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Biomedical subjects

P Hawkins

Publications and source records attributed to P Hawkins.

At least 37 records · Page 2Linked to original sources
PubMed2000

Inspiratory pressure support prolongs exercise induced lactataemia in severe COPD.

BACKGROUND: A physiological benefit from pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD) is more probable if exercise is performed above the lactate threshold. This study was undertaken to investigate whether it was possible to extend the lactataemia of exercise using non-invasive inspiratory pressure support (IPS). METHODS: Plasma lactate levels were measured in eight men with severe COPD who performed two treadmill walks at an identical constant work rate to a condition of severe dyspnoea; the second walk was supported by IPS. RESULTS: Mean plasma lactate levels before the free and IPS assisted walks were 1.65 mmol/l and 1. 53 mmol/l, respectively (p = NS). Lactate levels increased during both walks to 2.96 mmol/l and 2.42 mmol/l, respectively (p = 0.01 for each) but the duration of the IPS assisted walk was significantly greater than the free walk (13.6 minutes versus 5.5 minutes, p = 0.01). CONCLUSIONS: Patients with severe COPD can sustain exercise induced lactataemia for longer if assisted with IPS. This technique may prove to be a useful adjunct in pulmonary rehabilitation.

Acidosis, Respiratory↗
PubMed2000

Effect of maternal undernutrition in early gestation on ovine fetal blood pressure and cardiovascular reflexes.

Human epidemiological and animal experimental studies suggest that maternal undernutrition during pregnancy may alter cardiovascular development of the offspring. The extent to which these effects involve changes in fetal cardiovascular function and whether they are necessarily linked to reduced fetal growth is unknown. In sheep, we investigated the effect of a 15% reduction in maternal global nutrition for the first 70 days of gestation (term = 147 days) on fetal blood pressure development, baroreflex control of fetal heart rate (FHR), and cardiovascular responses to acute hypoxemia in late gestation. Basal mean arterial pressure (P < 0.05), systolic blood pressure (P < 0.05), diastolic blood pressure (P < 0.05), and rate-pressure product (P < 0.001) were significantly lower in fetuses of nutritionally restricted ewes (R) compared with controls (C). FHR was not altered. The operating point for the fetal baroreflex was significantly lower in R fetuses compared with C (P < 0.01), but there was no difference between the groups in the cardiovascular response to hypoxemia. We conclude that mild maternal undernutrition alters fetal cardiovascular development, producing low blood pressure and resetting of baroreflex control mechanisms. This effect occurs without any changes in fetal growth or blood gas status.

Animals↗
PubMed1999

Comparison of usefulness between exercise capacity and echocardiographic indexes of left ventricular function in cardiac amyloidosis.

In patients with primary systemic amyloidosis (AL), the echocardiographic assessment of ventricular function alone does not always correspond to patients' symptoms and functional status. Peak oxygen uptake and anaerobic threshold (AT), in contrast, constitute 2 objective, reliable and reproducible indicators of functional status in patients with circulatory failure. Thirty-two consecutive patients (mean age 50 +/- 13 years) with histologic evidence of systemic primary AL were studied (29 AL, 3 hereditary). There were 16 with echocardiographic features of cardiac infiltration (group I) and 16 without (group II). Twenty age- and gender-matched healthy subjects were also studied for comparison. Of the 32 patients, 12 were in New York Heart Association functional class I, 9 were in class II, and 11 were in class III. Each subject underwent 2-dimensional and Doppler echocardiography and cardiopulmonary exercise testing using a modified Bruce protocol. Left atrial (LA), left ventricular (LV) dimensions, wall thickness, and LV fractional shortening, as well as transmitral flow velocities and their E/A ratio were measured. Peak oxygen consumption (VO2max [ml/kg/min]), AT (ml/kg/min), and exercise duration (seconds) were also measured. VO2max and AT were lower in patients with AL than in controls (20.8 +/- 7.0 vs 35.0 +/- 8.5, p <0.001 and 13.1 +/- 3.7 vs 27.0 +/- 4.2, p <0.001, respectively). As a group, symptomatic patients had lower VO2max, AT, and exercise duration than those without symptoms (17.1 +/- 3.6 vs 27.0 +/- 6.9, p = 0.0001, 11.1 +/- 2.1 vs 16.2 +/- 3.6, p = 0.0001, and 489 +/- 235 vs 843 +/- 197, p = 0.0001, respectively), whereas LV dimensions only showed a small difference (p = 0.03). VO2max, AT, and exercise duration of patients in functional class I were higher than those in functional classes II and III (p = 0.01, p <0.05, and p = 0.007, respectively). Asymptomatic patients had lower VO2max, AT, and exercise duration than controls (p <0.0001). VO2max, AT, and exercise duration were poorly related to LA diameter, LV dimensions, fractional shortening, wall thickness, peak velocities of E and A waveforms, and E/A ratio. Patients with VO2max > 15 ml/kg/min had a better survival than patients with VO2max < 15 ml/kg/min. Thus, in patients with primary systemic AL, cardiorespiratory exercise testing is the preferred way of assessing functional capacity. Echocardiographic Doppler indexes at rest are not predictive of a patient's symptoms and exercise capacity. Furthermore, VO2max is a strong independent predictor of survival in these patients.

