Search PubMed⌕ Search

Biomedical subjects

A Bradford

Publications and source records attributed to A Bradford.

At least 19 recordsLinked to original sources
PubMed2006

Autocrine/paracrine regulation of breast cancer cell proliferation by growth hormone releasing hormone via Ras, Raf, and mitogen-activated protein kinase.

Although GHRH has previously been shown to regulate proliferation of breast cancer cells and prevent apoptosis, the intracellular pathways mediating this effect have not been clarified. Exogenous GHRH stimulated a dose-dependent proliferative response within 24 h in MDA-231, as well as in T47D cells and in MCF-7 cells transfected with the GHRH receptor. The proliferation of MDA-MB-231 (MDA-231) cells was associated with an increase in tritiated thymidine uptake. In addition, phosphorylation of MAPK was rapidly stimulated by GHRH. The phosphorylation of MAPK by GHRH was prevented by transfection of the cells with dominant-negative Ras or Raf or by pretreatment of cells with Raf kinase 1 inhibitor. The inhibition of Ras and Raf, as well as the inhibition of MAPK phosphorylation by PD98059, also prevented GHRH-induced cell proliferation. Finally, pretreatment of cells with the somatostatin analog, BIM23014, also prevented GHRH-induced MAPK phosphorylation and cell proliferation. These results indicate that GHRH stimulates dose-dependent cell proliferation of MDA-231 breast cancer cells through a pathway that requires Ras, Raf, and MAPK phosphorylation. The results also provide support for a possible autocrine/paracrine antagonism between GHRH and somatostatin in the regulation of MDA-231 cell population maintenance. Taken together, the studies provide further insight into the possible role of GHRH as a growth factor in breast cancer.

Autocrine Communication↗
PubMed2005

Chronic intermittent asphyxia increases platelet reactivity in rats.

Sleep-disordered breathing is associated with chronic intermittent asphyxia and with a variety of cardiovascular abnormalities. Cardiovascular morbidity and mortality are linked to altered platelet function, and platelet function is affected in sleep-disordered breathing. As there is evidence that chronic continuous hypoxia may alter platelet number and function, the aim of the present study was to test the hypothesis that chronic intermittent asphyxia affects platelet count, activation and aggregation. Rats were treated with a hypercapnic hypoxic gas mixture (minimum of 6-8% O2, maximum of 10-14% CO2) for 15 s, twice per minute for 8 h per day for 3 weeks. Blood was analysed for platelet count, platelet activation (CD62p expression using flow cytometry), response to low dose ADP, haematocrit, red cell count and haemoglobin concentration. A platelet function analyser measured the closure time of an aperture, dependent on platelet aggregation. Compared to controls (n = 16), chronic intermittent asphyxia (n = 13) reduced body weight and increased right ventricular weight but had no significant effect on platelet count (control, 880.4 +/- 20.1; treated: 914.1 +/- 35.2 x 10(3) microl(-1); mean +/- S.E.M.), on the reduction in platelet count in response to ADP (control, reduced to 206.7 +/- 49.0; treated, reduced to 193.8 +/- 35.9 x 10(3) microl(-1)), or on the percentage of platelets positive for CD62p (control, 5.2 +/- 0.7; treated, 6.0 +/- 0.8%). Chronic intermittent asphyxia significantly (P = 0.037) reduced the closure time (control, 90.9 +/- 7.7; treated, 77.7 +/- 3.8 s), indicating greater adhesion and aggregation. There was no significant difference in haematocrit, red cell count and haemoglobin concentration. In conclusion, chronic intermittent asphyxia has no effect on platelet count but does increase platelet aggegation in rats. These data support the idea that chronic intermittent asphyxia alters platelet function in sleep-disordered breathing.

Animals↗
PubMed2004

Detailed analysis of the behavior of Lister and Wistar rats in anxiety, object recognition and object location tasks.

