bluuebunny/crossref_metadata_2025 huggingface dataset:
Aprotinin Reduces Nitric Oxide Production in Vitro and in Vivo in a Dose-Dependent Manner
Authors: Bruda N. L. , Hurlbert B. J. , Hill G. E.
Published: August 2015

1. Cardiopulmonary bypass is associated with an increase in nitric oxide concentrations, and plasma levels of tumour necrosis factor and interleukin-1. Aprotinin, a serine protease inhibitor, commonly used during cardiopulmonary bypass to reduce blood loss, has been demonstrated to exhibit significant anti-inflammatory effects during and after cardiopulmonary bypass.

2. Airway nitric oxide was measured during cardiopulmonary bypass in 10 controls (Group 1), 10 subjects receiving half-dose aprotinin (Group 2) and 10 patients receiving full-dose aprotinin (Group 3). In vitro, a murine bronchial epithelial cell line (LA-4) was cultured with cytomix (a combination of tumour necrosis factor, interleukin-1, and (γ-interferon) with and without aprotinin in increasing concentrations. Nitrite concentrations, the stable and measureable end-product of nitric oxide oxidative metabolism, were measured in the culture supernatant by chemiluminescence.

3. Airway nitric oxide concentrations were increased after 50 min cardiopulmonary bypass compared with that measured at 5 min in controls (53 ± 5 versus 29 ± 3 ppb, P < 0.05) but not in the aprotinin-treated groups (25 ± 4 versus 14 ± 5, Group 2; 21 ± 6 versus 15 ± 3 ppb, Group 3).

4. In a dose-dependent manner, nitrite levels (means ± S.E.M.) were significantly reduced by aprotinin at 500 and 1000 units/ml when compared with cells cultured in the presence of cytomix alone (P < 0.05).

5. These data demonstrate that aprotinin, in a dose-responsive manner, reduces nitric oxide production in vivo and reduces cytokine-induced nitrite production by murine bronchial epithelial cells in vitro. Since increased airway nitric oxide is found in inflammatory lung diseases, like asthma, and anti-inflammatory therapy reduces the concentration of airway nitric oxide, these data support the concept that aprotinin is anti-inflammatory during cardiopulmonary bypass.
A Circadian Variation Exists for Soluble Levels of Intercellular Adhesion Molecule-I and E-Selectin in Healthy Volunteers
Authors: Maple C. , Kirk G. , McLaren M. , Veale D. , Belch J.J.F.
Published: August 2015

1. We have previously shown a circadian variation in leucocyte activation and endothelial function which may explain why some inflammatory and vascular diseases show a circadian variation in disease activity/occurrence.

2. We have investigated the circadian variation of two soluble cell adhesion molecules, intercellular adhesion molecule-1 and E-selectin, in 10 healthy volunteers. Soluble intercellular adhesion molecule-1 is released from both activated leucocytes and endothelial cells while soluble E-selectin is released only from activated endothelium.

3. Results show a circadian variation exists for both soluble intercellular adhesion molecule-1 and E-selectin (both P < 0.0001, analysis of variance) with a peak activity at 12:00 h for both measures and a minimum activity at 04:00 h for intercellular adhesion molecule-1 and 00:00 h for E-selectin.

4. These results demonstrate the existence of a diurnal variation in cell adhesion molecules, providing evidence in support of a diurnal pattern in endothelial and leucocyte activation. An alteration in this biological rhythm may help to explain the diurnal variation in disease activity in certain inflammatory and vascular disease states. Furthermore, it stresses the importance of sample time point standardization in clinical studies.
Colour Doppler Sonographic Diagnosis of Upper Limb Venous Thromboses
Authors: Kröger K. , Schelo C. , Gocke C. , Rudofsky G.
Published: August 2015

1. Upper limb venous thromboses are considered to be a rare event, but in large hospitals with a lot of patients who receive aggressive intravenous therapy the number of thromboses seem to increase.

2. We have analysed all the cases of upper limb venous thrombosis which occurred at the Essen University Hospital between the years of 1992–1996. All patients were examined using colour Doppler sonography.

3. Out of 827 patients that were examined, a thrombosis was diagnosed in 334 cases. The subclavian vein was involved in 69% of all thromboses. Isolated jugular vein thrombosis was found in 17% of the thromboses, combined thromboses of the jugular and subclavian vein in 19%. In 182 cases the patients were treated for primarily a malignant illness. In 96 cases we found an association with venous port-systems or central venous catheters.

4. More than 40000 patients a year were treated at the university hospital. Considering this huge number of patients the thrombosis of the upper limb is still rare. The use of colour Doppler sonography allows an early and safe diagnosis of the thrombosis without straining the patient.
Effect of Topical Butyrate on Rectal Epithelial Kinetics and Mucosal Enzyme Activities
Authors: Gibson Peter R. , Kilias Diana , Rosella Ourania , Day Jenny M. , Abbott Margaret , Finch Caroline F. , Young Graeme P.
Published: August 2015

1. This study aimed to determine the effect of luminal butyrate on proliferative kinetics, a differentiation marker (alkaline phosphatase), and a molecule that controls cell-substratum adhesion (urokinase) in histologically normal human rectal mucosa.

2. Ten subjects with a colonoscopically normal colon (seven had previous adenomas) were given either butyrate or saline enemas for 4 days in a double-blind cross-over manner. Rectal biopsies were taken before and after each course of enemas. Epithelial proliferative kinetics were measured immunohistochemically using antibodies to proliferating cell nuclear antigen. Urokinase and alkaline phosphatase activities were measured spectrophotometrically in biopsy homogenates.