Adult↗
PubMed1999

Echocardiographic features of primary, secondary and familial amyloidosis.

BACKGROUND: Currently recognized types of amyloidosis include primary, familial and secondary, each of which may affect the heart. There may be differences in the heart response to the deposition of amyloid fibrils in these three forms of the disease. MATERIALS AND METHODS: Over a period of 10 years (1985-95), 28 consecutive patients with primary, 11 with secondary and 17 with familial amyloidosis were studied at the Departments of Cardiology of Laiko and Hammersmith Hospitals. The diagnosis of amyloidosis was confirmed by biopsies of subcutaneous fat, rectum, kidney, bone marrow, gum or sural nerve. Diagnosis of cardiac involvement was based on typical electrocardiographic and echocardiographic findings. RESULTS: The left ventricular fractional shortening (%) was reduced in primary compared with familial or secondary amyloidosis (29.8 +/- 10.2 vs. 36.2 +/- 6.5 vs. 36 +/- 5.9, P < 0.05). The transmitral flow velocity pattern was compatible with abnormal relaxation in most patients in the three groups [primary 16 (57%), familial 11 (64. 7%), secondary 6 (54.5%), P = NS]. Right ventricular systolic dysfunction (right ventricular dP/dt < 220 mmHg s-1 or tricuspid annulus systolic excursion < 10 mm) was present in 8 (28.6%), 2 (11. 8%) and 0 patients. Patients with primary amyloidosis were followed up for 15 +/- 6 months. There were 12 deaths, and repeat echocardiography in the survivors revealed a significant deterioration of left ventricular systolic function (fractional shortening = 23.6% +/- 8.8%, P < 0.05 vs. baseline). CONCLUSION: Primary amyloidosis is characterized by more severe cardiac involvement than the familial or secondary amyloidosis and has an ominous course.

Adult↗
PubMed1999

Effect of maternal nutrient restriction in early gestation on development of the hypothalamic-pituitary-adrenal axis in fetal sheep at 0.8-0.9 of gestation.

The fetal hypothalamic-pituitary-adrenal (HPA) axis has numerous key roles in development. Epidemiological data have linked adverse prenatal nutrition with altered organ development and increased incidence of disease in adult life. We studied HPA axis development in resting and stimulated states in late gestation fetal sheep, following 15% reduction in maternal nutritional intake over the first 70 days of gestation (dGA). Fetuses from control (C) and nutrient-restricted (R) ewes were chronically catheterised and response profiles for ACTH and cortisol were determined at 113-116 and 125-127 dGA after administration of corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP). At 126-128 dGA cortisol profiles were also determined following ACTH administration. Basal ACTH and cortisol concentrations were not different between C and R fetuses. In R fetuses, ACTH response to CRH+AVP was significantly smaller at 113-116 dGA (P<0.01), and cortisol responses were smaller at both 113-116 dGA (P<0.01) and 125-127 dGA (P<0.0001). Cortisol response to ACTH was also smaller in R fetuses (P<0.001). We conclude that, in late gestation fetal sheep, pituitary and adrenal responsiveness is reduced following modest maternal nutrient restriction in early gestation.

