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At least 811 records · Page 45Linked to original sources

Survival signals within the tumour microenvironment suppress drug-induced apoptosis: lessons learned from B lymphomas.

The suppression of apoptosis is one mechanism by which tumours become drug resitant. Extracellular signals from the germinal centre (GC) of secondary lymphoid tissue can rescue B cells from physiological- and chemotherapy-induced apoptosis. Such survival signals include CD40 receptor ligation, interleukin-4 (IL-4) receptor stimulation and the interaction of the integrin ligand VCAM-1 with its receptor. The GC environment was modelled in vitro by providing B lymphoma cells with these survival signals. JLP119 B lymphoma cells underwent apoptosis after exposure to the topisomerase II inhibitor etoposide and this was dramatically reduced when the cells were cultured in the GC system. CD40 receptor ligation resulted in increased levels of Bcl-XL. Etoposide diminished the binding between Bax and Bcl-XL but this was restored by IL-4 and VCAM-1 triggered signals. These data demonstrate combined effects of three microenvironmental signals on the Bcl-2 family and illustrate the potential importance of such signalling pathways in drug resistance of tumour cells.

Animals↗

Comparison of finger and intra-arterial blood pressure monitoring at rest and during laboratory testing.

The accuracy of blood pressure values obtained by continuous noninvasive finger blood pressure recording via the FINAPRES device was evaluated by comparison with simultaneous intraarterial monitoring both at rest and during performance of tests known to induce fast and often marked changes in blood pressure. The comparison was performed in 24 normotensive or essential hypertensive subjects. The average discrepancy between finger and intra-arterial blood pressure recorded over a 30-minute rest period was 6.5 +/- 2.6 mm Hg and 5.4 +/- 2.9 mm Hg for systolic and diastolic blood pressure, respectively; a close between-method correspondence was also demonstrated by linear regression analysis. The beat-to-beat changes in finger systolic and diastolic blood pressure were on average similar to those measured intra-arterially during tests that induced a pressor or depressor response (hand-grip, cold pressor test, diving test, Valsalva maneuver, intravenous injections of phenylephrine and trinitroglycerine) as well as during tests that caused vasomotor changes without major variations in blood pressure (application of lower body negative pressure, passive leg raising). The average between-method discrepancy in the evaluation of blood pressure changes was never greater than 4.3 and 2.0 mm Hg for systolic and diastolic blood pressure, respectively; the corresponding standard deviations ranged between 4.6 and 1.6 mm Hg. Beat-to-beat computer analysis of blood pressure variability over the 30-minute rest period provided standard deviations almost identical when calculated by separate consideration of intra-arterial and finger blood pressure tracings (3.7 and 3.8 mm Hg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

"Behavioral despair" test predicts stress ulcer in WKY rats.

Spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) and Wistar rats were exposed to Porsolt's forced-swimming test of "behavioral despair." In addition to floating time, which was the measure of despair, headshakes, bobbing, diving and struggling time were also recorded. Rats were subsequently exposed to the activity stress (A-S) ulcer procedure. Wistar rats had the highest struggling time scores and the fewest A-S ulcers. WKY rats were judged as more depressed and their ulcer severity scores were significantly greater as compared to SHR and Wistar rats. In addition, a within strains analysis revealed that WKY rats with high despair scores also had the most severe stress-ulcer scores. These data suggested that stress-ulcer disease may be more prevalent in animals which are prone to depression as defined by the Porsolt test. The value of WKY rats as an animal model to study the relationship between depression and stress ulcer is discussed.

Animals↗

In vivo microbubble detection in decompression sickness using a second harmonic resonant bubble detector.