3. Both saline and butyrate enemas were well tolerated and induced no histological change except for a significant increase in crypt length (P < 0.05). The number of proliferating cells per crypt also increased significantly after butyrate (P = 0.018).

4. Compared with saline enemas, butyrate did not affect kinetic indices nor alkaline phosphatase activities. However, mucosal urokinase activities were significantly lower in butyrate-treated patients (9.5 ± 2.0 i.u./g) than in saline-treated patients (12.8 ± 2.0 i.u./g; P = 0.045).

5. Delivering of extra butyrate to the distal colon in healthy subjects may stabilize cell-substratum adhesion in surface epithelium and therefore offer a potential mechanism by which elevating distal colonic luminal butyrate concentrations might be beneficial in patients with colitis or hyperproliferative large bowel epithelium.
Role of T-cells in the development of arthritis
Authors: GASTON J. S. H.
Published: August 2015

1.Arthritis can be induced in rodents by priming T-cells to respond to a foreign antigen and then challenging with antigen intra-articularly. This may be a model of the situation in human reactive arthritis in which T-cell responses are induced by antigens from organisms which trigger reactive arthritis (e.g. Chlamydia trachomatis) and antigen finds its way to the joint, most probably within macrophages. Priming by previous exposure to antigens similar to those of the triggering organism could also play a part in pathogenesis. Genetic factors determining the nature and control of the immune response affect the severity and duration of the arthritis.

2.T-cell-dependent arthritis can be induced in rodents by immunization with an antigen known to be expressed in the joint (e.g. Type II collagen). Whether this is an important mechanism in human arthritis is still unclear, even though diseases such as rheumatoid arthritis are conventionally thought of as ‘autoimmune'. No convincing candidate autoantigen has yet been identified in rheumatoid arthritis, and recent experiments in transgenic mice indicate that arthritis can be induced by an autoimmune T-cell response which does not target an antigen confined to the joint.

3.Adjuvant arthritis is a classical T-cell-dependent animal model of human arthritis; recently arthritis has been described as a rare complication in patients receiving adjuvant (intra-vesical live BCG organisms) for bladder cancer. Increasing attention is being paid to the role of adjuvants as ‘danger signals', which allow the immune system to determine whether an antigenic challenge poses a threat. Inappropriate attachment of danger signals to self antigens may result in T-cell-mediated immune responses, which could play a part in the pathogenesis of arthritis.

4.Animal studies indicate that autoimmune/inflammatory diseases can be produced by imbalances within T-cell populations, and that certain T-cells also have the capacity to regulate inflammatory responses. Among the latter are T-cells specific for conserved epitopes within heat shock protein 60. The extent to which T-cells of this kind operate in human disease has yet to be determined.
Predicting composition of leg sections with anthropometry and bioelectrical impedance analysis, using magnetic resonance imaging as reference
Authors: FULLER N. J. , HARDINGHAM C. R. , GRAVES M. , SCREATON N. , DIXON A. K. , WARD L. C. , ELIA M.
Published: August 2015

Magnetic resonance imaging (MRI) was used to evaluate and compare with anthropometry a fundamental bioelectrical impedance analysis (BIA) method for predicting muscle and adipose tissue composition in the lower limb. Healthy volunteers (eight men and eight women), aged 41 to 62 years, with mean (S.D.) body mass indices of 28.6 (5.4) kg/m2 and 25.1 (5.4) kg/m2 respectively, were subjected to MRI leg scans, from which 20-cm sections of thigh and 10-cm sections of lower leg (calf) were analysed for muscle and adipose tissue content, using specifically developed software. Muscle and adipose tissue were also predicted from anthropometric measurements of circumferences and skinfold thicknesses, and by use of fundamental BIA equations involving section impedance at 50 kHz and tissue-specific resistivities. Anthropometric assessments of circumferences, cross-sectional areas and volumes for total constituent tissues matched closely MRI estimates. Muscle volume was substantially overestimated (bias: thigh, -40%; calf, -18%) and adipose tissue underestimated (bias: thigh, 43%; calf, 8%) by anthropometry, in contrast to generally better predictions by the fundamental BIA approach for muscle (bias: thigh, -12%; calf, 5%) and adipose tissue (bias: thigh, 17%; calf, -28%). However, both methods demonstrated considerable individual variability (95% limits of agreement 20–77%). In general, there was similar reproducibility for anthropometric and fundamental BIA methods in the thigh (inter-observer residual coefficient of variation for muscle 3.5% versus 3.8%), but the latter was better in the calf (inter-observer residual coefficient of variation for muscle 8.2% versus 4.5%). This study suggests that the fundamental BIA method has advantages over anthropometry for measuring lower limb tissue composition in healthy individuals.
Effects of angiotensin II on remodelling of the airway and the vasculature in the rat
Authors: RAMSAY Scott G. , KENYON Christopher J. , WHYTE Niall , MCKAY Ian C. , THOMSON Neil C. , LINDOP George B. M.
Published: August 2015