The present study, examines some issues in the measure and analysis of behavior in animals. Two strains of rats of both genders were used to illustrate and discuss these issues. We examined to what extent various behavioral measures reflect different or identical emotional or cognitive factors and, how sensitive are the various parameters of a task to differences between strains and genders. Wistar and Lister males and females rats were tested in an anxiety test then in the object recognition task followed by the object location task. Taking advantage of a simple computer program it is possible to: (1) record several parameters of theses tasks and examine the pattern of animal responses toward novelty and/or familiarity; (2) examine whether different measurements of the same response would reflect anxiety response to novelty and, can they discriminate between novelty and familiarity responses to objects; and (3) examine if changes in the pattern of animal responses are reflected by these measurements and, whether anxiety or discrimination is evident mainly during the first minute of the test. The results on the anxiety test show that different measures of the same response proved concordant and revealed significant differences between Lister males and Wistar males. Lister males approached more frequently an object and spent more time on an object in each approach compared to Wistar males in the first 5 min of test and in the total 10 min. They have also shorter latencies between approaches compared to Wistar males. The examination of performance over different time bins was significant with the measure of frequency. Lister male rats approached less frequently the object in the last 5 min of the test compared to the first 5 min. Their performance, however, did not differ from that of the other groups in this last 5 min. In the memory tasks, the measure of the frequency of approaches suggests that Lister male rats were able to discriminate between novel and familiar objects and, between novel and familiar location of objects. The measure of latency of first approach shows that Wistar female rats were able to discriminate between objects only in the spatial memory test. Discrimination in the object recognition task was observed in the first and second minute, and in the total 3 min sessions. Discrimination in the object location task was observed with the measure of frequency of approaches, in the first minute, and in the total 3 min sessions. Results from the total 3 min sessions were more concordant between the different measures of discrimination than results from separate 1 min bins. The results from the two memory tasks show that novelty prevented habituation to re-exposure to the testing environment. In many cases, novelty increased exploration of the objects in the choice phase compared to the sample phase. However, this lack of habituation or increased exploration in the choice phase is not concordant with most results of discrimination between novelty and familiarity from the same type of measurements.

Analysis of Variance↗
PubMed2003

Upper airway EMG responses to acute hypoxia and asphyxia are impaired in streptozotocin-induced diabetic rats.

Obstructive sleep apnoea (OSA) is a major clinical disorder that is characterised by multiple episodes of upper airway obstruction due to failure of the upper airway dilator muscles to maintain upper airway patency. The incidence of OSA is high in many endocrine disorders including both insulin-dependent and non-insulin-dependent diabetes but the reasons for this are not known. We wished to test the hypothesis that central respiratory motor output to the upper airway muscles is preferentially impaired in a rat model of diabetes mellitus. Sternohyoid (SH) and diaphragm (DIA) EMG activities were recorded in control and streptozotocin (STZ)-induced diabetic rats during normoxia, hypoxia (7.5% O2 in N2) and asphyxia (7.5% O2 and 3% CO2) under pentobarbitone anaesthesia. SH EMG responses to acute hypoxia and asphyxia were significantly impaired in STZ-induced diabetic rats compared to control animals (+47.1 +/- 5.7 vs. +11.7 +/- 1.9% during hypoxia in control and diabetic animals respectively and +56.5 +/- 7.9 vs. +15.7 +/- 5.0% during asphyxia). However, DIA EMG responses to hypoxia and asphyxia were not different for the two groups. We propose that the higher prevalence of OSA in diabetic patients is related to preferential impairment of cranial motor output to the dilator muscles of the upper airway in response to physiological stimuli.

Analysis of Variance↗
PubMed2003

The effect of vitamin E on the structure of membrane lipid assemblies.

