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PubMed2001

Pathophysiology of dyspnea.

Dyspnea may be defined as an uncomfortable sensation of breathing. The sense of respiratory effort, chemoreceptor stimulation, mechanical stimuli arising in lung and chest wall receptors, and neuroventilatory dissociation may all contribute to the sensation of dyspnea. Different mechanisms likely give rise to qualitatively different sensations of dyspnea. In most patients, dyspnea is probably due to a combination of mechanisms. For example, in asthma, a heightened sense of effort, neuroventilatory dissociation, and vagal stimuli arising from bronchoconstriction and airway inflammation may all play a role. Patients with different disorders and different mechanisms of dyspnea use different phrases to describe their breathing discomfort. Hence, the language patients use to describe their dyspnea may provide clues to the etiology of their symptoms.

Asthma↗
PubMed2004

NF-kappaB, macrophage migration inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the acetaminophen- and NSAID-prevention of the ovarian cancer.

Recent epidemiological studies indicated risk reductions in ovarian cancer with consumption of acetaminophen or non-steroid anti-inflammatory drugs. Until now, there is not a systematic analysis, why these agents may reduce risk of ovarian cancer, as it has been performed to explain aspirin-reduction of colon cancer risk. This review tries to explain molecular mechanisms pertinent to acetaminophen- and NSAID-reduction of ovarian cancer. It is proposed that the major mechanism by these anti-inflammatory agents is a shared pathway dependent on the suppression of NF-kappaB activity, which may subsequently decrease transcription of growth factors, chemokines and proteases such as COX-2, VEGF, IL-8/CXCL8, MCP-1/CCL-2, MIP1alpha/CCL-3, tPA and uPA, which are shown to be elevated in ovarian carcinoma, and which play diverse roles such as inducing angiogenesis, invasion, autocrine growth loops and resistance to apoptosis. Besides these, specific mechanisms of action can be attributed to acetaminophen-reduction of ovarian cancer risk via I. Induction of specific reproductive atrophy due its sex-steroid resembling phenolic ring; II. Reduction of glutathione pools due to its NAPQI metabolite, which may play an important role for sterilizing pre-malignant ovarian lesions, since they are shown to lack proper levels of glutathione; III. Inhibition of tautomerization activity of MIF (macrophage migration inhibitory factor), which is shown to be released from ovarian cancer, and which is necessary for proper ovulation; IV. Inhibition of cytokine-induced and endothelia-origined cyclooxygenases. Except the chemosensitization studies, acetaminophen and NSAIDs should be investigated in animal models to test likely benefits in ovarian cancer, since most of their activity may origin from intervening with the cancer growth-stimulating inflammatory stimuli, rather than with the direct cellular toxicity.

Acetaminophen↗
PubMed1990

Dissociation of the proliferation and differentiation stimuli of granulocyte colony-stimulating factor (G-CSF).

One proposed therapeutic application of granulocyte colony-stimulating factor (G-CSF) is in differentiation induction therapy of myelodysplastic states (MDS) or acute myeloid leukemia (AML). G-CSF however has a substantial growth including effect which limits its potential as a differentiation inducing agent. We have therefore made a systematic search for agents which might restrain the proliferative effects of G-CSF whilst retaining the differentiation stimulus. Of all the agents we have tested on human bone marrow progenitor cells: (6-thioguanine, all-trans retinoic acid, vincristine, recombinant human alpha-2b and gamma-interferon) only the latter abolished the stimulation of cell growth and retained, or possibly increased, the differentiation effect of G-CSF. The antiproliferative drugs 6-thioguanine and vincristine both antagonized the neutrophil-granulocyte differentiation inducing action of G-CSF. Retinoic acid and alpha-2b interferon both had weak effects on proliferation and failed to enhance differentiation. These results suggest that it may be possible, by combining G-CSF with a suitable second agent, to utilize its substantial differentiation inducing effect without incurring the potentially hazardous effects of increased leukemic cell growth.

Cell Differentiation↗
PubMed1987

Cerebral vasodilating and vasospasmolytic action of the cerebral circulation improver 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)-1- piperazinyl]methyl)isoquinoline in experimental animals.