Airway remodelling occurs in chronic asthma. Angiotensin II promotes growth in cardiovascular remodelling. Since the renin–angiotensin system is activated in acute severe asthma, we hypothesized that angiotensin II has a role in airway remodelling. A total of 14 young male Wistar rats were randomly divided into two groups. All received 2-week infusions of bromodeoxyuridine, and the experimental group also received angiotensin II. Blood pressure rose in the angiotensin II-infused group [mean levels: pre-infusion, 134.9 (S.D. 14.7) mmHg; post-infusion, 197.1 (22.5) mmHg], and expression of renin mRNA in the renal juxtaglomerular cells was suppressed in these animals. The proportion of bromodeoxyuridine-positive cell nuclei was no different in the airways of control and angiotensin II-infused animals for smooth muscle [mean bromodeoxyuridine index: control, 8.6% (S.E.M. 1.1%); angiotensin II, 9.3% (1.1%)], epithelium [control, 16.7% (2.3%); angiotensin II, 16.0% (2.2%)] and adventitia [control, 26.4% (2.2%); angiotensin II, 26.6% (2.4%)]. In the arteries, bromodeoxyuridine indices were higher in the angiotensin II-infused rats [18.4% (2.3%)] than in the control animals [9.4% (2.8%)], but no difference was found in the veins [12% (2.9%) and 11.4% (2.6%) respectively]. Morphometry of the airway wall and mesenteric vasculature was no different in the two groups. Therefore a 2-week infusion of angiotensin II increases blood pressure and DNA synthesis in the mesenteric arteries, but does not cause airway remodelling, in the rat.
Na+/H+ exchanger activity and phosphorylation in temperature-sensitive immortalized proximal tubule cell lines derived from the spontaneously hypertensive rat
Authors: NG Leong L. , JENNINGS Sonja , DAVIES Joan E. , QUINN Paulene A.
Published: August 2015

Freshly isolated proximal tubules from the spontaneously hypertensive rat (SHR) demonstrate elevated Na+/H+ exchanger (NHE) activity, but the underlying mechanism is unclear. Because of the difficulties in preparing sufficient numbers of proximal tubule cells for detailed biochemical studies, we have generated cell lines from SHR and Wistar–Kyoto rat (WKY) proximal tubule cells. Cell lines were obtained by transforming the cells with an origin-defective mutant of simian virus 40 encoding a heat-labile T antigen (tsA58 transformant). Such cells proliferate at the permissive temperature of 33 °C, but growth is abolished at the restrictive temperature of 39 °C. The predominant NHE isoform expressed was isoform 1, as determined by sensitivity to HOE-694 (3-methylsulphonyl-4-piperidinobenzoyl guanidine) and Western blotting using specific polyclonal antisera to NHE-1. NHE-3 protein was also present. Northern blots of poly(A) mRNA extracts of the cell lines revealed a low abundance of transcripts for NHE-2, -3 and -4, with no systematic difference between the lines. Although the intracellular pH was similar in the SHR and WKY lines, HOE-694-sensitive H+ efflux due to NHE-1 was substantially elevated in SHR lines compared with WKY lines (95.0±2.8 and 39.9±5.7 mmol·min-1·l-1 respectively; P < 0.001; n = 6). H+ efflux due to non-Na+-dependent mechanisms were similar in lines from the two strains. Western blotting revealed that NHE-1 density was also very similar in SHR and WKY lines, and subcellular fractionation of homogenates indicated that NHE-1 was localized predominantly to plasma membranes. Thus the turnover number of NHE-1 was increased. Immunoprecipitation of 32P-labelled phosphoproteins from these lines demonstrated an approximately 2-fold higher degree of phosphorylation of NHE-1 in SHR compared with WKY lines. These cell lines form a useful model for defining the biochemical mechanisms leading to the NHE-1 phenotype in the SHR kidney, in addition to investigations of other SHR phenotypic markers.
Short-term analysis of the relationship between blood pressure and urinary sodium excretion in normotensive subjects
Authors: CENTONZA Leonardo , CASTOLDI Giovanna , CHIANCA Roberto , BUSCA Giuseppe , GOLIN Raffaello , ZANCHETTI Alberto , STELLA Andrea
Published: August 2015

The aim of this study was to investigate whether, in the short term, physiological blood pressure changes are coupled with changes in urinary sodium excretion in normotensive subjects, maintained at fixed sodium intake and under controlled postural and behavioural conditions. Twelve normotensive subjects were recruited. For each subject, seven urine samples were collected at fixed time intervals during an overall 26 h period: late afternoon (16.00–20.00 hours), evening (20.00–24.00 hours), night (24.00–06.00 hours), quiet wakefulness (06.00–09.00 hours), morning (09.00–12.00 hours), post-prandial (12.00–15.00 hours) and afternoon (15.00–18.00 hours). Blood pressure was monitored by an ambulatory blood pressure device during the whole 26 h period. Each urine sample was used to measure urinary sodium excretion and glomerular filtration rate (creatinine clearance). Blood pressure, heart rate, urinary sodium excretion and glomerular filtration rate recorded in the daytime were higher than those measured during the night-time. A significant positive correlation between mean blood pressure and urinary sodium excretion was found during the night, over the whole 26 h period, and during two subperiods of the daytime: quiet wakefulness and the post-prandial period. The coefficient of the pressure–natriuresis curve was significantly decreased by postural changes. We conclude that, in normotensive subjects, blood pressure and urinary sodium excretion are coupled in the short term. The assumption of an upright posture can mask this relationship, presumably by activating neurohumoral factors.
Perception of bronchoconstriction and bronchial hyper-responsiveness in asthma
Authors: OTTANELLI R. , ROSI E. , ROMAGNOLI I. , RONCHI M. C. , LANINI B. , GRAZZINI M. , FILIPPELLI M. , STENDARDI L. , DURANTI R. , SCANO G.
Published: August 2015