The effects of vitamin E on the activity of membrane-dependent enzymes suggest that it acts indirectly by modifying some properties of the lipid host. The effects of alpha-tocopherol (alpha-T) and alpha-tocopherol hemisuccinate (alpha-THS) on phospholipid monolayer structure, curvature, and bending elasticity were examined using X-ray diffraction and the osmotic stress method. These ligands were mixed with the hexagonal phase-forming lipid, dioleoylphosphatidylethanolamine (DOPE). Increasing levels up to 50 mol% alpha-T in DOPE in excess water result in a systematic decrease in the lattice dimension. Analysis of the structural changes imposed by alpha-T shows that it contributes a spontaneous radius of curvature of -13.7 A. This unusually negative value is comparable to diacylglycerols. alpha-T does not affect the bending elasticity of these monolayers. alpha-THS in its charged form decreases membrane curvature, but in its undissociated neutral form has a qualitatively similar but reduced effect on monolayer curvature, as does alpha-T. We discuss these results in terms of the local stresses such ligands would produce in the vicinity of a membrane protein, and how one might expect proteins to respond to such stress.

Cell Membrane↗
PubMed2003

Effects of chronic hypobaric hypoxia on contractile properties of rat sternohyoid and diaphragm muscles.

1. Chronic hypoxia occurs in a variety of circumstances, including respiratory disease and exposure to altitude, and is known to affect respiratory muscle structure. However, little is known about its effects on respiratory muscle contractile properties. 2. Rats were exposed to normoxia (n = 16) or hypobaric hypoxia (n = 16; barometric pressure 450 mmHg) for 6 weeks. Contractile properties were measured in isolated sternohyoid and diaphragm muscles in warmed, oxygenated Krebs' solution. Isometric twitch and tetanic tension, contraction time, half-relaxation time and tension-frequency relationship were determined using field stimulation with platinum electrodes. Fatigue was induced by stimulation at 40 Hz with 300 msec trains of 0.5 Hz for 5 min. 3. Chronic hypoxia had no effect on bodyweight, but did increase haematocrit. Chronic hypoxia increased specific force development in both muscles and increased sternohyoid fatigue. Chronic hypoxia had no effect on contractile kinetics in either muscle, but shifted the tension-frequency relationship to the left in the diaphragm. 4. Therefore, chronic hypoxia alters rat respiratory muscle force and fatigue, either due to the direct effects of hypoxia or to increased muscle activation.

Air Pressure↗
PubMed2002

Contractile properties of the diaphragm in creatine-fed rats.

1. Creatine feeding increases the oxidative capacity of type 1 skeletal muscle fibres and, in soleus muscles, consisting mainly of type 1 fibres, increases fatigue resistance. The diaphragm contains a relatively large content of type 1 fibres and respiratory muscle fatigue is a cause of respiratory failure. The aim of the present study was to determine whether creatine supplements increase fatigue resistance in the diaphragm. 2. Rats were given creatine monohydrate (2.55 g/L) in the drinking water. After 5-6 days, isometric contractile properties were measured in strips of costal diaphragm in Krebs' solution at 30 degrees C. Measurements were also made in soleus muscle strips. Values for strips from creatine-fed rats were compared with those from control rats. 3. Creatine feeding did not increase fatigue resistance and had no effect on twitch or tetanic tension or twitch kinetics in the diaphragm. Creatine increased fatigue resistance in soleus muscles, as reported previously.

Animals↗
PubMed2002

Effects of creatine loading and depletion on rat skeletal muscle contraction.

1. In humans, the effects of dietary creatine supplementation are controversial, with some studies showing increased muscle force and fatigue resistance and others reporting no effect on exercise performance. Little is known about the effects of creatine on muscle contractile properties. 2. Rats were fed a standard diet, creatine for 10 days or beta-guanidinopropionate, which depletes muscle creatine, for 7 days. Contractile properties were measured in isolated extensor digitorum longus and sternohyoid muscle as representative limb and upper airway dilator muscles, respectively. 3. Creatine had no effect on specific twitch and tetanic tension, contractile kinetics, twitch/tetanus tension ratio, the tension-frequency relationship or fatigue in both muscles. beta-Guanidinopropionate had no effect on the twitch and tetanic tension, contractile kinetics, twitch/tetanus tension ratio or tension-frequency relationship, but significantly increased (P < 0.05, anova) fatigue in both muscles. 4. Therefore, although creatine depletion increases fatigue, creatine loading has no effects on extensor digitorum longus and sternohyoid muscle contractile properties.

