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PubMed2004

Communication training for health professionals who care for patients with cancer: a systematic review of training methods.

BACKGROUND: Effective communication is increasingly recognised as a core clinical skill. Many health and social care professionals, however, do not feel adequately trained in communicating and in handling interpersonal issues that arise in the care of patients with cancer. AIM: The aim of this paper was to assess the effectiveness of different training methods used in communication training courses for health professionals. METHOD: We searched six computerised databases and augmented this with follow-up of references and grey (unpublished) literature. We included all studies evaluating communication training and assessed methodological quality according to the standard grading system of the Clinical Outcomes Group. Data on author, year, setting, objectives, study design and training methods were extracted and compared in tabular format. RESULTS: A total of 47 studies potentially assessing communication training were identified. Sixteen papers were included evaluating 13 interventions. Four were randomised controlled trials (RCTs) (grade a); the others were grade III. Eleven interventions trained health professionals; two trained medical students. Interventions for training in communication skills were characterised by the variety of communication approaches used and a diversity of methods. They were applied to health professionals with very different roles, served different purposes and evaluated a variety of outcome measures: behavioural assessments, patient outcomes and professionals' self-report. CONCLUSIONS: The best results are to be expected from a training programme that is carried out over a longer period of time. Learner-centred programmes using several methods combining a didactic component focusing on theoretical knowledge with practical rehearsal and constructive feedback from peers and skilled facilitators proved to be very effective. Small groups encouraged more intensive participation. Training in communication for both medical or nursing students and senior health professionals is advisable.

Communication↗

PubMed1998

A study of auditory afferent organization in children with dyslalia.

The auditory afferent (AA) control is an important feedback mechanism in the speech generation. A different organization of AA pathways in children with speech alterations is suggested. In order to investigate this possibility we recorded the auditory brainstem responses (ABR) and middle latency responses (MLR) on monoaural and binaural click stimulation in a group of 17 normal children with no alteration of the speech (N) and in 16 children with dyslalia (eight with systematic (S) and eight with non-systematic errors of the speech (NS)). All of children were normal hearing, with normal ORL and neurological status, right-handed and with the age approximately 7 years old. A lateralization effect was found in the S group. Normally, it was only found for wave I. The efficiency of both AA pathways was the same in NS group, indicating a more effective right pathway in more rostral areas. A prolonged latency (X = 0.25 ms) of wave III was registered on the right side in the NS group compared to normals, as well for wave V (X = 0.175 ms) with increased sweep rate (21 vs. 51 and 71). The effect of sweep rate augmentation was also studied (21-51-71) on latency values and inter-wave differences in these groups. A successive latency prolongation (X = 2.97 ms) of MLR wave Na was registered between the N-S-NS groups. In the S group a latency binaural interaction (BI) of MLR left wave Na was prolonged for 3.52 ms and in the NS group for a further 1.32 ms compared to normals. Only in the NS group was a prolongation of the BI of the right wave Pa detected (6.76 ms) compared to normals. Results suggest a different AA organization in children with dyslalia. Possible locations of alterations in functioning could be pons, and thalamocortical projections. ABR and MLR could evaluate the auditory-speech capability of children.

Auditory Pathways↗

PubMed1999

How muscles deal with real-world loads: the influence of length trajectory on muscle performance.

The performance of skeletal muscles in vivo is determined by the feedback received when the muscle interacts with the external environment via various morphological structures. This interaction between the muscle and the 'real-world load' forces us to reconsider how muscles are adapted to suit their in vivo function. We must consider the co-evolution of the muscles and the morphological structures that 'create' the load in concert with the properties of the external environment. This complex set of interactions may limit muscle performance acutely and may also constrain the evolution of morphology and physiology. The performance of skeletal muscle is determined by the length trajectory during movement and the pattern of stimulation. Important features of the length trajectory include its amplitude, frequency, starting length and shape (velocity profile). Many of these parameters interact. For example, changing the velocity profile during shortening may change the optimum values of the other parameters. The length trajectory that maximizes performance depends on the task to be performed. During cyclical work, muscles benefit from using asymmetric cycles with longer shortening than lengthening phases. Modifying this 'sawtooth' cycle by increasing the velocity during shortening may further increase power by augmenting force output and speeding deactivation. In contrast, when accelerating an inertial load, as in jumping, the predicted 'optimal' velocity profile has two peak values, one early and one late in shortening. During level running at constant speed, muscles perform tasks other than producing work and power. Producing force to support the body weight is performed with nearly isometric contractions in some of the limb muscles of vertebrates. Muscles also play a key role in producing stability during running, and the intrinsic properties of the musculoskeletal system may be particularly important in stabilizing rapid running. Recently, muscles in running invertebrates and vertebrates have been described that routinely absorb large amounts of work during running. These muscles are hypothesized to play a key role in stability.