The inter-relationship between the perception of bronchoconstriction, bronchial hyper-responsiveness and temporal adaptation in asthma is still a matter of debate. In a total of 52 stable asthmatic patients, 32 without airway obstruction [forced expiratory volume in 1 s (FEV1)/vital capacity (VC) 84.1% (S.D. 7.9%)], and 20 with airway obstruction [FEV1/VC 60% (4%)], we assessed the perception of bronchoconstriction during methacholine inhalation by using: (i) the slope and intercept of the Borg and VAS (Visual Analog Scale) scores against the decrease in FEV1, expressed as a percentage of the predicted value; and (ii) the Borg and VAS scores at a 20% decrease in FEV1 from the lowest post-saline level (PB20). Bronchial hyper-responsiveness was assessed as the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20FEV1). The reduction in FEV1 was significantly related to the Borg and VAS scores, with values for the group mean slope and intercept of this relationship of 0.13 (S.D. 0.08) and -1.1 (3.02) for Borg, and 1.5 (1.19) and -12.01 (35) for VAS. PB20 was 3 (1.75) with Borg scores and 34.6 (20.5) with VAS scores. Compared with the subgroup without airway obstruction, the obstructed subgroup exhibited similar slopes, but lower Borg and VAS intercepts. For similar decreases in FEV1 (5–20% decreases from the lowest post-saline values), the Borg and VAS scores were lower in the non-obstructed than in the obstructed subgroup. PC20FEV1 was significantly related to both Borg PB20 and VAS PB20 when considering all patients. When assessing the subgroups, PC20FEV1 was related to Borg PB20 and VAS PB20 in the non-obstructed subjects, but not in the obstructed subjects. In neither subgroup was the log of the cumulative dose related to the Borg and VAS scores at the end of the test. We conclude that, unlike in previous studies, the ability to perceive acute bronchoconstriction may be reduced as background airflow obstruction increases in asthma. Bronchial hyper-responsiveness did not play a major role in perceived breathlessness in patients without airway obstruction, and even less of a role in patients with obstruction. The cumulative dose of agonist did not appear to influence the perception of bronchoconstriction.
Blood pressure and renal haemodynamic response to salt during the normal menstrual cycle
Authors: PECHÈRE-BERTSCHI Antoinette , MAILLARD Marc , STALDER Hans , BRUNNER Hans R. , BURNIER Michel
Published: August 2015

The purpose of the present study was to evaluate prospectively blood pressure and the renal haemodynamic response to salt during the normal menstrual cycle. A total of 35 healthy normotensive young women not on oral contraceptives were enrolled; 17 were studied in the follicular phase and 18 in the luteal phase of the menstrual cycle. The women in each group were then randomly allocated to receive a low-sodium (40 mmol/day) or a high-sodium (250 mmol/day) diet for a 7-day period in two consecutive menstrual cycles. At the end of each dietary period, 24 h ambulatory blood pressure, urinary sodium excretion, plasma renin activity, plasma catecholamine levels and renal haemodynamics were measured. Our results show that the blood pressure response to salt is comparable during the luteal and the follicular phases of the normal menstrual cycle and is characterized by a salt-resistant pattern. In the kidney, effective renal plasma flow was significantly greater and the filtration fraction lower (P < 0.05) after salt loading in women studied in the luteal phase compared with women investigated in the follicular phase. This study thus demonstrates that the female hormone status does not affect the blood pressure response to sodium in young normotensive women. However, in contrast with systemic haemodynamics, the renal response to salt varies during the normal menstrual cycle, suggesting that female sex hormones play a role (direct or indirect) in the regulation of renal haemodynamics.
On the mechanism of growth hormone-induced stimulation of renal acidification in humans: effect of dietary NaCl
Authors: JEHLE Sigrid , HULTER Henry N. , KRAPF Reto
Published: August 2015

Sustained administration of growth hormone (GH) to human subjects with NH4Cl-induced chronic metabolic acidosis (CMA) results in a large (4.5±0.5 mmol/l) increase in the plasma HCO3- concentration, as mediated by a large increase in renal net acid excretion. The renal mechanism(s) responsible for the potent stimulation of renal hydrogen ion secretion by GH remain to be elucidated. Accordingly, we have assessed the Na+ dependence of prolonged GH-stimulated renal acidification in four normal NaCl-restricted subjects (Na+ intake 0.3 mmol⋅kg-1⋅day-1) during CMA (4.2 mmol of NH4Cl⋅kg-1⋅day-1 for 7 days), CMA plus GH (0.1 unit/kg every 12 h for 5 days) and then CMA plus GH plus NaCl (1.7 mmol⋅kg-1⋅day-1 for 6 days). During CMA, urine Na+ excretion averaged 22.4±4.1 mmol/24 h. In response to GH administration, urinary net acid excretion was essentially unchanged, and the accumulated increment over 5 days of GH treatment was not different from zero (14±12 mmol; not significant). The plasma HCO3- concentration increased only slightly, from 14.2±0.8 to 15.0±1.1 mmol/l (P < 0.05). Despite the constraint on net acid excretion imposed by NaCl restriction, renal ammonia production increased, as suggested by increases in urine pH from 5.58±0.05 to 5.82±0.04 (P < 0.005) and unchanged NH4+ excretion (202±17 to 211±19 mmol/24 h; not significant). In response to dietary NaCl, urine pH decreased to 5.27±0.1 (P < 0.001) and a large increment in net acid excretion accumulated (233±20 mmol; P < 0.05), in association with an increase in plasma HCO3- to 18.7±1.3 mmol/l (P < 0.001), a plasma HCO3- value similar to that reported previously in salt-replete, NH4Cl-fed subjects. These results demonstrate for the first time in any species that the acid excretory effect of GH administration is critically dependent on the availability of a surfeit of Na+ for tubular reabsorption. GH and/or insulin-like growth factor-1 affect renal acid excretion proximally (by stimulation of NH3 production) and by a Na+-transport-dependent mechanism in the collecting duct (voltage-driven acidification) in humans. The present results indicate that an isolated increase in renal NH3 production is insufficient to obligate an increase in net acid excretion.
Organization and reorganization of human swallowing motor cortex: implications for recovery after stroke*
Authors: HAMDY Shaheen , ROTHWELL John C. , AZIZ Q. , THOMPSON David G.
Published: August 2015