Animals↗
PubMed2002

Effects of almitrine on diaphragm contractile properties in young and old rats.

BACKGROUND: Diaphragm muscle force and fatigue are key factors in the development of respiratory failure. Almitrine is used to improve ventilatory drive and ventilation-perfusion matching in respiratory failure. Recently, it has also been shown to improve diaphragm muscle force and endurance in young rats, but it is not known if this effect persists with ageing. OBJECTIVES: To determine the effects of almitrine on diaphragm contractile properties in young and old rats. METHODS: In young and old rats, isometric contractile properties were measured in strips of isolated diaphragm muscle in physiological saline solution at 30 degrees C with or without almitrine. RESULTS: In young animals, almitrine increased twitch tension, reduced half-relaxation time and increased endurance, but had no effect on tetanic tension, contraction time or tension-frequency relationship. Ageing had no effect on endurance, but did reduce twitch and tetanic tension and contraction and half-relaxation time. Almitrine had no effect on contractile tension and kinetics, tension-frequency relationship or on endurance in the old animals. CONCLUSIONS: Ageing negates the beneficial effects of almitrine on diaphragm muscle force and endurance.

Aging↗
PubMed2001

Effect of almitrine on upper airway muscle contraction in young and old rats.

The effects of almitrine on the contractile properties of isolated geniohyoid and sternohyoid muscles were determined in physiological salt solution at 30 degrees C in young and old rats. In young rats, almitrine had no effect on twitch or tetanic tension, twitch:tetanic tension ratio, contractile kinetics, active or passive tension-length relationships or frequency-tension relationship in both muscles. Almitrine significantly increased resistance to fatigue in both muscles. In old rats, almitrine had no effect on twitch or tetanic tension, twitch:tetanic tension ratio, contractile kinetics, active or passive tension-length relationships, frequency-tension relationship or fatigue in both muscles. These results show that almitrine, in both young and old rats, has no effect on most of the contractile properties of isolated geniohyoid and sternohyoid muscles. However, almitrine increases resistance to fatigue in both muscles in young but not in old rats.

Age Factors↗
PubMed2001

Contractile and electrical properties of sternohyoid muscle in streptozotocin diabetic rats.

1. The effects of diabetes on the electrical and contractile function of skeletal muscle are variable, depending on muscle fibre type distribution. The muscles of the upper airway have a characteristic fibre distribution that differs from previously studied muscles, but the effects of diabetes on upper airway muscle function are unknown. Normally, contraction of upper airway muscles, such as the sternohyoids, dilates and/or stabilizes the upper airway, thereby preventing its collapse. Diabetes is associated with obstructive sleep apnoea in which there is collapse of the upper airway due to failure of the upper airway musculature to maintain airway patency. Therefore, the purpose of the present study was to determine the effects of diabetes on the electrical and contractile characteristics of upper airway muscle. 2. Rats were treated with vehicle (sodium citrate buffer; pH 4.5) or with streptozotocin to induce diabetes, confirmed by the presence of hyperglycaemia, and the contractile and electrical properties of the sternohyoid were compared in these two groups. Isometric contractile properties and membrane potentials were determined in isolated sternohyoid muscles in physiological saline solution at 25 degrees C. 3. Streptozotocin had no effect on sternohyoid muscle fatigue, the tension-frequency relationship or membrane potentials, but did increase contraction time, half-relaxation time, twitch tension and tetanic tension. 4. Streptozotocin-induced diabetes has no effect on sternohyoid muscle fatigue or the tension-frequency relationship, but does reduce contractile kinetics and increases force generation. These effects are not due to changes in resting membrane potential. These data are evidence that the association of sleep apnoea and diabetes is not due to effects on upper airway muscle contractile properties.