Adrenocorticotropic Hormone↗
PubMed1998

Neuropsychological functioning in HIV-positive African-American women with a history of drug use.

This preliminary investigation examined neuropsychological performance in a sample of human immunodeficiency virus (HIV)-positive and HIV-negative African-American women with a history of drug use. The study population was comprised of 10 HIV-negative, 9 asymptomatic HIV-positive, 13 symptomatic HIV-positive, and 10 acquired immunodeficiency virus (AIDS) patients. A neuropsychological battery designed to assess attention, psychomotor processing, verbal memory, and visual memory was administered to participants. No evidence of HIV-related cognitive impairment was found in patients in the early stages of HIV infection. Multivariate analyses of variance revealed significant deficits in psychomotor processing and verbal recall in persons with AIDS. These individuals showed greater difficulty in tasks requiring maintained attention and performed poorly on measures of immediate and delayed verbal recall. In contrast, HIV status was not related to visual memory, verbal recognition, or the number of errors made during a verbal recall task. The pattern of cognitive deficits observed in persons with AIDS resembles that commonly associated with subcortical pathology. The cognitive deficits observed were not related to depression or recentness of drug use.

Adult↗
PubMed1997

Heat increment of feeding in Brunnich's guillemot

The rate of oxygen consumption (O2), respiratory quotient (RQ) and deep body temperature (TB) were recorded during a single, voluntary ingestion of Arctic cod Boreogadus saida (mean mass 18.9+/-1.1 g, s.e.m., N=13) by five postabsorptive Brunnich's guillemots (thick-billed murre, Uria lomvia). The birds were resting in air within their thermoneutral zone, and the fish were refrigerated to 0-2 degreesC. The rate of oxygen consumption increased by a factor of 1.4 during the first few minutes after ingestion, but there was no significant change in TB. Mean rate of oxygen consumption returned to preingestive levels 85 min after the birds ate the fish. The telemetered temperature of one fish reached TB within 20 min. This suggests that the persistent elevation in O2 over the next hour corresponded to the obligatory component of the heat increment of feeding (HIF) and was not related to heating the fish. Abdominal temperature increases after diving bouts in free-ranging common guillemots (common murre, Uria aalge) are possibly achieved through the HIF, since meals are processed at sea. Of the increase in O2 measured in the laboratory, it is calculated that 30 % is required to heat the fish, while 70 % is due to the HIF. In free-ranging birds, the excess heat provided by the HIF could contribute 6 % of the daily energy expenditure. This suggests that the HIF augments heat production in Uria spp. and thus reduces the energetic cost of thermoregulation.

Journal Article↗
PubMed1996

Separation of toxic peptides (microcystins) in capillary electrophoresis, with the aid of organic mobile phase modifiers.

A capillary electrophoretic (CE) method incorporating sodium dodecyl sulphate (SDS)-organic modifier solvents in the CE buffer was developed for the detection of toxic cyclic heptapeptide toxins (microcystins) produced by blue-green algae (cyanobacteria). The applicability of these run buffers for the analysis of microcystins was evaluated and optimum conditions for separation were determined. The migration times, elution order and selectivity of the toxic peptides were influenced by modifying the composition of the electrophoretic buffer with organic solvents [0 to 20% (v/v)]. At maximum addition, the organic solvents with the exception of acetonitrile, increased the viscosity of the buffer solution. In contrast to the migration time of the other microcystins, that of microcystin-RR was not increased by the addition of 2-propanol to the buffer solution. Rather, microcystin-RR eluted more quickly with the increase in 2-propanol, thereby effecting changes in the elution order of the microcystins. In addition, this solvent resulted in comigration of microcystin-LR and microcystin-YR. No significant relationship was found between the elution order and separation and the structure of the toxic peptides studied in micellar electrokinetic capillary chromatography with an organic modifier in the buffer solution; but there is an agreement between the effects of the organic modifiers and their dipole moments. Parameters such as linearity, sensitivity and reproducibility were also evaluated. High-efficiency separations of toxic peptide molecules having equal or nearly equal mass to charge ratios have been achieved using SDS as an additive to the running buffer. The influence of the pH has been examined.