Swallowing problems can affect as many as one in three patients in the period immediately after a stroke. In some cases this can lead to serious morbidity, in particular malnutrition and pulmonary aspiration. Despite this, swallowing usually recovers to a safe level in the majority of patients within weeks. This propensity for recovery is likely to relate to how the swallowing motor cortex is organized and then reorganized after cerebral injury. In this review, we examine present knowledge on the cortical control of swallowing in humans, and examine the aspects of its organization that are important for compensating for recovery after damage. In addition, we examine approaches which may be useful in speeding up the process of recovery. Swallowing may turn out to be a useful model for studying central nervous system plasticity.
Characterization of an in vitro model for the study of the short and prolonged effects of myocardial ischaemia and reperfusion in man
Authors: ZHANG Jin-Gang , GHOSH Sudip , OCKLEFORD Colin D. , GALIÑANES Manuel
Published: August 2015

The mechanisms underlying myocardial ischaemia and reperfusion-induced injury have been investigated, mainly by using animal experimental preparations in vitro and in vivo, but little is known of the process in human myocardium. The present studies characterize an in vitro model using human myocardium for the study of early and delayed effects of ischaemia and reperfusion. The right atrial appendage was manually sliced and incubated in buffer through which was bubbled O2/CO2 (19:1, v/v) for various time periods. Lactate dehydrogenase (LDH) leakage, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl-2H-tetrazolium bromide (MTT) reduction, oxygen consumption, nucleotide levels and tissue morphology were all investigated as markers of myocardial injury. The specimens remained stable and viable up to 24 h, but had significantly deteriorated by 48 h. The preparation responded to ischaemia in a time-related manner. Tissue viability was reduced by 25% after 30 min ischaemia, declined to 60% after 60 min ischaemia and to 75% after 120 min ischaemia. Interestingly, the tissue was more susceptible when ischaemia was induced after 24 h of aerobic incubation. The effects of the duration of reperfusion were investigated after a fixed 60 min ischaemic insult. The results of LDH leakage suggest that reperfusion injury is mainly sustained within the first 2 h of reperfusion. However, the results of MTT reduction show that there is a progressive decrease in tissue viability over the 24 h reperfusion period, possibly reflecting the occurrence of tissue necrosis and apoptosis at different reperfusion times. In conclusion, the data provide evidence that the incubation of human atrial tissue in vitro is stable, and slices are viable for at least 24 h, which permits the study of early and delayed consequences of ischaemia and reperfusion in the human myocardium.
Allometric analysis of the association between cardiac dimensions and body size variables in 464 junior athletes
Authors: GEORGE K. , SHARMA S. , BATTERHAM A. , WHYTE G. , MCKENNA W.
Published: August 2015

Empirically derived relationships between body size variables and cardiac dimensions have not been published previously for a large sample of male and female athletes. This process would inform scaling practice and facilitate intra- and inter-group comparisons of cardiac data. Therefore we investigated the relationships of body mass (BM), height and body surface area (BS) with a range of cardiac dimensions derived by echocardiography in 464 male and female elite junior athletes (age range 14–18 years; sporting allocation included rowers, cyclists, footballers, tennis players, swimmers and a miscellaneous group). Initial linearity checks suggested that most of the relationships between the body size variables and cardiac dimensions were non-linear, thus precluding the simple ratio standard approach to scaling. Multiple log–log least-squares linear regression confirmed commonality of slopes (between males and females, across the age range and between sporting groups) for all relationships involving BM and BS. Subsequent analyses of the slope exponent (b) for left ventricular dimensions supported previous data and were dimensionally consistent (LVM–BM, b = 0.91±0.11; LVM–BS, b = 1.44±0.19; where LVM is left ventricular mass), except for left ventricular internal dimension in diastole (LVIDd) (LVIDd–BM, b = 0.25±0.04). Data for the left atria internal dimension (LA) were also dimensionally consistent (LA–BM, b = 0.29±0.09); however, this was not the case for the right ventricular internal dimension in diastole (RVIDd) (RVIDd–BM, b = 0.76±0.14). It is possible that these results were due to a study-specific limitation in the data range (LVIDd) and the geometric peculiarities of RVIDd compared with LVIDd. The gender/age/sporting group×body size interaction factor for virtually all relationships between height and cardiac dimensions was significant (P < 0.05), and thus whole-group b exponents could not be generated. Generally these data support previous small-sample research with athletes, and suggest that allometric scaling, as opposed to simple ratio scaling, should be adopted in studies of cardiac dimensions in athletes. This should allow, with minimal mathematical difficulty, the production of body-size-independent cardiac indices to be evaluated in laboratory or clinical work. Further research is required to develop normative ‘allometrically derived’ cardiac indices, and care should be taken to determine relationships in specific population groups as well as to confirm commonality of slopes in multiple group comparisons. Caution is expressed regarding the use of height as a scaling variable in future research.
Nitric oxide modulation of blood vessel tone identified by arterial waveform analysis
Authors: McVEIGH Gary E. , ALLEN Patrick B. , MORGAN David R. , HANRATTY Colm G. , SILKE Bernard
Published: August 2015