Animals↗

PubMed1987

Effect of Sar1-Ileu8-angiotensin on renal prostaglandin E2 biosynthesis and excretion.

To test the hypothesis that renal prostaglandin (PG) biosynthesis is regulated by angiotensin (AII), rabbits were given prolonged treatment with the AII analogue, Sar1-Ileu8AII (200 micrograms/kg/4 hr, subcutaneously), for 2 days during a low, normal, and high sodium intake. Sodium restriction augmented plasma renin activity (PRA), which was associated with a rise in basal renal PGE2 synthesis and urinary excretion, whereas sodium supplementation attenuated PRA with a decrease in renal PGE2 synthesis and urinary excretion. Sar1-Ileu8AII administration, with either a low, normal, or high salt intake, suppressed PRA. Sar1-Ileu8AII injection with a low sodium intake also suppressed renal PGE2 synthesis and excretion that was associated with a fall in blood pressure, suggesting an antagonistic action of this agent on vascular beds and renal PGE2 synthesis. On the other hand, with a high sodium intake Sar1-Ileu8-AII increased renal PGE2 synthesis and excretion as well as blood pressure, revealing an agonistic action of this compound under these conditions. The results suggest that exogenous AII analogue may act as an antagonist or agonist depending on sodium intake and endogenous AII levels, renal PGE2 synthesis is dependent on AII levels, either endogenously produced or exogenously administered (as an AII agonist), and the action of AII analogue on vascular beds and renal PGE2 synthesis does not appear to parallel its action on renin-AII feedback regulation at the juxtaglomerular cell especially under conditions of high sodium intake.

1-Sarcosine-8-Isoleucine Angiotensin II↗

PubMed2005

Involvement of glutamate receptors of the NMDA type in the modulation of acetylcholine and glutamate overflow from the guinea pig ileum during in vitro hypoxia and hypoglycaemia.

The involvement of NMDA glutamate receptors in the effects of glucose/oxygen deprivation (in vitro ischaemia) on spontaneous endogenous acetylcholine and glutamate overflow from the guinea pig ileum was studied. Neurotransmitter overflow was measured by HPLC. Deprivation of glucose in the medium slightly reduced acetylcholine overflow, and did not significantly influence glutamate overflow. During oxygen deprivation and glucose/oxygen deprivation, acetylcholine overflow augmented with a biphasic modality: an early peak was followed by a long lasting increase, whereas glutamate overflow increased with a rapid and sustained modality. The effects of glucose/oxygen deprivation on both acetylcholine and glutamate overflow were abolished after reperfusion with normal oxygenated medium. Acetylcholine and glutamate overflow induced by glucose/oxygen deprivation were significantly reduced in the absence of external Ca(2+) as well as by the addition of the mitochondrial Na(+)-Ca(2+) exchanger blocker, CGP 37157, and of the endoplasmic reticulum Ca(2+)/ATPase blocker, thapsigargin. +/-AP5, an NMDA receptor antagonist, and 5,7-diCl-kynurenic acid, an antagonist of the glycine site associated to NMDA receptor, markedly depressed glucose/oxygen deprivation-induced acetylcholine and glutamate overflow as well. Our results suggest that in vitro simulated ischaemia evokes acetylcholine and glutamate overflow from the guinea pig ileum, which is partly linked to an increase in intracellular Ca(2+) concentration dependent on both Ca(2+) influx from the extracellular space and Ca(2+) mobilization from the endoplasmic reticulum and mitochondrial stores. During glucose/oxygen deprivation, ionotropic glutamate receptors of the NMDA type exert both a positive feedback modulation of glutamate output and contribute to increased acetylcholine overflow.

Acetylcholine↗

PubMed1998

Angiotensin, thirst, and sodium appetite.

