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PubMed2005

Somatodendritic autoreceptor regulation of serotonergic neurons: dependence on L-tryptophan and tryptophan hydroxylase-activating kinases.

The somatodendritic 5-HT(1A) autoreceptor has been considered a major determinant of the output of the serotonin (5-HT) neuronal system. However, recent studies in brain slices from the dorsal raphe nucleus have questioned the relevance of 5-HT autoinhibition under physiological conditions. In the present study, we found that the difficulty in demonstrating 5-HT tonic autoinhibition in slice results from in vitro conditions that are unfavorable for sustaining 5-HT synthesis. Robust, tonic 5-HT(1A) autoinhibition can be restored by reinstating in vivo 5-HT synthesizing conditions with the initial 5-HT precursor l-tryptophan and the tryptophan hydroxylase co-factor tetrahydrobiopterin (BH(4)). The presence of tonic autoinhibition under these conditions was revealed by the disinhibitory effect of a low concentration of the 5-HT(1A) antagonist WAY 100635. Neurons showing an autoinhibitory response to L-tryptophan were confirmed immunohistochemically to be serotonergic. Once conditions for tonic autoinhibition had been established in raphe slice, we were able to show that 5-HT autoinhibition is critically regulated by the tryptophan hydroxylase-activating kinases calcium/calmodulin protein kinase II (CaMKII) and protein kinase A (PKA). In addition, at physiological concentrations of L-tryptophan, there was an augmentation of 5-HT(1A) receptor-mediated autoinhibition when the firing of 5-HT cells activated with increasing concentrations of the alpha(1) adrenoceptor agonist phenylephrine. Increased calcium influx at higher firing rates, by activating tryptophan hydroxylase via CaMKII and PKA, can work together with tryptophan to enhance negative feedback control of the output of the serotonergic system.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1997

Blind persons navigate in virtual reality (VR); hearing and feeling communicates "reality".

Can Virtual Reality (VR) developments in audio navigation for blind persons support therapies for all? Working with Crystal River Engineering we are developing navigable Virtual Reality worlds for blind users, using spatialized audio [1], [2]. All persons, however, use specialized channels, such as: visual, aural, and kinetic learning senses. Predominantly visual VR worlds and health informatics models from World Wide Webs, may be downloaded, tailored, augmented, and delivered to each of these learning senses using VR. We are also testing a proof of concept system with Boston Dynamics which downloads 3-dimensional, satellite-derived map models from the World Wide Web, and makes them navigable by "feeling" the terrain using haptic (tactual or force feedback to your hand) robotic interfaces. Ultimately, these multi-sensory VR access methods: sight, localization by audio, and "feeling" of data sets could open up the World Wide Web to individuals with sight impairments. This could also, however, benefit government, businesses, universities, and (elementary) education. It could contribute more powerful communications, education, and medical simulation applications on the World Wide Web. This work is part of government technology transfer to telemedicine, (elementary) education, disabilities access to the Web, and new Internet access and productivity efforts under Vice President Gore's National Performance Review.

Adult↗

PubMed2001

An enabling system for echocardiography providing adaptive support through behavioral analysis.

Echocardiography requires the integrated application of a broad spectrum of cognitive and practical skills, e.g. diagnostic knowledge (symbolic), image interpretation (visual perception) and handling of the ultrasound probe (sensorimotor). This complex expertise is acquired through extensive practical training guided by a skilled cardiologist that is often incompatible with clinical reality. Especially for beginners, the most critical point during an echocardiographic examination is the steering of the ultrasound probe to navigate between different cardiological standard planes (sensorimotor skill) without loosing orientation. These transitions or "standard trajectories" can roughly be described by specific movement patterns. We propose an enabling system based on an Augmented Reality simulator for two-dimensional echocardiography imitating this apprenticeship [1]-[3]. During a simulated ultrasound examination the system monitors the activities of the trainee and analyzes the motion pattern of the ultrasound probe. The simulator reacts by mapping the motion patterns onto cognitive orientation demands and providing adaptive feedback in the form of context sensitive help (animations). It partly takes the role of the critical teacher.