Animals↗
PubMed2001

The effects of dietary creatine supplements on the contractile properties of rat soleus and extensor digitorum longus muscles.

Daily creatine supplements (0.258 g kg(-1) ) were administered to adult male Wistar rats (n = 7) in the drinking water. Age matched rats (n = 6) acted as controls. After 5-6 days, contractile properties were examined in soleus and extensor digitorum longus (EDL) muscle strips in vitro at 30 degrees C. In soleus muscles, creatine supplements decreased the half-relaxation time of the isometric twitch from 53.6 +/- 4.3 ms in control muscles to 48.4 +/- 5.5 ms but had no effect on twitch or tetanic tension or on twitch contraction time. In EDL muscles twitch tension, tetanic tension, twitch contraction and half-relaxation times were all unaffected by creatine supplements. Creatine supplements increased the fatigue resistance of the soleus muscles but had no effect on that of the EDL muscles. After a 5 min low-frequency fatigue test, tension (expressed as a percentage of initial tension) was 56 +/- 3 % in control soleus muscles, whereas that in the creatine-supplemented muscles was 78 +/- 6 % (P < 0.01). In the EDL muscles, the corresponding values were 40 +/- 2 % and 41 +/- 9 %, respectively. The force potentiation which occurred in the EDL muscles during the initial 20-30 s of the fatigue test was 170 +/- 10 % of initial tension in the control muscles 24 s after the initial stimulus train but was reduced (P < 0.01) to 130 +/- 20 % in the creatine-supplemented muscles. In conclusion, soleus muscle endurance was increased by creatine supplements. EDL endurance was unaffected but force potentiation during repetitive stimulation was decreased. Experimental Physiology (2001) 86.2, 185-190.

Animals↗
PubMed2001

Effects of carbonic anhydrase inhibition on the responsiveness of laryngeal receptors in cats to CO2.

The effects of carbonic anhydrase inhibition on the responsiveness to CO2 of pressure-sensitive laryngeal receptors were examined in anaesthetised, paralysed cats. Laryngeal CO2-sensitive receptors from the superior laryngeal nerve were selected by their responsiveness to intralaryngeal pressure and to perfusion of solution equilibrated with 9% CO2. The carbonic anhydrase inhibitor, methazolamide, when given intralaryngeally at 10(-4) M, diminished or abolished the responses to the CO2-equilibrated solution in four of six pressure-sensitive receptors. Histochemical staining for carbonic anhydrase activity showed that the larynges perfused with methazolamide had diminished carbonic anhydrase activity, especially on the superficial layers of surface epithelium. Compared to untreated controls, when given intravenously (50 mg x kg(-1)) methazolamide diminished or abolished the responses to CO2 of five of the six fibres studied. Histochemical staining of these larynges showed no carbonic anhydrase reactivity at the sites of laryngeal receptors. These results suggest that the responses to CO2 of laryngeal pressure-sensitive receptors are dependent on the presence of carbonic anhydrase. Inhibition of laryngeal receptor carbonic anhydrase activity by methazolamide is more reliably achieved by systemic rather than by luminal administration.

Animals↗
PubMed2001

Chronic intermittent hypercapnic hypoxia increases pulmonary arterial pressure and haematocrit in rats.