Electrophoresis, Capillary↗
PubMed1996

Insulin and ATP stimulate actin polymerization in U937 cells by a wortmannin-sensitive mechanism.

ATP and insulin stimulate increases in phosphatidylinositol (3,4,5)-trisphosphate levels in myeloid-derived U937 cells. Quantification of FITC-phalloidin binding by fluorescence-activated cell sorting reveals that both ATP and insulin stimulate actin polymerization with distinctive kinetics in U937 cells. The response to ATP is rapid and dose-dependent with an EC50 of 200 nM, and is abolished by pre-incubation with the Ca2+ chelator BAPTA-AM. At 800 nM concentration, wortmannin, a potent inhibitor of phosphoinositide 3-kinase (PI3K), blocks the late, but not the early phase of actin polymerization stimulated by 100 nM ATP. Responses elicited by 10 micrograms/ml insulin are slower, smaller and more transient than responses to ATP, and are inhibited by preincubation with 100 nM wortmannin. Actin polymerization can also be stimulated by thapsigargin, but not by phorbol ester, providing further evidence for a role for Ca2+ in actin polymerization. These data implicate distinct Ca2+ and PI3K-mediated pathways in the regulation of actin polymerization.

Actins↗
PubMed1996

Volume-sensitive taurine efflux from mammary tissue is not obliged to utilize volume-activated anion channels.

Cell-swelling, induced by a hyposmotic shock, activates the release of taurine from lactating rat mammary tissue explants. The degree of stimulation of taurine efflux was dependent upon the extent of cell-swelling. Volume-sensitive taurine release was attenuated by the anion transport inhibitors NPPB, DIOA, DIDS, niflumate, flufenamate, mefenamate and diiodosalicylate but not by salicylate. Cell-swelling, following a hyposmotic challenge, did not increase the unidirectional efflux of radiolabelled I- or D-asparate from mammary tissue explants. The results suggest that although mammary tissue expresses a volume-sensitive amino acid transport system which is inhibited by anion transport blockers the pathway has no identity with volume-activated anion channels.

Animals↗
PubMed1996

An amino-terminal truncated progesterone receptor isoform, PRc, enhances progestin-induced transcriptional activity.

Previously we reported the identification of two unique progesterone receptor (PR) messenger RNA transcripts that encode a smaller PR isoform, termed the C-receptor (PRc). These two PR transcripts encode a protein that is N-terminally truncated, so that it lacks the first zinc finger of the DNA binding domain, but still contains a complete hormone binding region with sequences for dimerization and nuclear localization. We also have demonstrated the existence of a 60-kDa progestin-specific binding protein in progestin target cells using a monoclonal antibody directed to the C-terminus of PRs, suggesting that these two novel transcripts generate a truncated form of PR. In this paper, we address the hypothesis that the C-receptor arises from the initiation of translation of a methionine C-terminal to the methionine start sites that generate the larger 94-kDa A and 116-kDa B human PR isoforms. The studies shown here support the postulate that another downstream in-frame methionine within the PR-coding region can serve as a translation initiation site for the generation of a third PR protein. A partial PR complementary DNA, lacking the translation start sites for B- and A-receptors was translated in vitro. The synthetic protein product bound [3H]progestins and unlabeled progestins. The antiprogestin RU486 also competed for this binding. Transfection of this partial PR complementary DNA into PR-negative HeLa cells resulted in progestin-specific binding activity. Because the third PR isoform lacks the first zinc finger of the DNA binding domain, but contains sequences for dimerization, we reasoned that the C-receptor isoform would be transcriptionally in-active and not bind DNA directly. Surprisingly, however, in the presence of A- and/or B-receptors, we found that C-receptors can modulate the transcriptional activity of A- and/or B-receptors using a reporter gene. These studies emphasize that multiple receptor isoforms may have distinct biological properties, and that the truncated C-receptor may play a role in explaining some of the pleiotropic effects of progestins.

Antineoplastic Agents↗
PubMed1995

Activation of the small GTP-binding proteins rho and rac by growth factor receptors.