Vasodilating action of a new calmodulin antagonist, 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-4-([4-(2-methoxyphenyl)- 1-piperazinyl]methyl) isoquinoline (Ro 22-4839), was examined in anesthetized animals. In anesthetized dogs, Ro 22-4839 when given intra-arterially dilated various vessels in the potency order of vertebral greater than internal carotid greater than femoral = coronary much greater than renal vessels. Ro 22-4839 (0.1-1.0 mg/kg i.v.) produced brief increases in the cerebral parietal cortex, vertebral and coronary arterial blood flows more markedly than in femoral, mesenteric and renal arterial blood flows. The compound given intraduodenally decreased the vertebral vascular resistance more extensively than the femoral one in a dose-dependent (3-30 mg/kg) way. The effect of intraduodenal administration was longer-lasting than brief action after intravenous administration, and tended to decrease heart rate. Ro 22-4839 did not significantly change cerebral oxygen consumption regardless of its increase in cerebral oxygen supply, suggesting that its cerebral vasodilating effect was due to its direct relaxing effect on the vascular smooth muscle. Papaverine and ifenprodil produced a shorter-lasting decrease in vertebral vascular resistance and caused significant tachycardia. In the video camera system monitoring the constrictory response of feline pial small vessels of the parietal cortex to hypocapnia, Ro 22-4839 was found to reverse vasoconstriction of both pial arteries and veins at the dose of 0.3 mg/kg i.v./min, which did not dilate these vessels under normocapnia. The compound uniformly reduced the pressor responses to various stimuli (electrical stimulation, norepinephrine and angiotensin II) in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

Possible hormonal role of the angiotensin-like peptides in mammals' pineal gland.

An isorenin is synthetized in the pineal gland cells. The amount of isorenin as well as the synthesis of angiotensin I and II in the pineal gland depends on the circadian rhythm, osmotic stimuli and stimulation of the cervical sympathetic postganglionar fibres. Pineal angiotensin is released both into the blood and in the cerebrospinal fluid (CFS). The major site of the pineal angiotensin action are the circumventricular organs, the preiventricular receptors of the anterior hypothalamus and the epiphysis cerebri itself. Except its participation in regulating arterial pressure and the hydroelectrolytic metabolism, through its central effects on the brain, pineal angiotensin-like peptides also participate in the pool of circulating angiotensin and it may represent Farrell's pineal glomerulotropic factor.

Angiotensin I↗
PubMed1993

Metabolic mapping with cellular resolution: c-fos vs. 2-deoxyglucose.

2-Deoxyglucose (2DG) studies have been most useful in mapping activated regions of the nervous system. Cellular localization studies using 2DG have been less rewarding, but results are consistent with current views that increases of 2DG accumulation produced by synaptic activation represent increases in glycolytic glucose metabolism occurring mainly in presynaptic neuronal and possibly glial elements. Immediate early genes (IEGs), including the fos, jun, and NGFI-A families, are induced by a wide variety of intracellular signaling pathways. The nuclear localization of the protein products of these genes and their induction by a variety of stimuli make them useful in metabolic activation studies carried out at the cellular level. IEGs have been induced in neurons by osmotic, bacterial endotoxin, steroids, stress, and other hormonal stimuli; by light, auditory, painful, and other sensory stimuli; during stimulation of motor cortex and other motor behaviors; and by various drugs and toxins that act on a variety of neurotransmitter systems, including dopamine and glutamate. In addition, the localization of c-fos gene expression identifies cells that respond to growth factors in vivo. Retinal Muller cells, the major glial cell type of the retina, demonstrate nuclear Fos immunostaining after the intravitreal injection of epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha). This observation demonstrates that adult glia can respond to these growth factors in vivo. The investigation of early response gene expression may be particularly useful for elucidating the role of trophic factors in the cellular response to central nervous system injury.

Animals↗
PubMed1997

Reduced production of IL-12 and IL-12-dependent IFN-gamma release in patients with allergic asthma.