Angiotensin (ANG) II is a powerful and phylogenetically widespread stimulus to thirst and sodium appetite. When it is injected directly into sensitive areas of the brain, it causes an immediate increase in water intake followed by a slower increase in NaCl intake. Drinking is vigorous, highly motivated, and rapidly completed. The amounts of water taken within 15 min or so of injection can exceed what the animal would spontaneously drink in the course of its normal activities over 24 h. The increase in NaCl intake is slower in onset, more persistent, and affected by experience. Increases in circulating ANG II have similar effects on drinking, although these may be partly obscured by accompanying rises in blood pressure. The circumventricular organs, median preoptic nucleus, and tissue surrounding the anteroventral third ventricle in the lamina terminalis (AV3V region) provide the neuroanatomic focus for thirst, sodium appetite, and cardiovascular control, making extensive connections with the hypothalamus, limbic system, and brain stem. The AV3V region is well provided with angiotensinergic nerve endings and angiotensin AT1 receptors, the receptor type responsible for acute responses to ANG II, and it responds vigorously to the dipsogenic action of ANG II. The nucleus tractus solitarius and other structures in the brain stem form part of a negative-feedback system for blood volume control, responding to baroreceptor and volume receptor information from the circulation and sending ascending noradrenergic and other projections to the AV3V region. The subfornical organ, organum vasculosum of the lamina terminalis and area postrema contain ANG II-sensitive receptors that allow circulating ANG II to interact with central nervous structures involved in hypovolemic thirst and sodium appetite and blood pressure control. Angiotensin peptides generated inside the blood-brain barrier may act as conventional neurotransmitters or, in view of the many instances of anatomic separation between sites of production and receptors, they may act as paracrine agents at a distance from their point of release. An attractive speculation is that some are responsible for long-term changes in neuronal organization, especially of sodium appetite. Anatomic mismatches between sites of production and receptors are less evident in limbic and brain stem structures responsible for body fluid homeostasis and blood pressure control. Limbic structures are rich in other neuroactive peptides, some of which have powerful effects on drinking, and they and many of the classical nonpeptide neurotransmitters may interact with ANG II to augment or inhibit drinking behavior. Because ANG II immunoreactivity and binding are so widely distributed in the central nervous system, brain ANG II is unlikely to have a role as circumscribed as that of circulating ANG II. Angiotensin peptides generated from brain precursors may also be involved in functions that have little immediate effect on body fluid homeostasis and blood pressure control, such as cell differentiation, regeneration and remodeling, or learning and memory. Analysis of the mechanisms of increased drinking caused by drugs and experimental procedures that activate the renal renin-angiotensin system, and clinical conditions in which renal renin secretion is increased, have provided evidence that endogenously released renal renin can generate enough circulating ANG II to stimulate drinking. But it is also certain that other mechanisms of thirst and sodium appetite still operate when the effects of circulating ANG II are blocked or absent, although it is not known whether this is also true for angiotensin peptides formed in the brain. Whether ANG II should be regarded primarily as a hormone released in hypovolemia helping to defend the blood volume, a neurotransmitter or paracrine agent with a privileged role in the neural pathways for thirst and sodium appetite of all kinds, a neural organizer especially in sodium appetit

Angiotensin II↗

PubMed2007

Vagal modulation of intestinal afferent sensitivity to systemic LPS in the rat.

The central nervous system modulates inflammation in the gastrointestinal tract via efferent vagal pathways. We hypothesized that these vagal efferents receive synaptic input from vagal afferents, representing an autonomic feedback mechanism. The consequence of this vagovagal reflex for afferent signal generation in response to LPS was examined in the present study. Different modifications of the vagal innervation or sham procedures were performed in anesthetized rats. Extracellular mesenteric afferent nerve discharge and systemic blood pressure were recorded in vivo before and after systemic administration of LPS (6 mg/kg iv). Mesenteric afferent nerve discharge increased dramatically following LPS, which was unchanged when vagal efferent traffic was eliminated by acute vagotomy. In chronically vagotomized animals, to eliminate both vagal afferent and efferent traffic, the increase in afferent firing 3.5 min after LPS was reduced to 3.2 +/- 2.5 impulses/s above baseline compared with 42.2 +/- 2.0 impulses/s in controls (P < 0.001). A similar effect was observed following perivagal capsaicin, which was used to eliminate vagal afferent traffic only. LPS also caused a transient hypotension (<10 min), a partial recovery, and then persistent hypertension that was exacerbated by all three procedures. Mechanosensitivity was increased 15 min following LPS but had recovered at 30 min in all subgroups except for the chronic vagotomy group. In conclusion, discharge in capsaicin-sensitive mesenteric vagal afferents is augmented following systemic LPS. This activity, through a vagovagal pathway, helps to attenuate the effects of septic shock. The persistent hypersensitivity to mechanical stimulation after chronic vagal denervation suggests that the vagus exerts a regulatory influence on spinal afferent sensitization following LPS.