A resonant bubble detection method based on a second harmonic technique has been used to monitor the femoral vascular system of dogs subjected to rapid decompression. For this study, the detector consisted of two acoustic transducers mounted at right angles to each other that were packaged in a perivascular cuff configuration. This detector responds selectively only to bubbles near resonant size (4.2 mum in diameter); solid particles and large bubbles produce no response. The detector was used to monitor a total of 15 dogs. Eleven dogs were subjected to a series of simulated underwater dives until acute symptoms of decompression sickness occurred; 4 dogs served as controls. In the dived group, either the femoral vein or the femoral artery was monitored. Resonant bubbles were observed in the femoral veins of all 6 dogs monitored at this location. During arterial monitoring, most dogs showed no response, but an occasional weak response was observed in 2 of the dogs. No resonant bubbles were detected in the femoral artery or the femoral vein in any of the controls. The data suggest that this bubble detection method is feasible for in vivo use. Furthermore, 4 mum diameter bubbles are much more prevalent in the veins of dogs suffering from decompression sickness than they are in dog arteries, presumably because they are filtered out effectively by the pulmonary circulation. Modifications of this method are discussed to enhance its accuracy and applicability for quantifying bubble size, location, and number.

Animals↗

Prlonged bubble production by transient isobaric counter-equilibration of helium against nitrogen.

The production of systemic gas bubbles by isobaric counter-equilibration of helium against 5 atmospheres saturated nitrox (0.3 ATA O2 in both mixes) in awake goats was demonstrated. Sixteen animal exposures (8 dives, 2 animals per dive) to a sudden isobaric gas switch from saturation on N2 to He were conducted; 8 saturations occurred at 132 fsw and 8 at 198 fsw. Central venous bubbles were detected acoustically by means of a Doppler ultrasonic cuff surgically implanted around the inferior vena cava of each animal. Bubbles occurred from 20 to 60 min after the switch in both the 132 fsw and 198 fsw exposures, but were not always present in the 132 fsw exposure, and did not persist for as long. Bubbles or other Doppler events were often detected for the entire isobaric period-12 h-following the gas switch in the 198 fsw exposures. Decompressions were conducted according to the USN saturation tables and were uneventful, with only occasional bubbles. Supersaturation ratios calculated to have occurred for a considerable period after the gas switch were approximately 1.15 (tissue gas tension pi, divided by ambient hydrostatic pressure, P) with maxima at 1.26 for the faster tissues. These values are limiting ones in USN decompression only for the slower tissues. In general, therefore, these results argue for reducing the permissible ascent criteria for the faster tissues-assuming bubbles are to be avoided-and allowing more time at stops for non-saturation decompression. Gas switches from a more soluble to a less soluble and/or more rapidly diffusing gas should therefore be avoided until physiological limits are well worked out.

Animals↗

Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors.

Somatic angiotensin-converting enzyme (ACE) contains two homologous domains, each bearing a functional active site. The in vivo contribution of each active site to the release of angiotensin II (Ang II) and the inactivation of bradykinin (BK) is still unknown. To gain insights into the functional roles of these two active sites, the in vitro and in vivo effects of compounds able to selectively inhibit only one active site of ACE were determined, using radiolabeled Ang I or BK, as physiological substrates of ACE. In vitro studies indicated that a full inhibition of the Ang I and BK cleavage requires a blockade of the two ACE active sites. In contrast, in vivo experiments in mice demonstrated that the selective inhibition of either the N-domain or the C-domain of ACE by these inhibitors prevents the conversion of Ang I to Ang II, while BK protection requires the inhibition of the two ACE active sites. Thus, in vivo, the cleavage of Ang I and BK by ACE appears to obey to different mechanisms. Remarkably, in vivo the conversion of Ang I seems to involve the two active sites of ACE, free of inhibitor. Based on these findings, it might be suggested that the gene duplication of ACE in vertebrates may represent a means for regulating the cleavage of Ang I differently from that of BK.

Angiotensin I↗

Voice fundamental frequency levels of divers in helium-oxygen speaking environments.

Divers under hyperbaric conditions experience a marked deterioration in speech intelligibility. Included among the possible features that contribute to speech degradation is change/distrotion of speaking fundamental frequency (SFF). Based on the physics of the environment and the physiology of the diver, it would not be expected that SFF would change as a function of varying helium-oxygen pressure conditions. However, in an earlier pilot study, a rise in SFF was found with increases in depth. To test this hypothesis, and to expand the previous limited findings, a large number of U. S. Navy divers were studied. The diver/subjects produced speech samples at the surface and at depths of 200, 450, and 600 fsw in helium-rich environments. The resulting data revealed increases in fundamental frequency to the 450-fsw depth and a subsequent decrease at 600 fsw; further analysis, however, based on data transforms, showed a more linear increase in SFF. From other observations, it was judged that behavioral rather than physical conditions were the primary cause of these SFF shifts; specifically, they appear to have resulted from divers' attempts to speak more intelligibly.