Computer-Assisted Instruction↗

PubMed2001

Stage-specific differential activation of mitogen-activated protein kinases in hypertrophied and failing rat hearts.

Mitogen-activated protein kinases (MAPKs) are involved in the early development of cardiac hypertrophy, but their roles in chronic left ventricular hypertrophy (LVH) are unclear. We studied the angiotensin (Ang) II-induced cardiac MAPK activation of the hypertensive Dahl salt-sensitive (DS) rats in the subacute developing LVH stage, the chronic compensated LVH stage, and the congestive heart failure (CHF) stage. In the isolated, coronary-perfused heart preparation, Ang II infusion (1x10(-6)mol/l) activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38-MAPK in the LV myocardium. No substantial differences were observed in the Ang II-induced ERK activation between the normotensive control DS rats and the hypertensive DS rats in either stage. In contrast, the Ang II-induced activation of JNK and p38-MAPK was augmented in the subacute LVH stage of the hypertensive DS rats, but then progressively attenuated in the chronic LVH and CHF stages. Chronic treatment with an angiotensin converting enzyme inhibitor, temocapril (20 mg/kg/day), ameliorated the responsiveness of the JNK/p38-MAPK activation, suggesting that the decreased JNK/p38-MAPK activation is a consequence of negative feedback regulation for the activated cardiac renin-angiotensin system in chronic LVH and CHF. Thus, the Ang II-induced activation of multiple cardiac MAPK pathways are differentially regulated, depending on the stages of chronic hypertrophic process. The JNK and p38-MAPK activation may be involved in the early development of adaptive LVH. However, the responsiveness of the cardiac JNK/p38-MAPK pathways progressively decreased in chronic LVH and CHF under the chronic activation of tissue renin-angiotensin system.

Angiotensin II↗

PubMed2006

A reexamination of the size-weight illusion induced by visual size cues.

The size-weight illusion induced by visually perceived sizes was reexamined to investigate whether this illusion is a sensory based or cognitive-based phenomenon. A computer-augmented environment was utilized to manipulate visual size information of target objects independently of their haptic information. Two physical cubes of equal mass (30.0 g) and size (3.0 x 3.0 x 3.0 cm) were suspended in parallel by wires attached to small graspable rings, in order to keep haptically obtained information constant between lifts. Instead of directly seeing each physical cube, subjects viewed 3D graphics of a cube with a wire and a ring that were precisely superimposed onto each physical cube. Seventeen subjects vertically lifted these augmented cubes, one after the other, by grasping the attached rings, and then reported their perception of cube heaviness. The graphical size of a comparison cube pseudo randomly varied for every comparison from 1.0 x 1.0 x 1.0 to 9.0 x 9.0 x 9.0 cm, while that of a standard cube remained constant (5.0 x 5.0 x 5.0 cm). Results indicated that the size-weight illusion frequently and systematically occurred for all the subjects such that when the comparison cube was relatively smaller than the standard cube, it was perceived to be heavier, and vice versa. As the size difference increased between the standard cube and the comparison cube, more subjects experienced the illusion, and vice versa. Follow-up tests showed occurrence of the size-weight illusion was significantly correlated with subject's sensitivity to discriminate weight, but not with sensitivity to discriminate visual size. Results suggest that the size-weight illusion induced by only visual size cues in an augmented environment is sensory based, and depends on an individual's integrated perception based on multimodal sensory information.

Adult↗

PubMed1985

Pedagogic applications of a computerized data base.

The educational experience of medical students taking a 6-week clerkship in consultation psychiatry was augmented by clinical simulations. Using a microcomputer program and a video-display terminal the students are confronted with an actual case and asked to make specific recommendations. The program records their answers and then indicates what the consultant actually did. This method broadens the student's clinical exposure, provides prompt feedback, frees staff to supervise live patient contact, and offers the possibility of sharing clinical problems with other centers.