Traditionally, nitric oxide-mediated alteration in blood vessel tone has been inferred from changes in flow in response to physical and pharmacological interventions using plethysmographic or ultrasonic techniques. We hypothesized that alteration in pulsatile arterial function may represent a more sensitive measure to detect and monitor nitric oxide-mediated modulation of arterial smooth muscle tone. Healthy male volunteers (n = 15) had radial artery pressure pulse waveforms recorded using a calibrated tonometer device. A computer-based assessment of the diastolic pressure decay was employed to quantify changes in arterial waveform morphology in terms of altered pulsatile (arterial compliance) and steady-state (peripheral resistance) haemodynamics. NG-nitro-L-arginine methyl ester (L-NAME), a stereospecific inhibitor of nitric oxide synthesis, was infused intravenously in incrementally increasing doses of 0.25, 0.5 and 0.75 mg/kg for 8 min each. Subjects then received either L-arginine or D-arginine (200 mg/kg over 15 min) intravenously in a blinded fashion. On a separate day, subjects had radial artery pressure pulse waveforms recorded before and after the sublingual administration of glyceryl trinitrate, an exogenous donor of nitric oxide. Cardiac output and heart rate decreased and mean arterial blood pressure increased significantly (P < 0.01 for all) in response to the incremental intravenous infusion of L-NAME. Small artery compliance decreased, whereas systemic vascular resistance increased in response to nitric oxide synthesis inhibition (P < 0.01 for both). The intravenous infusion of L-arginine restored the pulsatile and steady-state haemodynamic parameters to pre-treatment values, whereas D-arginine had no effect. Sublingual glyceryl trinitrate decreased systemic vascular resistance by 11%, whereas large artery- and small artery-compliance increased by 25% and 44% respectively. Pressure pulse contour analysis represents a sensitive and convenient technique capable of tracking changes in the pulsatile function of arteries accompanying nitric oxide-mediated alteration in arterial smooth muscle tone.
Angiotensin receptors: distribution, signalling and function
Authors: DINH Diem T. , FRAUMAN Albert G. , JOHNSTON Colin I. , FABIANI Maurice E.
Published: August 2015

Angiotensin II (Ang II) is a multi-functional hormone that plays a major role in regulating blood pressure and cardiovascular homoeostasis. The actions of Ang II are mediated by at least two receptor subtypes, designated AT1 and AT2. In addition, other angiotensin receptors have been identified which may recognize other angiotensin peptide fragments; however, until now only the AT1 and AT2 receptor have been cloned in animals or humans. Most of the well-described actions of Ang II, such as vasoconstriction, facilitation of sympathetic transmission, stimulation of aldosterone release and promotion of cellular growth are all mediated by the AT1 receptor. Much less is known about the function of the AT2 receptor, but recent studies suggest that it may play a role in mediating anti-proliferation, cellular differentiation, apoptosis and vasodilatation. In this review, we discuss recent advances in our understanding of Ang II receptors, in particular, their distribution, signalling and function.
Effect of a phytoestrogen food supplement on reproductive health in normal males
Authors: MITCHELL Julie H. , CAWOOD Elizabeth , KINNIBURGH David , PROVAN Anne , COLLINS Andrew R. , IRVINE D. Stewart
Published: August 2015

Animal studies and human intervention trials have demonstrated the cancer chemopreventive properties of plant phytoestrogens, and phytoestrogen supplements are now widely available ‘over-the-counter’. However, consumption of phytoestrogen-rich diets can cause impaired fertility and reproductive tract disorders in some animals and the apparent decline in human sperm quality over recent decades may be related to increased exposure to environmental endocrine disruptors. The present study determines the effects of a short-term phytoestrogen supplement on semen quality and serum sex steroid and gonadotrophin levels in human males. Healthy volunteers took a supplement containing 40 mg of isoflavones daily for 2 months and donated blood and semen samples monthly for 2 months before and 4 months after supplementation. Semen samples were analysed for ejaculate volume, sperm concentration, total sperm count, motility and morphology. Blood samples were analysed for sex hormone and gonadotrophin levels and phytoestrogen concentrations, and testicular volume was measured using an orchidometer. The phytoestrogen supplement increased plasma genistein and daidzein concentrations to approx. 1 µM and 0.5 µM respectively; yet, there was no observable effect on endocrine measurements, testicular volume or semen parameters over the study period. This is the first study to examine the effects of a phytoestrogen supplement on reproductive health in males. We conclude that the phytoestrogen dose consumed had no effect on semen quality.
Bimodal effects of platelet-derived growth factor on rat mesangial cell proliferation and death, and the role of lysophosphatidic acid in cell survival
Authors: INOUE Chiyoko N. , NAGANO Isao , ICHINOHASAMA Ryo , ASATO Natsumi , KONDO Yoshiaki , IINUMA Kazuie
Published: August 2015