Atmosphere Exposure Chambers↗

Estimation of oxygen uptake from heart rate response to undersea work.

The efficacy of using a diver's heart rate (HR) response to work performed formed in the open sea to estimate the oxygen uptake (VO2) and work stress by general and depth-specific regression equations was examined in six scuba divers. A diver-carried data recording system and an underwater gas sampler were used to obtain measures of physiological responses to work in the ocean. The HR and VO2 were measured during dry cycling at 1 ATA, and during moderate to very heavy work fin-swimming against an ergometer at 2, 3, and 4 ATA. Underwater VO2 and HR at 2-4 ATA ranged from 1.41 to 3.89 liters/min (39%-89% VO2max observed on land) and 105-180 beats/min, respectively. Individual data points at three work levels at 1-4 ATA were used to compute correlation coefficients (r) and regression equations. Only one significant difference in regression slopes was found (1 ATA vs. 4 ATA), but large differences in intercept were observed in each comparison. From 1 ATA to 4 ATA r decreased from 0.78 to 0.53 while the standard error of VO2 estimated from HR (Syx) increased from 0.229 to 0.582 liters O2. The regression equation for dry exercise (1 ATA) underestimated VO2 over most of the work range by 0.4 to 0.9 liters/min or 11% to 25% of VO2max. The accuracy of estimating VO2 from cardiac response by general (1 ATA) or depth-specific regression equations is insufficient to justify their use in research or diver monitoring systems. Attempts to estimate VO2 from pulmonary ventilation (VE) gave similar results with more differences between slopes among the conditions. These observations and those of other investigators support the idea that underwater work loads and stress cannot be estimated or evaluated by simple HR measurements that are made during diving operations and interpreted in terms of sea-level standards.

Adult↗

Influence of wet suit wear on anxiety responses to underwater exercise.

The purpose of this investigation was to evaluate the effect of wearing a wet suit on selected psychological and physiologic variables. Certified divers (n = 13) finned underwater at 0.52 m/s for 20 min with and without a wet suit. Order was randomly assigned and performed on separate days. Heart rate, respiration rate, use of compressed air, ratings of perceived exertion, and breathing ratings increased significantly (P < 0.05) for both conditions, and increases in heart rate, use of compressed air, and breathing ratings were significantly greater for the wet-suit condition. Rectal temperature increased significantly (P < 0.001) for the wet-suit but not the bathing-suit condition. State anxiety and body awareness increased (P < 0.001) following the wet-suit condition. Furthermore, state anxiety decreased significantly (P < 0.001) by 15 min after exercise in the bathing-suit condition. It is concluded that wet suit wear can result in elevated anxiety when performed at a water temperature and exercise intensity sufficient to produce increased core temperature.

Adult↗

Subjective and behavioral effects associated with repeated exposure to narcosis.

Below 30 m, nitrogen narcosis can severely degrade the performance of air breathing divers. Within the diving community it is generally thought that this effect can be reduced by repeating deep air dives on successive days but laboratory studies have found no strong evidence to support the notion of adaptation to narcosis. One possible explanation for this discrepancy is that one's subjective impression or perception of narcosis may decrease during repeated exposure to hyperbaric air without parallel improvement on task performance. To examine this possibility, symptoms and performance were examined over the course of 5 days of repeated exposure to 30% nitrous oxide at 1 ATA. While the results revealed no clear cut changes in global perceptions of narcosis across days, several symptoms from an adjective checklist showed unequivocal signs of adaptation. With respect to performance effects, reaction time yielded no indications of improvement over days relative to the control. These findings suggest that subjective adaptation can occur without parallel performance improvement, an effect which could compromise safety and which may be of concern in other operational settings that involve repeated exposure to stimulus conditions which impact on performance and symptoms.