In atopic patients, allergen-specific T cells have acquired the Th2 phenotype, which is considered to be responsible for the class switch to IgE Ab formation. Because IL-12 is a key cytokine for the induction of Th1 responses, a reduced capacity to produce this cytokine could lead to aberrant Th2 development. Therefore, we examined the production of IL-12 in whole blood cultures from patients with allergic asthma (n = 15) in comparison with nonatopic control subjects (n = 15) to different stimuli. After stimulation with Staphylococcus aureus Cowan I strain (SAC) we observed a 2.6-fold reduction of IL-12 p70 production in the patient group (p < 0.005). This was not due to a general failure of monocytes from these patients to produce cytokines, because the production of IL-6 was normal. SAC also induced the production of IFN-gamma, which was blocked by neutralization of IL-12. In line with the reduced levels of IL-12 secretion, the patient group showed a 3-fold reduction of IL-12-dependent IFN-gamma production (p < 0.005). The amounts of IL-12 and IFN-gamma were positively correlated in both the patient (R = 0.51 at 0.05% SAC and R = 0.64 at 0.01% SAC) and the control groups (R = 0.64 at 0.05% SAC and R = 0.70 at 0.01% SAC). The IFN-gamma:IL-12 ratio was not different between patients and control subjects, indicating a normal response to IL-12. Diminished production of IL-12 and IFN-gamma could not be explained by an increased production of IL-10, because in SAC-stimulated cultures IL-10 was hardly induced in both groups. Furthermore, after stimulation with Escherichia coli, the production of IL-10 was similar in patients and control subjects.

Adult↗
PubMed1997

Reciprocal interactions between intralaminar and lateral thalamic nuclei in rats.

Reciprocal interactions between intralaminar thalamic nuclei (ncl. centralis lateralis, CL, and ncl. parafascicularis, Pf), the pretectal area (Pt) and lateral thalamic nuclei (ventrobasal complex, VB, ncl. anterior ventralis, AV, and ncl. ventralis anterior, VA) have been observed in ketamine-anaesthetized rats. Extracellular single unit activity has been recorded after single electrical stimuli. Electrical stimulation of the VB evoked a short latency orthodromic response followed by a pause in spontaneous activity in neurones of medial thalamic nuclei. Lateral thalamic neurones responded to electrical stimulation of the intralaminar nuclei or the pretectal area with the same pattern of response. Striatal, sensorimotor cortical or peripheral electrical stimulation also evoked similar responses. The pauses in spontaneous activity were shown to be the result of inhibition since the responsiveness of the intralaminar nuclei or the lateral thalamic neurones to all inputs was abolished or reduced after a conditioning electrical single-shock stimulation in the VB or in the intralaminar nuclei, respectively. The two components of the response were of a different origin, since most of the short latency responses disappeared after medullary, upper cervical sections or large decortications, while the inhibitions persisted. These inhibitions were shown to be of thalamic origin since their duration was decreased after extensive decortications increased after medullary section. It is concluded that the neuroneal properties studied in this report are probably broadly represented throughout the thalamus and that thalamic neurones are under inhibitory control elicited by afferent volleys. This inhibitory control includes a relay in the nucleus reticularis thalami (nRT). The mechanisms of sensory interaction can be purely thalamic, but they can be modulated by suprathalamic and/or mesencephalic loops.

Animals↗
PubMed1976

Neural modification by paired sensory stimuli.

With repetitive stimulation of two sensory pathways which are intact within the isolated nervous system of Hermissenda, features of a cellular conditioning paradigm were identified. Type A photoreceptors, unlike type B photoreceptors, produce fewer impulses in response to light following temporally specific pairing of light stimuli with rotation stimuli. Type A photoreceptor impulse wave-forms are also specifically changed by such stimulus regimens. These findings can be explained, at least in part, by increased inhibition of type A cells by type B cells after stimulus pairing.

Animals↗
PubMed1985

Reflex responses of the human jaw-closing system depend on the locus of intraoral mechanical stimulation.