Aged↗

PubMed1989

Somatostatin release from isolated ganglia of the myenteric plexus.

Somatostatin neurons of the myenteric plexus project caudad exclusively within the plexus synapsing with neurons in the same or other ganglia. Isolated ganglia offer a unique opportunity to examine peptide transmitter release from these interneurons. Ganglia were isolated from the myenteric plexus by sequential enzymatic digestion, centrifugation, and filtration. Single ganglia were harvested by suction and dispersed in polyacrylamide gel. The ganglia were placed in chambers (200 ganglia/chamber) and perfused with Krebs medium at the rate of 1 ml/min. Addition of the nicotinic agonist, dimethylphenylpiperazinium (DMPP), caused a concomitant increase in somatostatin (152%; P less than 0.001) and vasoactive intestinal peptide (VIP) (79%; P less than 0.05) release above basal level that was abolished by hexamethonium. Addition of the VIP antagonist, VIP-(10-28), (5 microM), to the perfusate augmented significantly DMPP-induced somatostatin release (440%; P less than 0.05), implying that the concomitant release of VIP attenuates somatostatin release. Addition of VIP (1 microM) to the perfusate abolished somatostatin release, confirming the ability of VIP to inhibit somatostatin release. The study shows that VIP interneurons exert a regulatory feedback control over somatostatin interneurons in the myenteric plexus.

Animals↗

PubMed1978

Regulation of delayed-type hypersensitivity reactions by cyclophosphamide-sensitive T cells.

The onset, intensity, and duration of DTH reactions elicited in mice immunized with either SRBC or products of the major histocompatibility complex can be altered significantly by pretreatment with CY 1 to 2 days before immunization. Such drug pretreatment tends to augment low DTH responses caused by the use of too much antigen and to diminish many responses that are optimal. Thus, pretreatment with CY does not specifically eliminate suppressor cells. Our results are most consistent with the notion that the cellular targets of low doses of CY are positive and negative feedback regulatory cells, which may consist of one population with two effects or, more likely, two distinct cell populations.

Animals↗

PubMed1998

Enhanced B-1 cell development, but impaired IgG antibody responses in mice deficient in secreted IgM.

The role of endogenous natural IgM in promoting the adaptive Ab response was investigated in newly constructed mutant mice in which B cells do not secrete IgM but still express surface IgM and IgD and undergo class switching to express other Ig isotypes. While the mutant mice had relatively normal numbers of conventional B (B-2) cells in all tissues examined, unexpectedly, B-1 cells in the peritoneum and spleen were approximately threefold more abundant. The elevated levels of B-1 cells were already detectable at 4 wk of age and were stably maintained throughout life. The levels of serum IgG2a, IgG3, and IgA were also elevated in the mutant mice at an early age. IgG2a response to a T cell-independent Ag was augmented, whereas IgG Ab responses to suboptimal doses of a T cell-dependent Ag were impaired. The latter defect was associated with fewer splenic germinal centers, impaired Ab affinity maturation, and less Ag trapping on follicular dendritic cells. Together, these findings demonstrate a physiologic role of natural IgM in the feedback regulation of B-1 cell development, the regulation of IgG2a production, and the promotion of efficient B-2 cell Ab responses.

Animals↗

PubMed1997

Oestradiol feedback stimulation of androgen biosynthesis by human theca cells.