Adaptation, Physiological↗

The physiology of hibernation among painted turtles: the midland painted turtle (Chrysemys picta marginata).

Midland painted turtles from Michigan were submerged at 3 degrees C in normoxic and anoxic water. In predive, and in turtles submerged for up to 150 days, plasma PO2, PCO2, pH, [Cl-], [Na+], [K+], total Mg, total Ca, lactate, glucose, and osmolality were measured; hematocrit and mass were determined, and plasma [HCO3-] was calculated. Anoxic turtles developed a severe metabolic acidosis, accumulating lactate from a predive value of 4.4 mmol/L to a 150-day value of 185 mmol/L, associated with a fall in pH from 7.983 to 7.189. To buffer lactate increase, total calcium and magnesium rose from 3.7 and 2.6 to 58.9 and 11.8 mmol/L, respectively. Plasma [HCO3-] was titrated from 39.2 to 4.8 mmol/L in anoxic turtles. Turtles in normoxic water had only minor disturbances of their acid-base and ionic statuses, associated with a much smaller increase of lactate to 23 mmol/L; there was a marked increase in hematocrit from 29.1% to 42.1%. We suggest that it is ecologic, rather than phylogenetic, relationships that determine the responses of painted turtles to prolonged submergence associated with hibernation.

Acid-Base Equilibrium↗

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites.

The human somatic angiotensin converting enzyme (ACE) contains two homologous domains, each bearing a zinc-dependent active site. All of the synthetic inhibitors of this enzyme used in clinical applications interact with these two active sites to a similar extent. Recently, several lines of evidence have suggested that the N-terminal active site of ACE might be involved in specific hydrolysis of some important physiological substrates, like Acetyl-Seryl-Aspartyl-Lysyl-Proline, a negative regulator of hematopoietic stem cell differentiation and proliferation. These findings have stimulated studies aimed at identifying new ACE inhibitors able to block only one of the two active sites of this enzyme. By screening phosphinic peptide libraries, we discovered a phosphinic peptide Ac-Asp-(L)Phepsi(PO2-CH2)(L)Ala-Ala-NH2, called RXP 407, which is able to differentiate the two ACE active sites, with a dissociation constant three orders of magnitude lower for the N-domain of the enzyme. The usefulness of a combinatorial chemistry approach to develop new lead structures is underscored by the unusual chemical structure of RXP 407, as compared with classical ACE inhibitors. As a highly potent and selective inhibitor of the N-terminal active site of wild ACE (Ki = 12 nM), RXP 407, which is metabolically stable in vivo, may lead to a new generation of ACE inhibitors able to block in vivo only a subset of the different functions regulated by ACE.

Amino Acid Sequence↗

Oxidative stress: animal adaptations in nature.

As a consequence of aerobic life, an organism must deal with the continuous generation of reactive oxygen species (O2-, H202, .OH) as byproducts of metabolism and defend itself against the harm that these can do to cellular macromolecules. Organisms protect themselves from such damage with both enzymatic and nonenzymatic antioxidant defenses. However, the reperfusion injuries noted after ischemic insult in mammalian organs and ascribed to a burst of reactive oxygen species produced when oxygenated blood is reintroduced demonstrate that the antioxidant defenses of many organisms can be overwhelmed, Although unusual among most mammals, many organisms routinely experience wide variation in oxygen availability to their tissues due to factors such as environmental oxygen lack, breath-hold diving, extracellular freezing, or apnoeic breathing patterns in arrested metabolic states. In recent studies using various animal models (anoxia-tolerant turtles, freeze-tolerant snakes and frogs, estivating snails) our laboratory has explored the adaptations of antioxidant defenses that allow such organisms to deal with rapid changes in tissue oxygenation with little or no accumulation of damage products. The key to successful transitions in several systems is the induction, during the oxygen-limited state, of elevated activities of antioxidant and associated enzymes, such as catalase, superoxide dismutase, glutathione-S-transferase, and glutathione peroxidase, so that damage during the reintroduction of oxygen (such as lipid peroxidation) is minimized. However, animals that are excellent facultative anaerobes, such as freshwater turtles, appear to deal with potential of oxidative stress during the anoxic-aerobic transition by maintaining constitutively high antioxidant defenses (e.g. enzyme activities similar to those of mammals and much higher than those of anoxia-intolerant lower vertebrates) that can readily accommodate the burst of reactive oxygen species generation when breathing is renewed.