The small GTP-binding proteins, rho and rac, control signal transduction pathways that link growth factor receptors to the activation of actin polymerization. In Swiss 3T3 cells, rho proteins mediate the lysophosphatidic acid and bombesin-induced formation of focal adhesions and actin stress fibres, whilst rac proteins are required for the platelet-derived growth factor-, insulin-, bombesin- and phorbol ester (phorbol 12-myristate 13-acetate)-stimulated actin polymerization at the plasma membrane that results in membrane ruffling. To investigate the role of p85/p110 phosphatidylinositol 3-kinase in the rho and rac signalling pathways, we have used a potent inhibitor of this activity, wortmannin. Wortmannin has no effect on focal adhesion or actin stress fibre formation induced by lysophosphatidic acid, bombesin or microinjected recombinant rho protein. In contrast, it totally inhibits plasma membrane edge-ruffling induced by platelet-derived growth factor and insulin though not by bombesin, phorbol ester or microinjected recombinant rac protein. We conclude that phosphatidylinositol 3,4,5 trisphosphate mediates activation of rac by the platelet-derived growth factor and insulin receptors. The effects of lysophosphatidic acid on the Swiss 3T3 actin cytoskeleton can be blocked by the tyrosine kinase inhibitor, tyrphostin. Since tyrphostin does not inhibit the effects of microinjected rho protein, we conclude that lysophosphatidic acid activation of rho is mediated by a tyrosine kinase.

3T3 Cells↗
PubMed1994

Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling.

BACKGROUND: There is substantial evidence that phosphoinositide 3-kinase (PI 3-kinase) is a critical component of signalling pathways used by the cell-surface receptors for a variety of mammalian growth factors and other hormones. The physiological product of this enzyme is a highly polar membrane lipid called phosphatidylinositol (3,4,5)-trisphosphate This lipid has been postulated to act as a second-messenger in cells but its putative targets are still unknown. RESULTS: A particular rearrangement of actin filaments, which results in membrane ruffling, is elicited by the activation of PDGF beta-receptors expressed in cultured porcine aortic endothelial cells. We have found that this consequence of PDGF beta-receptor activation is inhibited by three independent manipulations of PI 3-kinase activity: firstly, by the deletion of tyrosine residues in the PDGF beta-receptor to which PI 3-kinase binds; secondly, by the overexpression of a mutant 85 kD PI 3-kinase regulatory subunit to which the catalytic kinase subunit cannot bind; and thirdly, by the addition of the fungal metabolite wortmannin, which is a potent inhibitor of the catalytic activity of PI 3-kinase. CONCLUSIONS: These results argue strongly that phosphatidylinositol (3,4,5)-trisphosphate synthesis is required for growth-factor-stimulated membrane ruffling in porcine aortic endothelial cells, and suggest that synthesis of this lipid may be part of a signalling pathway leading to direct or indirect activation of the small GTP-binding protein Rac.

Androstadienes↗
PubMed1994

Multicentric evaluation of a new PT reagent based on recombinant human tissue factor and synthetic phospholipids.

A new PT reagent based on recombinant human tissue factor and synthetic phospholipids (phosphatidyl choline and phosphatidyl serine) with defined fatty acid side chains was calibrated against BCT/253 and CRM 149R. A small but consistent bias in the International Sensitivity Index (ISI) value was obtained using either the human or rabbit brain reference material. ISI values were around 1.0 or slightly lower depending on the respective instrument. Mixing studies with factor deficient plasmas showed a high factor sensitivity especially for factor VII as compared to commercial rabbit brain or human placenta thromboplastin. In an international field trial the reagent was tested using fully or semi automated Electra coagulometers in 4 different laboratories. Results with normal samples were in excellent agreement among the different laboratories. Mean values were 10.9, 10.9, 11.0, 11.2 s with a range of 9.5 to 12.5 s. Results of males and females were not different. In patients with liver disease very similar PT activities were found as compared to sensitive rabbit brain or human placental thromboplastins. In normals and patients with oral anticoagulation INR values correlated very well against BCT (r = 0.98, regression line y = -0.07 + 0.9 x). The distribution of samples was linear over the whole range. In the comparison against sensitive rabbit brain thromboplastin or human placental thromboplastin similar correlations were found. In a few cases higher INR values were observed for the recombinant reagent especially in patients with intensive treatment. Factor assays in those patients showed at least the strong reduction of one vitamin K-dependent coagulation factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