This study analysed the effect of oestradiol on basal and LH-stimulated production of androstenedione and progesterone by human theca cells in monolayer culture. Incubations were carried out for either 2 days (seven experiments) or 4 days (four experiments), in the presence or absence of luteinizing hormone (LH), oestradiol (10(-9)-10(-6) M) or inhibin. Medium collected at 48 and 96 h was stored until radioimmunoassay for steroid content. Theca pooled from small follicles (<10 mm) was used in all but two experiments; in these, ovaries were obtained from ovulatory women in the mid-follicular phase of their cycle and theca from small and large follicles was pooled. Oestradiol inhibited progesterone production in a dose-dependent manner in all experiments, irrespective of follicle size, ovulatory status and ovarian morphology, with maximum effect at 10(-6) M. At this dose, oestradiol had no effect on androstenedione production by theca from four anovulatory women with polycystic ovaries but produced a significant augmentation of both basal and LH-stimulated androstenedione production in theca from five of the seven ovulatory women, with maximal response in theca from the two pre-ovulatory subjects. During the 48-96 h period of incubation, oestradiol augmented androstenedione production in all four experiments and had a greater stimulatory effect than the physiological dose of inhibin (10 ng/ml). This is the first report of oestradiol regulating human theca cell steroidogenesis in a dose-dependent manner.

Adult↗

PubMed1997

Estrogen and testosterone, but not a nonaromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement.

Activation of the gonadotropic and somatotropic axes in puberty is marked by striking amplification of pulsatile neurohormone secretion. In addition, each axis, as a whole, constitutes a regulated network whose feedback relationships are likely to manifest important changes at the time of puberty. Here, we use the regularity statistic, approximate entropy (ApEn), to assess feedback activity within the somatotropic (hypothalamo-pituitary/GH-insulin-like growth factor I) axis indirectly. To this end, we studied pubertal boys and prepubertal girls or boys with sex-steroid hormone deficiency treated short-term with estrogen, testosterone, or a nonaromatizable androgen in a total of 3 paradigms. First, our cross-sectional analysis of 53 boys at various stages of puberty or young adulthood revealed that mean ApEn, taken as a measure of feedback complexity, of 24-h serum GH concentration profiles is maximal in pre- and mid-late puberty, followed by a significant decline in postpubertal adolescence and young adulthood (P = 0.0008 by ANOVA). This indicates that marked disorderliness of the GH release process occurs in mid-late puberty at or near the time of peak growth velocity, with a return to maximal orderliness thereafter at reproductive maturity. Second, oral administration of ethinyl estradiol for 5 weeks to 7 prepubertal girls with Turner's syndrome also augmented ApEn significantly (P = 0.018), thus showing that estrogen per se can induce greater irregularity of GH secretion. Third, in 5 boys with constitutionally delayed puberty, im testosterone administration also significantly increased ApEn of 24-h GH time series (P = 0.0045). In counterpoint, 5 alpha-dihydrotestosterone, a nonaromatizable androgen, failed to produce a significant ApEn increase (P > 0.43). We conclude from these three distinct experimental contexts that aromatization of testosterone to estrogen in boys, or estrogen itself in girls, is likely the proximate sex-steroid stimulus amplifying secretory activity of the GH axis in puberty. In addition, based on inferences derived from mathematical models that mechanistically link increased disorderliness (higher ApEn) to network changes, we suggest that sex-steroid hormones in normal puberty modulate feedback within, and hence network function of, the hypothalamo-pituitary/GH-insulin-like growth factor I axis.

Adolescent↗

PubMed2002

Feedback control of the ATP-sensitive K(+) current by cytosolic Ca(2+) contributes to oscillations of the membrane potential in pancreatic beta-cells.