Adaptation, Physiological↗

Physiologically and subjectively acceptable breathing resistance in divers' breathing gear.

To determine acceptable levels of breathing resistance in divers' gear, 6 subjects were exposed to varying levels of breathing resistance under demanding and realistic conditions. The immersed air-breathing subjects exercised in the prone position at 60% of their maximum oxygen uptake for 25 min in a hyperbaric chamber at 1.45 and 6.8 atm abs (145 and 690 kPa, 4.5 and 57 msw, 15 and 190 fsw). The breathing resistance ranged from minimal to 8-12 cmH2O (0.8-1.2 kPa).liter-1.s at flow rates of 2-3 liter/s. The higher resistance levels interfered with the respiration in terms of end-tidal PCO2 and dyspnea scores. There were considerable individual differences, and changes in one parameter were typically not paralleled by changes in the other. None of maximal voluntary ventilation, forced expiratory volume, expiratory reserve volume, vital capacities, or oxygen uptake was influenced by resistance. We set the maximum allowable end-tidal PCO2 at 60 mmHg and maximum dyspnea score at 1.0 on a scale from 0 (none) to 3 (severe). Based on these criteria we concluded that the external work of breathing should not exceed 1.5-2.0 J/liter in the ventilation range 30 to 75 liter/min BTPS.

Adult↗

Non-viral liposomal keratinocyte growth factor (KGF) cDNA gene transfer improves dermal and epidermal regeneration through stimulation of epithelial and mesenchymal factors.

Keratinocyte growth factor (KGF) stimulates epithelial cell differentiation and proliferation, which are of major importance for wound healing. Local protein administration, however, has been shown to be ineffective due to enzymes and proteases in the wound fluid. We hypothesized that delivering KGF as a non-viral liposomal cDNA gene complex is a new approach that would effectively enhance dermal and epidermal regeneration. Twenty-two rats were given an acute wound and divided into two groups to receive weekly subcutaneous injections of liposomes plus the LacZ gene (0.2 microg, vehicle), or liposomes plus the KGF cDNA (2.2 microg) and LacZ cDNA (0.2 microg). Transfection was confirmed by histochemical assays for beta-galactosidase. Planimetry, histological and immunohistochemical techniques were used to determine protein expression, dermal and epidermal regeneration. Transfection and subsequent KGF expression was found in diving cells in the granulation tissue. Epidermal regeneration was improved by 170% in rats receiving the KGF cDNA constructs by exhibiting the most rapid area and linear wound re-epithelialization, P < 0.0001. KGF improved epidermal cell net balance by increasing skin cell proliferation and decreasing skin cell apoptosis, P < 0.0001. Dermal regeneration was further improved in KGF cDNA treated animals by an increased collagen deposition and morphology, P < 0.0001. KGF cDNA increased neo-vascularization and concomitant VEGF concentrations when compared with vehicle, P < 0.01. KGF cDNA did not only stimulate epithelial cells, but also mesenchymal cells through increases in IGF-I concentration, P < 0.005. Liposomes containing the KGF cDNA gene constructs were effective in improving epidermal and dermal regeneration. KGF gene transfer to acute wounds may represent a new therapeutic strategy to enhance wound healing.

Animals↗

Exercise and forced submergence in the pond slider (Trachemys scripta) and softshell turtle (Apalone ferox): influence on bimodal gas exchange, diving behaviour and blood acid-base status