Although mesangial cell death has been shown to be correlated with mesangial cell mitosis in vivo, little is known about how these two apparently opposite events are regulated. We show that the addition of platelet-derived growth factor (PDGF; 10–50 ng/ml) to primary cultured rat mesangial cells for 24 h caused continuous proliferation along with simultaneous cell death. This process was accompanied by the fragmentation of DNA into nucleosomal oligomers, the development of apoptotic morphological changes in the nucleus, and increased expression of p53. Accumulation of lactate dehydrogenase (LDH) was also observed in the culture medium, suggesting that both apoptosis and necrosis are involved in the cell death mechanisms observed. We also observed that addition of 30 µM lysophosphatidic acid (LPA) to the culture medium greatly suppressed PDGF-induced cell death, leading to synergistically enhanced mesangial cell proliferation. DNA fragmentation, p53 expression and LDH release were all suppressed by LPA. We suggest that PDGF is a bifunctional molecule in mesangial cells that evokes both cell proliferation and cell death simultaneously, whereas LPA is a survival factor. We speculate that PDGF and LPA may play important roles in the progression or exacerbation of proliferative glomerulonephritis.
Effects of extracellular pH on tumour necrosis factor-α production by resident alveolar macrophages
Authors: HEMING Thomas A. , DAVÉ Sanat K. , TUAZON Divina M. , CHOPRA Ashok K. , PETERSON Johnny W. , BIDANI Akhil
Published: August 2015

Cellular acid–base status has been found to exert selective actions on the effector functions of activated macrophages (mϕ). We examined the effects of extracellular pH (pHo) on the production of tumour necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS) in resident alveolar mϕ. Cells were obtained by bronchoalveolar lavage of rabbits, activated in vitro with LPS, and cultured at pHo 5.5, 6.5 or 7.4 for up to 18 h. The relative abundance of TNF-α mRNA peaked at ~ 2 h. The peak transcript abundance was increased at lower pHo values. This finding probably reflected pre-transcription/transcription effects of pH, in as much as the stability of TNF-α mRNA induced with phorbol ester was unaffected by the experimental pHo values. TNF-α secretion by LPS-treated mϕ decreased at lower pHo values. The TNF-α content of mϕ-conditioned media decreased progressively with decrements in pHo. The reduced TNF-α secretion at pHo 5.5 was accompanied by an increase in the cytosolic TNF-α content (compared with that at pHo 7.4), indicating that pHo altered TNF-α secretion due, in part, to the intracellular retention of synthesized cytokine (i.e. a post-translation effect). The data show that pHo has multiple effects (pre-transcription/transcription and post-translation) on TNF-α production induced by LPS in resident alveolar mϕ. These results suggest that the role of alveolar mϕ in inflammatory responses is modulated by pHo, which may be important in tumours/abscesses and sites of infection where the external milieu is acidic.
Differential effects of cilostazol and pentoxifylline on vascular endothelial growth factor in patients with intermittent claudication
Authors: LEE Tsung-Ming , SU Sheng-Fang , TSAI Chang-Her , LEE Yuan-The , WANG Shoei-Shen
Published: August 2015

Cilostazol is a new phosphodiesterase inhibitor with anti-platelet and vasodilatory properties. Cilostazol and pentoxifylline are the only two drugs that have been approved for the treatment of patients with intermittent claudication. However, the mechanisms by which exercise tolerance is improved remain unclear. Vascular endothelial growth factor (VEGF) is a potent endothelial mitogen that results in angiogenesis when overexpressed in human subjects. To assess the potential role of VEGF in the improvement in exercise tolerance, we investigated plasma levels of VEGF in 50 patients with intermittent claudication who were allocated randomly to groups receiving cilostazol (n = 17), pentoxifylline (n = 17) or placebo (n = 16). Patients given either cilostazol or pentoxifylline showed a significant improvements in maximal walking distance compared with the placebo group (34 m and 33 m respectively, compared with 5 m; both P < 0.05). Neither cilostazol nor pentoxifylline increased the ankle-brachial index after treatment. Circulating VEGF levels were increased (from 116±29 to 169±45 pg/ml; P = 0.002), and the levels of VEGF were correlated significantly with exercise tolerance in a positive direction (r = 0.88, P = 0.004), in those patients treated with cilostazol that did not have diabetes mellitus. In contrast, VEGF levels remained stable after the administration of pentoxifylline. These findings suggest that VEGF may contribute to the cilostazol-related improvement in exercise tolerance in non-diabetic patients. However, pentoxifylline did not affect VEGF levels, although a similar improvement in maximal walking distance was achieved. Thus the mechanisms involved in the pentoxifylline-treated group were different from those in the cilostazol-treated group, and require further study.
Individuals with cystic fibrosis do not display impaired endothelial function or evidence of oxidative damage in endothelial cells exposed to serum
Authors: McGRATH Lawrence T. , McCALL Damien , HANRATTY Colm G. , BRENNAN Siobhan , DEVINE Adrian , McCAULEY Daniel F. , SILKE Bernard , ELBORN Stuart
Published: August 2015