Animals↗

PubMed2005

Transcriptional regulatory functions of heterogeneous nuclear ribonucleoprotein-U and -A/B in endotoxin-mediated macrophage expression of osteopontin.

Osteopontin (OPN) is a highly hydrophilic and negatively charged sialoprotein of approximately 298 amino acids with diverse regulatory functions, including cell adhesion and migration, tumor growth and metastasis, atherosclerosis, aortic valve calcification, and repair of myocardial injury. OPN is unique as an endogenous negative feedback inhibitor of NO expression. However, the specific cis- and trans-regulatory elements that determine the extent of endotoxin (LPS)- and NO-mediated induction of OPN synthesis are unknown. We have previously shown that LPS-induced S-nitrosylation of heterogeneous nuclear ribonucleoprotein (hnRNP)-A/B inhibits its activity as a constitutive trans-repressor of the OPN transcription by significantly decreasing its DNA binding activity. hnRNPs were originally described as chromatin-associated RNA-binding proteins that form complexes with RNA polymerase II transcripts. The hnRNP family is comprised of >20 proteins that contribute to the complex around nascent pre-mRNA and are thus able to modulate RNA processing. In this subsequent study, again using RAW 264.7 murine macrophages and COS-1 cells, we demonstrate that hnRNP-A/B and hnRNP-U proteins serve antagonistic transcriptional regulatory functions for OPN expression in the setting of LPS-stimulated NO synthesis. In the presence of NO, hnRNP-A/B dissociates from its OPN promoter site with subsequent derepression of OPN promoter activity. Subsequently, hnRNP-U binds to the same site to further augment OPN promoter activation. This has not been previously described for the hnRNP proteins. Our results represent a unique transcriptional regulatory mechanism which involves interplay between members of the hnRNP protein family.

Animals↗

PubMed1998

Development and evaluation of a CD-ROM computer program to teach residents telephone management.

OBJECTIVE: Under managed care, telephone management is crucial to pediatric practice, but an effective method is needed to teach residents telephone skills. Our objective was to design an interactive CD-ROM program to teach residents an organized, consistent approach to telephone complaints and to determine whether use of the program was associated with better subsequent telephone management than reading the same information. SETTING: The general pediatric ambulatory center of a tertiary care children's hospital. PARTICIPANTS: A total of 24 PL-2 and PL-3 pediatric residents. DESIGN: A randomized, prospective, controlled comparison was conducted of resident management of two telephone calls: a 5-year-old with cough and trouble breathing, and a 7-year-old with fever. Thirteen residents were randomized to the computer group and 11 to the reading control group. Intervention. Scripts, scoring, and feedback for 10 CD-ROM-simulated calls were developed from texts and pediatrician survey using a modified Delphi technique. Volunteers acted out the caller's role in scenario scripts and were recorded onto a CD-ROM. The computer simulated calls by recognizing questions typed in a free-form format and answering with a voice response. Feedback was provided for omissions in history-taking and errors in assessment, triage, and home management. The computer group worked through the CD-ROM calls while the control group had equal time to read the same information. Evaluation Measures. A trained, standardized patient acted as the mother in pretest calls placed at the beginning of the month and posttest calls at the end. Calls were recorded and scored in a blinded manner using scoring templates and on interpersonal skills using the Patient Perception Questionnaire. RESULTS: Pretest scores for the two calls were similar in the computer versus the control group (cough, 70.33% +/- 8.36 vs 68.46% +/- 6.73; fever, 75.64% +/- 9.82 vs 73.59% +/- 9.06). Posttest scores were significantly higher in the computer group than in the control group on both calls (cough, 79.08% +/- 8.17 vs 69 +/- 13.3; fever: 83.33% +/- 9.96 vs 70.35% +/- 9.66). Interpersonal skills also were similar pretest (19 +/- 3.4 vs 20 +/- 2.7). There was modest improvement in both groups without a statistically significant difference in posttest scores (24.2 +/- 2.9 vs 22.5 +/- 3.1). CONCLUSIONS: Use of this CD-ROM telephone management program was associated with better postintervention telephone management. The program augments faculty instruction by teaching a consistent, general approach to telephone management.