During glucose stimulation, pancreatic beta-cells display membrane potential oscillations that correspond to intermittent Ca(2+) influx, leading to oscillations of the cytosolic free calcium concentration ([Ca(2+)](c)) and insulin secretion. The role of ATP-sensitive K(+) (K(+)-ATP) channels in the control of these oscillations was investigated by measuring the K(+)-ATP current (I(KATP)) with the perforated mode of the patch-clamp technique. No oscillations of I(KATP) were observed when glucose-stimulated beta-cells were kept hyperpolarized, thus with low and stable [Ca(2+)](c). However, increasing [Ca(2+)](c) by Ca(2+) influx (depolarizing pulses) or Ca(2+) mobilization (acetylcholine) transiently augmented I(KATP). This effect was abolished by tolbutamide, attenuated by increasing the glucose concentration in the medium, and prevented by abrogation of the [Ca(2+)](c) rise, which demonstrates that the current is really I(KATP) and that its increase is Ca(2+)-dependent. Injection of a current of a similar amplitude to that of the Ca(2+)-induced increase in I(KATP) was sufficient to repolarize glucose-stimulated beta-cells. These results suggest that, in the absence of [Ca(2+)](c) oscillations, no metabolic oscillations affect I(KATP) in pancreatic beta-cells. In contrast, [Ca(2+)](c) oscillations evoke I(KATP) oscillations. This mechanism may constitute the feedback loop controlling the glucose-induced oscillating electrical activity in beta-cells.

Adenosine Triphosphate↗

PubMed1995

Bombesin and [Leu8]phyllolitorin promote fetal mouse lung branching morphogenesis via a receptor-mediated mechanism.

Pulmonary neuroendocrine cells are localized predominantly at airway branchpoints. Previous work showed that gastrin-releasing peptide (GRP), a major pulmonary bombesin-like peptide, occurred in neuroendocrine cells exclusively in branching human fetal airways. We now demonstrate that GRP and GRP receptor genes are expressed in fetal mouse lung as early as embryonic day 12 (E12), when lung buds are beginning to branch. By in situ hybridization, GRP receptor transcripts were at highest levels in mesenchymal cells at cleft regions of branching airways and blood vessels. To explore the possibility that bombesin-like peptides might play a role in branching morphogenesis, E12 lung buds were cultured for 48 hr in serum-free medium. In the presence of 0.10-10 microM bombesin, branching was significantly augmented as compared with control cultures, with a peak of 94% above control values at 1 microM (P < 0.005). The bombesin receptor antagonist [Leu13- psi(CH2NH)Leu14]bombesin alone (100 nM) had no effect on baseline branching but completely abolished bombesin-induced branching. A bombesin-related peptide, [Leu8]phyllolitorin also increased branching (65% above control values at 10 nM, P < 0.005). [Leu8]Phyllolitorin also significantly augmented thymidine incorporation in cultured lung buds. Fibronectin, which is abundant at branchpoints, induces GRP gene expression in undifferentiated cell lines. These observations suggest that BLPs secreted by pulmonary neuroendocrine cells may contribute to lung branching morphogenesis. Furthermore, components of branchpoints may induce pulmonary neuroendocrine cell differentiation as part of a positive feedback loop, which could account in part for the high prevalence of these cells at branchpoints.

Animals↗

PubMed1999

Tactical audio and acoustic rendering in biomedical applications.

Complexity of biomedical data requires novel sophisticated analysis and presentation methods. Sonification is used as a new information display in augmented reality systems to overcome problems of existing human-computer interface (e.g., opaque or heavy head-mounted displays, slow computer graphics, etc.). A novel taxonomy of sonification methods and techniques is introduced. We present our experience with tactical audio and acoustic rendering in biomedical applications. Tactical audio as an audio feedback is used as support for precise manual positioning of a surgical instrument in the operating room. Acoustic rendering is applied as an additional information channel and/or warning signal in biomedical signal analysis and data presentation.

Acoustics↗

PubMed2005

The Telemedicine Information Exchange: 10 years' experience.