Heightened systemic oxidative stress is increasingly recognized as a feature of cystic fibrosis (CF). The consequences of long-term exposure to free radical attack include a predisposition to diseases such as cancer and atherosclerosis. An increased incidence of malignancy among adult patients with CF has been reported, but the absence of atherosclerotic disease is well described. The aim of the present study was to assess endothelial function in vivo and relate this to the potential of serum from patients with CF to induce oxidative-mediated damage in cultured human endothelial cells. A group of 11 CF patients was matched with a group of healthy volunteers with regard to age and sex. Endothelial function was assessed as endothelium-dependent and -independent vasodilation by measuring forearm blood flow in response to infused acetylcholine and sodium nitroprusside respectively. Confluent monolayers of cultured human endothelial cells were exposed to serum from CF patients and control subjects. Following exposure, cell death was assessed by lactate dehydrogenase release, and the degree of lipid peroxidation in the membrane was assessed by measuring the content of lipid hydroperoxides, malondialdehyde and 4-hydroxynonenal. Endothelial monolayers exposed to serum from CF patients released significantly less lactate dehydrogenase following exposure than those exposed to serum from healthy controls (1.8% and 3.0% respectively; mean difference -1.2%; 95% confidence intervals -1.9% to -0.1%; P < 0.05) and contained significantly less 4-hydroxynonenal (0.75 and 3.41μmol/g of protein respectively; mean difference -2.66μmol/g; 95% confidence intervals -5.10 to -0.22μmol/g; P < 0.05). There was no significant difference between patients and controls in the extent of serum-induced membrane peroxidation, as assessed by malondialdehyde or lipid hydroperoxides, or in endothelial function, as assessed by forearm blood flow. In conclusion, despite evidence for heightened systemic oxidative stress in CF, patients displayed no impairment of endothelial function, and their serum caused significantly less damage to human endothelial cells than that from matched controls.
Vasoactive intestinal peptide has a direct positive inotropic effect on isolated human myocardial trabeculae
Authors: SAETRUM OPGAARD Ole , KNUTSSON Mikael , DE VRIES René , TOM Beril , SAXENA Pramod R. , EDVINSSON Lars
Published: August 2015

The aim of the present study was to assess the inotropic effects of vasoactive intestinal peptide (VIP) on isolated myocardial trabeculae from the right atrium and the left ventricle of human hearts. Furthermore, using reverse transcriptase-PCR, we wanted to determine the presence of mRNAs encoding the three cloned human VIP receptors, VPAC1, VPAC2 and PAC1. The trabeculae were paced at 1.0Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. VIP had a potent positive inotropic effect in some of the atrial and ventricular trabeculae tested. This effect was almost completely blocked by the VIP-receptor antagonist VIP-(6-28). mRNAs encoding the human VPAC1, VPAC2 and PAC1 receptors were detected in human myocardial trabeculae from both the right atrium and the left ventricle. In conclusion, VIP has a direct positive inotropic effect in both the atria and the ventricles of the human heart. The presence of mRNAs for the VPAC1, VPAC2 and PAC1 receptors suggest that VIP may mediate its effect via these receptors.
Exercise training increases arterial compliance in patients with congestive heart failure
Authors: PARNELL Melinda M. , HOLST Diane P. , KAYE David M.
Published: August 2015

Systemic arterial compliance (SAC) makes an important contribution to cardiac afterload, and thus is a significant determinant of left ventricular work. Previous studies have suggested that arterial compliance may be reduced in patients with congestive heart failure (CHF), and that SAC is increased after a 4-week exercise training programme in healthy, sedentary individuals. The present study aimed to investigate the effects of an 8-week exercise training programme on arterial mechanical properties, left ventricular performance and quality of life in CHF patients. A total of 21 patients with NYHA class II or III CHF (mean±S.D. age 55±13 years) were randomly allocated to either an 8-week exercise training group or a ‘usual lifestyle’ control group. SAC, as determined non-invasively using applanation tonometry and Doppler aortic velocimetry, increased from 0.57±0.11 to 0.77±0.14 arbitrary compliance units (mean±S.E.M.; P = 0.01) in the exercise group, while no change occurred in the control group. Left ventricular structure and function was assessed by echocardiography, and these parameters were unchanged over the 8-week study period. Exercise training significantly increased exercise capacity, measured by a 6-min walking test (474±27 to 547±34 m; P = 0.008). Quality of life, as assessed using the Minnesota Living with Heart Failure Evaluation, demonstrated a decrease in heart failure symptoms from 46±7 to 24±5units (P = 0.01) following the exercise training programme. These data show that exercise training improves SAC in patients with CHF. The accompanying improvement in exercise capacity may be due, in part, to an improvement in arterial function.
Dynamics of the heart rate response to sinusoidal work in humans: influence of physical activity and age
Authors: FUKUOKA Yoshiyuki , NAKAGAWA Yoko , OGOH Katsutoshi , SHIOJIRI Tomoyuki , FUKUBA Yoshiyuki
Published: August 2015

The purpose of the present study was to define the influence of age and exercise training on the heart rate (HR) dynamic response (i.e. kinetics) to sinusoidal work. A total of 63 healthy subjects (31 men and 32 women; age range 19-69 years) underwent a three-step incremental work test, during which peak oxygen uptake (o2peak) was estimated by the YMCA method. Sinusoidal work varying between 20% and 60% of HRreserve was employed for periods of 1, 3, 6, 9 and 12min. HR was monitored in a beat-by-beat manner with a cardiotachometer. The kinetics of the HR response were analysed by frequency analysis and estimated by a first-order transfer function with time constant (τ) and time delay (TD). Physical training status was estimated as stepping frequency, as measured with a pedometer during the daytime, and averaged over seven consecutive days. The mean response time of HR kinetics (HRMRT: τ pulse TD) tended to increase gradually with age (0.36sċyear-1), and linear regression analysis revealed that the correlation between HRMRT and age was significant (r = 0.31, P < 0.05), although not as highly significant as that between HRMRT and physical activity (r =-0.48, P < 0.0001). HRMRT was not related to the S.D. of HR variation (an indicator of parasympathetic mediation) at rest. In addition, o2peak showed a significantly greater correlation with age (r =-0.60, P < 0.0001) than with physical activity (r =-0.14, not significant). In conclusion, these findings suggest that HR dynamics, which may depend on sympathetic nervous activity, are more sensitive to physical activity than to age, but that o2peak, as estimated by the age-associated decline in maximum HR, is unrelated to physical training status.