Sleep-disordered breathing is associated with pulmonary hypertension and raised haematocrit. The multiple episodes of apnoea in this condition cause chronic intermittent hypoxia and hypercapnia but the effects of such blood gas changes on pulmonary pressure or haematocrit are unknown. The present investigation tests the hypothesis that chronic intermittent hypercapnic hypoxia causes increased pulmonary arterial pressure and erythropoiesis. Rats were treated with alternating periods of normoxia and hypercapnic hypoxia every 30 s for 8 h per day for 5 days per week for 5 weeks, as a model of the intermittent blood gas changes which occur in sleep-disordered breathing in humans. Haematocrit, red blood cell count and haemoglobin concentration were measured each week and systemic and pulmonary arterial blood pressure and heart weight were measured after 5 weeks. In relation to control, chronic intermittent hypercapnic hypoxia caused a significant increase in systemic (104.3+/-4.7 mmHg versus 121.0+/-10.4 mmHg) and pulmonary arterial pressure (20.7+/-6.8 mmHg versus 31.3+/-7.2 mmHg), right ventricular weight (expressed as ratios) and haematocrit (45.2+/-1.0% versus 51.5+/-1.5%). It is concluded that the pulmonary hypertension and elevated haematocrit associated with sleep-disordered breathing is caused by chronic intermittent hypercapnic hypoxia.

Animals↗
PubMed2000

Effects of upper airway carbon dioxide on upper airway resistance and muscle activity in young guinea-pigs.

The upper airway (UA) of adult animals is known to contain carbon dioxide-sensitive receptors and UA CO2 reflexly affects breathing, UA dilator muscle activity and UA resistance. These effects may function in the control of UA patency. There is evidence that some UA reflexes are stronger in young than in adult animals, but it is not known whether CO2-sensitive receptors are present in the UA of young animals, and the effects of UA CO2 on UA resistance and on UA dilator muscle activity have not been investigated in young animals. The responses of ventilation, UA resistance and geniohyoid muscle electromyographic activity to warm air containing 10% CO2 applied to the isolated UA were measured in anaesthetized, vagotomized young guinea-pigs breathing spontaneously through a low-cervical tracheostomy. Upper airway carbon dioxide caused an increase in ventilation (46.7+/-16.3 to 49.9+/-16.8 mL x min(-1) x 100 g body weight(-1)) and upper airway resistance (56.8+/-14.8 to 63.7+/-17.7 cmH2O x L(-1) x s(-1) x kg body weight(-1)). Similar effects were obtained following vagotomy. Geniohyoid activity became apparent following vagotomy and this activity was reduced by upper airway carbon dioxide. These responses were abolished by topical anaesthesia of the upper airway. This suggests that the reflexes seen are due to carbon dioxide-sensitive receptors in the upper airway.

Age Factors↗
PubMed2000

Effects of age and gender on rat upper airway muscle contractile properties.

Upper airway muscles regulate upper airway patency. Obstructive sleep apnea is caused by upper airway collapse, and its incidence increases with age and is higher in men than women. The reasons for this are unknown, as little is known about the effects of age and gender on upper airway muscle. Isometric contractile properties were determined using strips of geniohyoid and sternohyoid muscles from young and old, male and female rats in physiological saline solution at 30 degrees C. There were no differences between the male and female rats in any of the contractile properties of either muscle, and this was true for both young and old animals. Aging had no effect on sternohyoid contractile properties, but geniohyoid force was greater in old than in young rats.

Age Factors↗
PubMed1999

Chronic intermittent hypoxia increases haematocrit and causes right ventricular hypertrophy in the rat.

Chronic continuous hypoxia increases haematocrit and causes right ventricular hypertrophy and pulmonary hypertension. In obstructive sleep apnoea, the exposure to hypoxia is intermittent rather than continuous but the effects of chronic intermittent hypoxia on haematocrit and right ventricular mass are unclear. Wistar rats were exposed to alternating periods of hypoxia and normoxia twice per min for 8 h per day for 5 weeks in order to mimic the intermittent hypoxia of obstructive sleep apnoea in humans. Haematocrit was significantly raised at day 7, 14, 21, 28 and 35 of the treatment period. At the end of the treatment, there was a significant increase in right ventricular mass. Therefore, chronic intermittent hypoxia increases haematocrit and right heart mass. These results suggest that the raised haematocrit and pulmonary arterial pressure observed in some cases of obstructive sleep apnoea in humans may be caused by intermittent nocturnal hypoxaemia.

Animals↗