The Telemedicine Information Exchange (TIE) Website has provided information on telemedicine since 1995. The site could be considered successful from its longevity alone; however, it can also be considered a success using other measures. The usage of the site has grown steadily over the years, to more than 20,000 visitors per month by 2005. The Bibliographic database has over 16,000 telemedicine-related citations, more than found anywhere else, and is the most visited section of the Website. The second most visited database, Active Telemedicine Programs, is the result of 10 years of tracking activity and growth using a voluntary online survey. This continuous monitoring of telemedicine literature and activity has allowed TIE research staff to anticipate user needs and interests. For instance, a Home Telehealth section was initiated after it became apparent that interest in the subject was increasing. Longevity also provides a perspective about the best ways of maintaining a content-heavy online resource. Efforts to augment federal funding (the TIE's sole source of support) by selling packaged information products have taught us that online users will not pay for information. Our raison d'être for the past 10 years has been the provision of credible, up-to-date information, and our reward has been positive feedback from thousands of TIE users.

Communication↗

PubMed1991

Reflex activities of the upper airway muscles during experimental nasal occlusion in anesthetized dogs.

Reflex responses of the upper airway muscles during experimental nasal and tracheal occlusions were studied in 21 anesthetized dogs breathing through the nose or a tracheostomy (tracheal cannula). Out of them, five animals were examined for maintained negative and positive pressures applied to the isolated upper airway. When the nose was occluded at end-expiration during three consecutive breathings, the electromyographic (EMG) activity of alae nasi (AN) and posterior cricoarytenoid (PCA) muscle markedly increased. The upper airway was subjected to negative pressure, -2.41 approximately -3.04 kPa (n = 34) by these nasal occlusions. The activity of upper airway muscles was also increased by tracheal occlusions. However, such augmentation of PCA activity was much less in tracheal occlusions than nasal occlusions, whereas there was the smaller difference in AN activity between both occlusions. During nasal occlusions, a prolongation of the inspiratory time (TI) was observed. Furthermore, maintained negative pressure applied to the isolated upper airway provoked an augmentation of PCA activity. Such an augmented EMG activity of PCA and the prolongation of TI were largely diminished by sectioning the superior laryngeal nerves. These results proves that the upper airway muscles play an important role to protect the upper airway from collapsing by nasal occlusions. In addition, it is suggested that a lack of lung volume feedback is substantially concerned with the activation of AN, while negative pressure in the upper airway is essential to stimulate PCA.

Airway Obstruction↗

PubMed1995

Building a hybrid patient's model for augmented reality in surgery: a registration problem.

In the field of Augmented Reality in Surgery, building a hybrid patient's model, i.e. merging all the data and systems available for a given application, is a difficult but crucial technical problem. The purpose is to merge all the data that constitute the patient model with the reality of the surgery, i.e. the surgical tools and feedback devices. In this paper, we first develop this concept, we show that this construction comes to a problem of registration between various sensor data, and we detail a general framework of registration. The state of the art in this domain is presented. Finally, we show results that we have obtained using a method which is based on the use of anatomical reference surfaces. We show that in many clinical cases, registration is only possible through the use of internal patient structures.

Algorithms↗

PubMed2005

SOD2 overexpression: enhanced mitochondrial tolerance but absence of effect on UCP activity.

We have created P1 artificial chromosome transgenic mice expressing the human mitochondrial superoxide dismutase 2 (SOD2) and thus generated mice with a physiologically controlled augmentation of SOD2 expression leading to increased SOD2 enzyme activities and lowered superoxide levels. In the transgenic mice, effects on mitochondrial function such as enhanced oxidative capacity and greater resistance against inducers of mitochondrial permeability were observed. Superoxide in the mitochondrial matrix has been proposed to activate uncoupling proteins (UCPs), thus providing a feedback mechanism that will lower respiratory chain superoxide production by increasing a proton leak across the inner mitochondrial membrane. However, UCP1 and UCP3 activities and mitochondrial ATP production rates were not altered in isolated mitochondria from SOD2 transgenic mice, despite lowered superoxide levels. Globally, the transgenic mice displayed normal resting metabolic rates, indicating an absence of effect on any UCP activities, and normal oxygen consumption responses after norepinephrine injection. These results strongly suggest that endogenously generated matrix superoxide does not regulate UCP activity and in vivo energy expenditure.

Animals↗