CD-ROM↗

PubMed1992

Pressure-induced activation of membrane K+ current in rat saphenous artery.

Pressurization of isolated arteries may result in Ca(2+)-dependent contraction and membrane depolarization. Because the open state probability of some vascular muscle K+ channels is augmented by rises in cytosolic Ca2+ and membrane depolarization, we investigated the possibility that increases in intraluminal pressure activate K+ channels in isolated, perfused rat saphenous arteries. Stepwise increases in intraluminal pressure from 5 to 205 mm Hg resulted in increasing, active arterial contraction, measured as smaller diameters in physiological salt solution than in Ca(2+)-free solution. Addition of 10 mM tetraethylammonium to the physiological salt solution to block arterial muscle K+ channels caused progressively greater diameter reductions at pressures above 25 mm Hg. Microelectrode measurements of membrane potential showed that tetraethylammonium depolarized arterial muscle more at 105 mm Hg (16 +/- 1 mV) than at 25 mm Hg (10 +/- 1 mV). The sensitivity of K+ current to tetraethylammonium was also demonstrated in patch-clamped vascular muscle cells from the same arteries. Peak whole-cell K+ current was suppressed 47% and 79% by 1 and 10 mM tetraethylammonium, respectively. This same current was enhanced 3.6-fold by the Ca2+ ionophore A23187 (10 microM), suggesting a Ca2+ dependence. We conclude that increases in intraluminal pressure progressively activate tetraethylammonium-sensitive K+ channels in the arterial muscle membrane. This can serve as a negative feedback mechanism to limit pressure-induced arterial constriction.

Animals↗

PubMed2005

Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung.

Preterm neonates with respiratory distress syndrome (RDS) often develop a chronic form of lung disease called bronchopulmonary dysplasia (BPD), characterized by decreased alveolar and vascular development. Ventilator treatment with supraphysiological O2 concentrations (hyperoxia) contribute to the development of BPD. Hyperoxia down-regulates and hypoxia up-regulates many angiogenic factors in the developing lung. We investigated whether angiogenic responses could be augmented through enhancement of hypoxia-inducible factors 1alpha and 2alpha (HIF-1alpha and -2alpha, respectively) via blockade of prolyl hydroxylase domain-containing proteins (HIF-PHDs) in human microvascular endothelial cells from developing and adult lung, in epithelial A549 cells, and in fetal baboon explants in relative or absolute hyperoxia. PHD inhibitor (FG-4095) and positive control dimethyloxaloylglycine (DMOG), selective and nonselective HIF-PHD inhibitors, respectively, enhanced HIF-1alpha and -2alpha, vascular endothelial growth factor (VEGF), and platelet-endothelial cell adhesion molecule 1 expression in vitro in 95% and 21% O2. Furthermore, VEGF receptor fms-like tyrosine kinase 1 (Flt-1) was elevated, whereas kinase insert domain-containing receptor/fetal liver kinase 1 (KDR) was diminished in endothelial, but not epithelial, cells. Intracellular Flt-1 and KDR locations were unchanged by PHD blockade. Like VEGF, FG-4095 and DMOG increased angiogenesis in vitro, both in 95% and 21% O2, an effect that could be blocked through either Flt-1 or KDR. Notably, FG-4095 was effective in stimulating HIFs and VEGF also in fetal baboon lung explants. FG-4095 or DMOG treatment appeared to stimulate the feedback loop promoting HIF degradation in that PHD-2 and/or -3, but not PHD-1, were enhanced. Through actions characterized above, FG-4095 could have desirable effects in enhancing lung growth in BPD.

Amino Acids, Dicarboxylic↗

PubMed2002

Possible role of adenosine in macula densa control of glomerular hemodynamics.