Innocuous mechanical stimuli were applied to eight sites on the tongue dorsum and palate while subjects used feedback to maintain a constant isometric biting force. Reflex responses of the jaw-closing system were measured as changes in force and in EMGs recorded from right and left masseter muscles. Stimulation at each of the eight sites produced reflex force and EMG responses in most subjects tested. The nature of the reflex responses strongly depended on the site of stimulation. Stimulation of the palate tended to produce suppression of ongoing EMG activity and decreases in background biting force. In contrast, stimulation of sites on the tongue posterior to the tip, most often resulted in excitatory EMG responses and increases in jaw-closing force. Unilateral, early excitatory responses were observed in the right masseter with stimulation of the right side of the tongue. The existence of spatially organized responses of the human jaw-closing system to innocuous intraoral stimulation is not consistent with the view that these cutaneous reflexes are primarily of protective significance.

Adolescent↗
PubMed1977

Responses of crayfish muscle preparations to nerve stimulation with various patterns of impulse sequence. Effects of intermittent, intercalated and adaptational types of impulse sequence.

The present study was carried out with an attempt to see what effects would be produced by various patterns of impulse trains other than pulses of a definite frequency in nerve-muscle systems of the crayfish. Single axons of nerves of the opener, the slow closer and the fast closer of the crayfish claw were stimulated and the tension development of muscles were recorded. The impulse trains tested are as follows: (i) intermittent stimulation; e.g., paired (doublet) and triplet stimuli, (ii) the intercalated stimulation during stimulation by constant-frequency pulses and (iii) the adaptational type of stimulation, i.e. a train of pulses of which interval gradually increases as seen in the process of the adaptation in the sensory nerve. Results obtained are as follows. Intermittent doublet stimuli produced a greater tension than the monotonous stimulation of the same average frequency. Repetitive triplet or quadruplet stimuli caused further increments in the tension development. Intercalation of a stimulus during usual monotonous stimulation induced a catch-like effect on the tension. Intercalated triplet stimuli provoked a stronger catch action. With the adaptational type of stimulation, an initial rapid tension development occurred with a least latency and this was followed by a maintained tension. There are certain temporal configurations of stimuli which produced a greater tension or a more physiologically meaningful time course of tension development. This suggests the significance of nervous coding.

Animals↗
PubMed1994

Illusory contours and linear filters.

The border between two abutting gratings is sometimes referred to as an illusory contour. In the Fourier spectrum of such a pattern there is no energy corresponding to the precise orientation of this contour. Neuronal responses elicited by such stimuli are therefore thought to be incompatible with linear filtering. The present investigation tested this notion. Abutting gratings were Fourier analyzed and passed through spatial and temporal filters with properties comparable with those of cortical neurons. It was found that the distribution of amplitudes in the Fourier spectrum is such that these stimuli may indeed stimulate neurons based on linear filtering. In the case of drifting stimuli the amount of stimulation may be maximal when the illusory contour is at the optimal orientation for bars with less stimulation on either side of this orientation.

Cerebral Cortex↗
PubMed2006

Cortical oscillatory changes occurring during somatosensory and thermal stimulation.

Brief somatosensory stimuli are followed by amplitude decreases (event-related desynchronization, ERD) of the 10 and 20 Hz oscillations over the bilateral primary sensorimotor cortices, and by post-stimulus synchronization (event-related synchronization, ERS) of the 20 Hz oscillations in the contralateral primary sensorimotor cortex and in the supplementary motor area (SMA). The 10 and 20 Hz ERD differentiate weak and strong somatosensory stimuli but not fine intensity gradations, and the ipsilateral ERD is especially sensitive to habituation. Stimulus anticipation, motor imagery, action viewing as well as voluntary movements modulate the stimulus-related changes of cortical oscillations. Noxious laser stimuli, selectively activating Adelta and/or C fibers, and innocuous warm and cold stimuli are associated with 10 and 20 Hz ERD but not with the post-stimulus 20 Hz ERS suggesting that the post-stimulus ERS is only related to neuronal transmission in the lemniscal system. It is proposed that phase-unlocked cortical oscillations modulate the preparedness of a particular sensory channel for upcoming somatosensory processing.

