investigate the firing behavior of populations of muscle spindle afferents in all the muscles acting on the ankle while this joint was being subjected to writing-like movements. First it was proposed to determine whether the ensemble of muscle spindles give rise to a unique, specific, and reproducible feedback information characterizing each letter, number or short word. Secondly, we analyzed how the proprioceptive feedback on the whole encodes the spatial and temporal characteristics of writing movements using the vector population model. The unitary activity of 51 primary and secondary muscle spindle afferents was recorded in the tibial and common peroneal nerves at the level of the popliteal fossea, using the microneurographic method. The units recorded from belonged to the tibialis anterior, the extensor digitorum longus, the extensor hallucis longus, the peroneus lateralis, the gastrocnemius-soleus and the tibialis posterior muscles. The writing-like movements were randomly imposed at a natural velocity via a computer-controlled machine in a two-dimensional space. In general, muscle spindle afferents from any of the six muscles responded according to the tuning properties of the parent muscle, i.e. increasing their discharge rate during the phases where the direction of movement was within the preferred sensory sector of the parent muscle. The whole trajectory of the writing movements was coded in turn by the activity of Ia afferents arising from all the muscles acting on the joint. Both single afferent responses and population responses were found to be highly specific and reproducible with each graphic sign. The complex multi-muscle afferent pattern involved, with its timing and distribution in the muscle space, seems to constitute a true proprioceptive signature for each graphic symbol. The ensemble of muscle spindle afferents were therefore found to encode the instantaneous direction and velocity of writing movements remarkably accurately. It was concluded that the proprioceptive feedback from all the muscles with which the moving joint is equipped provides the CNS with highly specific information that might contribute to a graphic sign identification process.This work was supported by grants from the Ministère de la Recherche, ACI Cognitique     

Are there naturally occurring pleomorphic bacteria in the blood of healthy humans?

Dark-field microscopy of blood from healthy individuals revealed the existence of pleomorphic microorganisms. These bacteria exhibited limited growth and susceptibility to antibiotics and could be detected by fluorescent in situ hybridization and flow cytometry. They were further characterized by analysis of their 16S rRNA and gyrB genes.     

Involvement of muscarinic cholinergic and α2-adrenergic mechanisms in growth hormone secretion during exercise in humans

The purpose of this study was to examine the role of muscarinic cholinergic and α₂-adrenergic mechanisms in growth hormone (GH) secretion during exercise in humans. The GH responses induced during moderate-intensity exercise (using a cycle ergometer at 60% maximal oxygen uptake, V˙O_2max, for 30 min) without treatment (control) and after the administration of a muscarinic cholinergic antagonist (atropine 1 mg) or after an α₂-adrenergic antagonist (yohimbine 15 mg) were compared in seven healthy men. Although, serum GH concentration had increased significantly after exercise in the control experiment [mean peak GH concentration 52.64 (SEM 18.60) ng · ml⁻¹], the increase was suppressed by the administration of either atropine [mean peak GH concentration 8.64 (SEM 7.47)  ng · ml⁻¹] or yohimbine [mean peak GH concentration 17.50 (SEM 7.89) ng · ml⁻¹]. The area under the curve of serum GH concentration against time was significantly lower in the experiment using these drugs [with atropine, mean area 458 (SEM 409) ng · ml⁻¹ · min], with yohimbine mean area 946 (SEM 435) ng · ml⁻¹ · min] than in the control experiment [mean area 3135 (SEM 1098) ng · ml⁻¹ · min]. These results suggest that muscarinic cholinergic and α₂-adrenergic mechanisms are involved in GH secretion during exercise in humans. Accepted: 9 March 2000     

Exercise-induced changes in circulating levels of transforming growth factor-β-1 in humans: methodological considerations

Mechanical loading of cells induces the expression of transforming growth factor-beta-1, and acute exercise, which involves mechanical loading of several tissues, could thus increase its circulating level in humans. However, no consensus exists regarding the plasma concentration of this cytokine in resting subjects (reported values range from 500 to 18,300 pg ml(-1)) and also the extent of intra-individual variation is unknown. As a basis for detecting exercise-induced changes in transforming growth factor-beta-1, we measured its concentration, by enzyme-linked immunosorbent assay, in plasma from eight healthy resting subjects. Plasma was sampled from each subject on five successive days according to a procedure designed to minimize activation of platelets, as platelet alpha-granules contain large amounts of transforming growth factor-beta-1. The mean plasma level was relatively low [1155 (30) pg ml(-1), mean (SE)], and did not differ between days, indicating that platelet activation was minimal. Several alterations in the blood sampling procedure did not affect results, while a 40% increase was seen when blood was not cooled appropriately prior to centrifugation. A moderate intra-individual variation (average CV=9.8%) indicated a stable plasma level at rest. In response to exercise (1 h of treadmill running) the plasma concentration of transforming growth factor-beta-1 increased from 992 (49) pg ml(-1) (at rest) to 1301 (39) pg ml(-1) (post exercise) ( P<0.05) ( n=6). In conclusion, the resting plasma level of transforming growth factor-beta-1 was stable over time when blood samples were treated appropriately. Exercise increased the plasma concentration, perhaps indicating a release from mechanically loaded tissues.     

Mastoid: a vestigial function in humans?

At the present time, the function of the mastoid remains unknown. One of the main hypotheses accredited in the literature interprets the mastoid as a pressure buffer. Other theories underline the role of the mastoid mucosa in pressure regulation by transmucosal gas exchanges. The question is what advantage does air reabsorption and the creation of a certain degree of negative pressure that mastoid seems to produce, bring to the middle ear and hearing? In the authors’ opinion, it is possible that the mastoid, or, in general, every kind of mucosa contained in the middle ear of mammals, would act to create a quite constant, although slight, negative pressure to obtain favorable compliance and impedance conditions in the middle ear to hear and transmit high frequency sounds and ultrasounds. The Eustachian tube, in this perspective, would compensate excessive values of negative pressure. Clearly, that function of mastoid pneumatization in humans would have lost its role, due to the absence of a sensorineural system to analyse ultrasounds.     

Wiskott–Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans

Wiskott–Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott–Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21^low B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells.In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients.     

Is somnambulism a distinct disorder of humans and not seen in non-human primates?

Though somnambulism (sleepwalking) is a well-recognized sleep disorder in humans, a biomedical literature search in Medline and Primate Literature bibliographic databases showed no publications on sleepwalking in non-human primates. From this finding, two inferences can be made. First is that somnambulism may be present in non-human primates; but due to limitations in expertise and methodological resources as well as narrow focus of research interest, until now researchers have not detected it in wild and/or captive conditions. Second, somnambulism does not exist in non-human primates including apes (chimpanzee, gorilla, orang-utan and gibbon); and thus, it is a unique behavioral disorder present only in humans. It is premature to conclude which of these two inferences is correct. In Jane Goodall's view, sleepwalking behavior is absent in chimpanzees. If further field observations can confirm Goodall's assertion that somnambulism is indeed absent in chimpanzees, it will be of evolutionary and medical interest to know why this parasomnic behavior became established in humans during the past 5.5 million years or so.