BACKGROUND: The macula densa (MD), a plaque of specialized tubular epithelial cells, senses changes in tubular NaCl concentration and sends a signal(s) that controls the resistance of the glomerular afferent arteriole (Af-Art). This mechanism, called tubuloglomerular feedback (TGF), is thought to be important in the homeostasis of body fluids and electrolytes. Our aim was to determine the range of NaCl concentrations in tubular fluid at the MD that would elicit the Af-Art response. In addition, we examined the possible involvement of adenosine in transmitting the signal from the MD to the Af-Art. METHODS: Rabbit Af-Arts and attached MD were simultaneously microperfused in vitro, keeping pressure in the Af-Art at 60 mm Hg. RESULTS: Increasing the Na+/Cl- concentration of the MD perfusate from 26/7 to 41/22 mEq/L decreased the luminal diameter of the terminal Af-Art segment by 10 +/- 4% (N=9; P < 0.01). The response was maximal at 55/36 mEq/L (18 +/- 6%), so that further elevation of NaCl concentration had no additional effect (20 +/- 6% at 84/65 mEq/L). When FK838 (10(-6) mol/L), a specific adenosine A1 receptor antagonist, was added to both Af-Art perfusate and bath, Af-Art constriction was completely abolished. The maximum response was 20 +/- 3% before FK838 and 0.6 +/- 1% afterward (N=12). Adding adenosine at 10(-8) mol/L to both bath and perfusate significantly augmented Af-Art constriction induced by increased NaCl at the MD (P < 0.01); however, adding 10-8 to 10-6 mol/L adenosine to the MD perfusate had no effect regardless of the NaCl concentration at the MD. CONCLUSIONS: These results demonstrate that MD control of Af-Art resistance is induced by relatively low NaCl concentrations at the MD, and that activation of the adenosine A1 receptor in the vascular and interstitial space (but not the tubular lumen) may be essential for signal transmission from the MD to the Af-Art.

Adenosine↗

PubMed2006

Role of potassium in regulating blood flow and blood pressure.

Unlike sodium, potassium is vasoactive; for example, when infused into the arterial supply of a vascular bed, blood flow increases. The vasodilation results from hyperpolarization of the vascular smooth muscle cell subsequent to potassium stimulation by the ion of the electrogenic Na+-K+ pump and/or activating the inwardly rectifying Kir channels. In the case of skeletal muscle and brain, the increased flow sustains the augmented metabolic needs of the tissues. Potassium ions are also released by the endothelial cells in response to neurohumoral mediators and physical forces (such as shear stress) and contribute to the endothelium-dependent relaxations, being a component of endothelium-derived hyperpolarization factor-mediated responses. Dietary supplementation of potassium can lower blood pressure in normal and some hypertensive patients. Again, in contrast to NaCl restriction, the response to potassium supplementation is slow to appear, taking approximately 4 wk. Such supplementation reduces the need for antihypertensive medication. "Salt-sensitive" hypertension responds particularly well, perhaps, in part, because supplementation with potassium increases the urinary excretion of sodium chloride. Potassium supplementation may even reduce organ system complications (e.g., stroke).

Animals↗

PubMed2002

Cysteinyl leukotrienes and uridine diphosphate induce cytokine generation by human mast cells through an interleukin 4-regulated pathway that is inhibited by leukotriene receptor antagonists.

We previously reported that interleukin (IL)-4 upregulates the expression of leukotriene C(4) synthase (LTC(4)S) by human cord blood--derived mast cells (hMCs), augments their high-affinity Fc receptor for IgE (Fc(epsilon)RI)-dependent generation of eicosanoids and cytokines, and induces a calcium flux in response to cysteinyl leukotrienes (cys-LTs) and uridine diphosphate (UDP) that is blocked by cys-LT receptor antagonists. We speculated that this IL-4-dependent, receptor-mediated response to the cys-LTs and UDP might induce cytokine generation by hMCs without concomitant exocytosis. Unlike hMCs maintained in cytoprotective stem cell factor (SCF) alone, hMCs primed for 5 d with IL-4 responded to UDP (1microM), LTC(4) (100 nM), and LTD(4) (100 nM) by producing IL-5, tumor necrosis factor (TNF)-alpha, and especially large quantities of macrophage inflammatory protein (MIP)-1beta de novo at 6 h, preceded by the induced expression of the corresponding mRNAs. Cys-LT- and UDP-mediated cytokine production by the primed hMCs occurred without histamine release or PGD(2) generation and was inhibited by the CysLT1 receptor antagonist MK571. Additionally, pretreatment of hMCs with MK571 or with the cys-LT biosynthetic inhibitor MK886 decreased IL-5 and TNF-alpha production in response to IgE receptor cross-linkage, implying a positive feedback by endogenously produced cys-LTs. Cys-LTs and UDP thus orchestrate a novel, IL-4-regulated, non-IgE-dependent hMC activation for cytokine gene induction that could be initiated by microbes, cellular injury, or neurogenic or inflammatory signals; and this pathobiologic event would not be recognized in tissue studies where hMC activation is classically defined by exocytosis.