The dynamics of bimodal respiration, diving behaviour and blood acid-base status in the softshell turtle Trachemys scripta and the pond slider Apalone ferox were investigated at rest and under conditions of stress induced by exercise and forced submergence. During periods of forced submergence, only A. ferox doubled its aquatic gas exchange rate. Both A. ferox and T. scripta increased their aerial gas exchange profoundly following exercise and forced submergence, a pattern indicative of increased anaerobic respiration. Emersion duration increased significantly in A. ferox following forced submergence, and mean apnoeic time decreased significantly in A. ferox following exercise, indicating that a larger proportion of time at the surface was spent ventilating. Also, A. ferox maintained a one-breath breathing bout regardless of treatment. Submergence produced a respiratory acidosis in the plasma of approximately 0.2 pH units in magnitude in T. scripta and a mixed respiratory/metabolic acidosis of 0.4 pH units in A. ferox. Exercise induced an acidosis of 0.2 pH units of primarily metabolic origin in both species. Intra-erythrocyte pH was also reduced in both species in response to submergence and exercise. Both intracellular and extracellular acidoses were more severe and longer lasting in A. ferox after each treatment. Plasma [HCO3-] decreased by 25 % in both species following exercise, but only in A. ferox following submergence. Plasma lactate concentrations increased by equal amounts in each species following exercise; however, they returned to resting concentrations sooner in T. scripta than in A. ferox. A. ferox had significantly higher lactate levels than T. scripta following forced submergence as well as a slower recovery time. A. ferox, which is normally a good bimodal gas exchanger at rest, utilizes aerial respiration to a greater extent when under respiratory and/or metabolic stress. T. scripta, although almost entirely dependent on aerial respiration, is physiologically better able to deal with the respiratory and metabolic stresses associated with both forced submergence and exercise.

Journal Article↗

Cognitive deficiency induced by the acute stress in rats: a possible role of brain catecholaminergic systems.

The evaluation of the male albino rats cognitive capacity was performed by placing the animals in glass cylinder plundged into water (22 degrees C.) In order to escape from that stress situation the rat should dive under the cylinder's edge, solving by this way the extrapolatory escape task (EET). Two groups of rats (A and B) have been selected and characterized within the total laboratory population. The A rats have shown a smaller number of attempts to achieve successful escape and a shorter latency of that reaction in comparison with the B animals. The latter displayed a higher behavioral activity in "open field" test. The combination of 100 mg/kg L-DOPA with 25 mg/kg of benzerazide (DOPA-BENZ) was shown to impair dramatically the cognitive capacity of the two groups of animals. DOPA-BENZ treated rats failed to demonstrate any correct solution of EET. The rats of the two groups were distinguished clearly in terms of dopamine contents and turnover rate measured in three brain areas by the HPLC technique. Among psychotropic drugs studied only haloperidol and fluphenazine were found to restore partially the animals capacity to cope with the EET after DOPA-BENZ administration.

3,4-Dihydroxyphenylacetic Acid↗

Forced swim stress activates rat hippocampal serotonergic neurotransmission involving a corticotropin-releasing hormone receptor-dependent mechanism.

Serotonin is important for adequate coping with stress. Aberrant serotonin function is implicated in the aetiology of major depression and anxiety disorders. Dysregulation of the hypothalamic-pituitary-adrenocortical axis, involving elevated corticotropin-releasing hormone (CRH) activity, also plays a role in these stress-related illnesses. Here we studied the effects of stress on hippocampal serotonin and the role of the CRH system using in vivo microdialysis. First, rats were subjected to a forced swim stress, resulting in a dramatic increase in hippocampal serotonin (1500% of baseline), which was associated with the occurrence of diving behaviour. The diving-associated increase in serotonin depended on activation of CRH receptors, as it was antagonized by intracerebroventricular pretreatment with D-Phe-CRH12-41. Secondly, the effects of intracerebroventricular administration of CRH and urocortin (0.03-1.0 microg) were studied. Both CRH and urocortin caused a dose-dependent rise in hippocampal serotonin (maximally 350% of baseline) and 5-hydroxyindoleacetic acid levels, suggesting the involvement of CRH receptor type 1. Because the effects of urocortin were prolonged, CRH receptor type 2 could play a role in a later phase of the neurotransmitter response. Experiments using adrenalectomized rats showed that CRH-induced serotonin changes were adrenally independent. These data suggest that the raphe-hippocampal serotonin system is able to mount, CRH receptor-dependent, responses to specific stressful situations that surpass the usually observed maximal increases of about 300% of baseline during stress and enhanced vigilance.

Animals↗