Animals↗
PubMed1998

Assessment of afferent gut--brain function using cerebral evoked responses to esophageal stimulation.

Increasing awareness is attributed to altered sensory perception in the pathogenesis of gastrointestinal disorders. Evoked potentials (EP), which represent the brain's electrical response to peripheral stimulation, have recently been used to investigate where and how (GI) afferent information is processed along the brain-gut axis. EP can be obtained with electrical stimulation or balloon distention in the esophagus in humans. Stimulation of afferent neural pathways in the esophagus produces cerebral evoked responses allowing assessment of the peripheral afferent neural pathways involved, and of the function of integrative neural centers within the brain. Recent studies using esophageal EP indicate that the cerebral response to either mode of stimulation depends on the perception of the stimuli. Using electrical stimulation, a clear dose-response relationship is found. The EP response obtained with electrical stimulation is in keeping with those recorded using direct cervical stimulation of the vagus nerve, supporting evidence that esophageal EP are produced by activation of afferent vagal pathways. From the conduction velocity of the autonomic (vagal) nerves conveying information from esophagus to brain, it was concluded that non-painful electrical stimuli predominantly activate fast conducting myelinated afferent sensory fibers (A-fibers), while EP to balloon distention are largely due to activation of unmyelinated C-fibers. Techniques, however, vary widely amongst different investigators, and some electrophysiological parameters remain controversial, as there is no standard approach. Using balloon distention, EP waveforms vary widely between laboratories, suggesting that EP are substantially influenced by the stimulator devices (pump, respirator). EP to balloon distention are hampered by a relatively low signal-to-noise ratio (SNR), which is probably due to long inflation-deflation time (> 200 ms). With electrical stimulation, there is much less variability between different groups, and SNR is distinctly higher. This method appears to be most attractive for studies of afferent esophageal function. Standardization of the techniques is important, before esophageal EP can be regarded as a useful diagnostic approach in patient groups.

Afferent Pathways↗
PubMed1990

Effects of solvents and detergents on the contractions of isolated smooth muscle preparations.

In testing poorly soluble substances in-vitro on isolated organs, organic solvents and solubilizers are used to increase water-solubility. To facilitate selection of appropriate substances, the effects of eleven of these chemicals have been studied in the following isolated smooth muscle preparations: guinea-pig ileum stimulated by carbachol, histamine, 5-HT or single field stimuli; rat fundus stimulated by 5-HT; and mouse vas deferens stimulated by noradrenaline or trains of field stimuli. Nine solvents (acetone, diethyleneglycol monoethylether, dimethyl sulphoxide, ethanol, glycerol, methanol, polyethylene glycol 400, 1,2-propanediol, Tetraglycol (tetrahydrofurfurylalcohol polyethyleneglycolether)) and two detergents (Triton-X 100 and Tween 80) were examined. The vas deferens proved to be most resistant, whereas rat fundus and guinea-pig ileum were more sensitive to the effects of solvent when present from 1 to 10 g L-1. Most solvents caused non-specific, concentration-dependent reversible inhibition of contractions. Dimethyl sulphoxide in high concentrations increased the contractile responses of guinea-pig ileum stimulated by 5-HT and in both experiments with electrical stimulation. Polyethylene glycol 400 augmented the response of mouse vas deferens to electrical stimulation. Overall, 1,2-propylene glycol and polyethylene glycol 400 had the least effect and can be used in a concentration of 3 g L-1, and in qualitative studies even up to 10 g L-1. Glycerol, both monohydric alcohols and dimethyl sulphoxide produced more intense effects and should not exceed concentrations of 1-3 g L-1. Stronger inhibition was caused by diethyleneglycol monoethylether, acetone and Tetraglycol, and the bath concentrations of these substances should not exceed 0.5-1g L-1. Of the detergents only Tween 80 is suitable as a solubilizer in smooth muscle preparations in-vitro, forming micelles at 10 mg L-1 a concentration tolerated by isolated organs in this study.

Animals↗