Cysteine↗

PubMed1994

Nocturnal naloxone fails to reverse the suppressive effects of testosterone infusion on luteinizing hormone secretion in pubertal boys.

LH secretion is maximal during the night in pubertal boys, and testosterone (T) administration blunts this nocturnal rise of LH. We have previously shown that in pubertal boys, the acute negative feedback effects of T infusion on LH secretion during the daytime cannot be reversed by opioid receptor blockade. To determine whether the nocturnal secretion of LH in early puberty is regulated by endogenous opioid pathways, we determined whether naloxone during the night affected LH secretion or T-mediated suppression of LH secretion. Seven pubertal boys (bone age, 11-13.5 yr) were given a control infusion of saline, followed 1 week later by an infusion of T at 960 nmol/m2.h for 41 h starting at 2000 h. During both saline and T infusions, six iv boluses of saline were given hourly beginning at 2400 h on the first day, and six iv boluses of naloxone (0.1 mg/kg each) were given hourly beginning at 2400 h on the second day. Starting at 2200 h, blood was obtained every 15 min for LH and every 30 min for T determinations for 14 h each night. Pituitary responsiveness was assessed at the end of each study night by i.v. bolus administration of 250 ng/kg synthetic GnRH. T infusion increased the mean T concentration 6-fold (P < 0.0001) and suppressed the mean plasma LH concentrations from 5.6 +/- 0.6 to 3.8 +/- 0.6 IU/L (P < 0.01). The nocturnal augmentation of LH secretion was suppressed by the infusion of T, and this suppression was not reversed by naloxone. The mean nighttime plasma LH (2400-0600 h) was 8.1 +/- 1.1 IU/L during the control saline infusion and 5.1 +/- 0.6 IU/L during the T infusion (P < 0.01). The mean LH level was 4.0 +/- 0.7 IU/L during the administration of naloxone boluses concomitantly with the T infusion, not significantly different from that during the T infusion. Likewise, LH pulse frequency during the same time period was decreased by T infusion from 0.6 +/- 0.1 to 0.36 +/- 0.04 pulses/boy.h (P < 0.05), and it was unaltered by coadministration of naloxone (0.38 +/- 0.12 pulses/boy.h). Naloxone administration during the saline infusion did not increase either the mean plasma LH concentration (7.5 +/- 0.7 IU/L; P = NS vs. saline control) or the LH pulse frequency (0.69 +/- 0.1 pulses/boy.h; P = NS vs. saline control). Pituitary responsiveness to GnRH was similar on each of the 4 nights during either saline or T infusions.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed2002

Signaling pathways of mechanotransduction in arteriolar endothelium and smooth muscle cells in hypertension.

Hypertension, a disease with a high incidence in the population, affects all parts of the cardiovascular system. Studying the alteration of vasomotor responses of microvessels of hypertensive animals or responses of vessels following short-term increases in hemodynamic forces helps us to better understand the underlying cellular signaling events responsible for their functional adaptation. These adaptations are likely to precede the structural remodeling of arterioles, resulting in irreversible increases in peripheral vascular resistance in hypertension. Although malfunction of several mechanisms can lead to the development of hypertension, hemodynamic forces (such as pressure and shear stress) are increased in all forms of hypertension. Thus, local mechanisms that sense the level of these forces and transduce the signals into vasomotor responses must be affected in all forms of hypertension. The endothelium has a central role in the early functional adaptations. Pressure-induced myogenic constriction is enhanced due to the augmented release of endothelium-derived constrictor factors that modulate arteriolar smooth muscle sensitivity to Ca(2+). In contrast, flow/shear stress-induced dilation of arterioles is reduced in hypertension, due to the impaired mediation of the response by nitric oxide (NO). The magnitude of impairment is gender specific, primarily due to an estrogen-dependent enhancement of NO release in females. It is proposed that the elevated hemodynamic forces present in hypertension may themselves initiate these alterations, probably by enhancing the release of reactive oxygen species (ROS; produced by xanthine oxidase, NAD(P)H oxidoreductase, eNOS, etc.), which then interfere with the synthesis and/or action of endothelium-derived mediators. Interfering early on with these mechanisms may prevent the development of irreversible structural changes of the microcirculation observed in hypertension.

Animals↗

PubMed1993

[From myocardial hypertrophy to heart failure: role of the interstitium].

In the progression from myocardial hypertrophy to heart failure, abnormalities in the interstitial space of the heart seem to play a critical role. The formation of an extracellular oedema and the alterations in coronary subendocardial perfusion are associated with the development of interstitial fibrosis. Cardiac experimental studies documented the presence of augmented interstitial fluid volume and pressure and a subsequent remodelling of the fibrillar network of the extracellular space of the myocardium during the phases of the cardiovascular response to a sudden overload. Variations of the Starling's forces balance caused by enhanced endothelial permeability or due to an impairment of cardiac lymphatic drainage may contribute to the development of an acute heart failure. During stable hyperfunction, the organization of a chronic oedema should account for interstitial changes in the hypertrophic myocardium. Reactive fibrosis seems to be under hormonal control. The activation of the renin-angiotensin-aldosterone system is responsible for interfascicular and intercellular accumulation of fibrillar collagen within the cardiac interstitium. Perivascular fibrosis in the subendocardium may impair intramyocardial distribution of coronary flow. When an inadequate hypertrophy occurs, because of an elevation in ventricular wall stress, myocardial oxygen consumption rises and this may lead to the exhaustion of coronary blood flow reserve in the subendocardial layers. This underperfusion may be responsible for the development of myocardial ischemia. Coronary hemodynamic changes in the microcirculation as those prompted by interstitial alterations may contribute to the onset of myocyte necrosis and to the formation of restorative fibrosis. The progressive mechanical overload of the spared hypertrophied myocytes could explain the initiation of a positive feedback mechanism which perpetuates endomyocardial perfusion impairment, interstitial oedema and remodelling, finally, causing myocyte deaths and fibrous tissue proliferation. These structural alterations and their pathophysiological counterparts appear to be closely related to the evolution from compensatory hypertrophy to chronic myocardial failure in hypertrophic heart disease.

Acute Disease↗

PubMed2002

Education on-demand: the development of a simulator-based medical education service.

OBJECTIVES: Clinical medical education depends on the availability of instructive patient encounters, or "good teaching cases." While all medical students hope to see enough patients of sufficient scope and variety, exposure to good teaching cases has been traditionally limited by time and chance. Students may graduate from medical school without having seen a number of important cases, each of which may represent a knowledge gap they will carry forward into internship and future patient care. Recently, however, the advent of high-fidelity patient simulators has enabled instructors to recreate realistic patient scenarios in a standardized fashion. Using the simulator, we wanted to create a medical education service-like any other clinical teaching service, but designed exclusively to help students fill in the gaps in their own education, on demand. We hoped to mitigate the inherent variability of standard clinical teaching, and to augment areas of deficiency. DESCRIPTION: Using a Human Patient Simulator(TM) (Medical Education Technologies, Inc.), which is equipped with a transmitted voice and reactive eyes, chest movements and breath sounds, heart tones and palpable pulses, a multidisciplinary group of physicians and educators designed a simulator-based medical education service. The premise was that students should have the ability to realistically practice and discuss medicine with a physician-mentor at any time they wish, with full access to simulator-enabled cardiac monitoring, diagnostic resources, pharmacologic agents, and invasive procedures. Students were informed of the program by e-mail and by course instructors. A dedicated pager was established for the on-call physician-educator, and the number disseminated to students. Physician-educators included faculty members scheduled for dedicated teaching time, and senior residents participating in a medical education elective. On-call physicians were responsible for fielding educational requests, developing appropriate scenarios, and scheduling instructional time. Upon arriving at the skills lab for their appointments, students would proceed to interview, evaluate, and treat the mannequin-simulator as if it were a real patient, using the instructor for assistance as needed. All students participated in an educational debriefing after each session. Instructors could also request formal observation and feedback on their teaching style, in collaboration with an existing faculty development program. DISCUSSION: Students enjoy the opportunity to practice medicine on-demand with dedicated clinical mentoring by a practicing physician. Course directors are interested in scheduling simulator time to help bring to life tutorial-based teaching cases and other course material for their students. By offering a medical education elective for residents, we have bolstered the pool of available instructors, provided a valuable learning experience for residents as teachers, and fostered additional opportunities for collaboration between the medical school and clinical training sites. Customized, realistic clinical correlates are now readily available for students and teachers, allowing reliable access to "the good teaching case."

Education, Medical, Continuing↗