bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of Effect of Vitamin E on l-Arginine-Responsive Endothelial Dysfunction in Patients with Mild Hypercholesterolaemia and Coronary Artery Disease
Authors: Chowienczyk P. J. , Kneale B. J. , Brett S. E. , Paganga G. , Jenkins B. S. , Ritter J. M.
Published: August 2015

1. Dietary supplementation with vitamin E reduces ischaemic events in patients with established coronary artery disease and improves endothelial function in cholesterol-fed rabbits. We examined whether such dietary supplementation with vitamin E improves endothelial function in patients with mild hypercholesterolaemia and coronary artery disease.

2. Twenty patients (total cholesterol 6.8 ± 1.1 mmol/l, mean ± SD) with angiographically documented coronary artery disease were randomly allocated to receive placebo (n = 10) or vitamin E, 400 i.u. daily, (n = 10) for 8 weeks. Endothelium-dependent and independent vasodilatation within forearm vasculature was assessed by brachial artery infusion of acetylcholine (co-infused with saline vehicle and l-arginine) and nitroprusside before and after supplementation.

3. Plasma concentrations of vitamin E increased from 32.9 ± 3.8 to 69.1 ± 11.8 μmol/l (means ± SE) in the vitamin E-supplemented group (P < 0.01) but did not change significantly in the placebo group. Lipid profiles remained similar before and after supplementation in both groups. Forearm blood flow responses to acetylcholine (7.5 and 15 μg/min) and nitroprusside (3 and 10 μg/min) were similar before and after supplementation in both groups. Acute intra-arterial administration of l-arginine (10 mg/min) augmented the response to acetylcholine (15 μg/min) in both groups before and after supplementation to a similar degree (mean augmentation: 60 ± 18%, P < 0.01).

4. Acute administration of l-arginine reverses endothelial dysfunction in forearm vasculature of patients with mild hypercholesterolaemia and coronary artery disease but supplementation with vitamin E (400 i.u. daily) for 8 weeks does not reverse l-arginine-responsive endothelial dysfunction.
Pharmacological Characterization of Coronary Small Arteries from Pigs with Chronic Ischaemic Myocardial Remodelling
Authors: Buus Niels H. , Terp Kim , Baandrup Ulrik , Mulvany Michael J. , Nyborg Niels C. B.
Published: August 2015

1. The effect of chronic ischaemic myocardial remodelling on small coronary artery reactivity in vitro was studied in a newly developed pig model.

2. Pigs were subjected to selective intracoronary embolizations with microspheres in the left anterior descending artery and circumflex artery causing scattered myocardial fibrosis. After an observation period of 130 days, heart dimensions and ejection fraction were determined with magnetic resonance imaging. Small arteries were isolated from the left ventricle and mounted as ring preparations in a myograph. Control arteries were taken from matched non-embolized pigs.

3. Compared with control pigs, end-systolic and -diastolic volumes increased and left ventricular mass nearly doubled in embolized pigs. This indicates substantial myocardial hypertrophy, as the fraction area of fibrosis was only 12%.

4. Coronary small arteries preconstricted with 30 mmol/l KCl showed a normal contractile response to acetylcholine and 5-hydroxytryptamine. Sensitivity of the relaxation to bradykinin was nearly 3-fold increased and also slightly enhanced to isoprenaline in arteries from embolized pigs compared with controls, whereas relaxation to 5-hydroxytryptamine in the presence of ketanserin was similar. After inhibition of nitric oxide synthase with NG-nitro-l-arginine the sensitivity to acetylcholine increased to a similar extent in arteries from embolized pigs and controls. NG-Nitro-l-arginine abolished the relaxing effects of bradykinin and of 5-hydroxytryptamine in the presence of ketanserin.

5. We conclude that both the contractile function of the smooth muscle cells and the endothelial production or action of nitric oxide is preserved or slightly enhanced in coronary small arteries from pigs with chronic myocardial remodelling.
Relationship between Serum Alkaline Phosphatase and Pyridoxal-5′-Phosphate Levels in Hypophosphatasia
Authors: Iqbal S. J. , Brain A. , Reynolds T. M. , Penny M. , Holland S.
Published: August 2015

1. Hypophosphatasia is a disorder characterized by low serum levels of alkaline phosphatase (ALP) and a range of skeletal deformities. The levels of a number of phosphorylated metabolites, namely phosphoethanolamine and pyrophosphate, are characteristically raised. Levels of pyridoxal-5′-phosphate (PLP) have also been reported to be raised.

2. Hypophosphatasia is a rare disease and experience of measuring PLP in patients is lacking. We have had the chance to look at PLP levels in four families with hypophosphatasia, specifically to examine the quantitative relationship between ALP and PLP which has not been described before.

3. We confirmed that PLP levels are raised in hypo-phosphatasia and related to the disease severity. A significant negative linear relationship was found between the log PLP and log ALP (log PLP = 5.99−2.76 log ALP; r = − 0.85, P < 0.001).

4. Measurement of PLP is simpler than some of the phosphorylated compounds, e.g. pyrophosphate. PLP may be a useful measure in patients with a suspected diagnosis of hypophosphatasia or for screening family members to detect potential heterozygotes and to monitor any response to therapy.

5. There did not appear to be any adverse clinical effects in relation to disturbed vitamin B6 metabolism in hypophosphatasia.

6. Vitamin B6 is used therapeutically in a number of conditions with monitoring of PLP levels. In these conditions PLP levels should be interpreted in conjunction with the prevailing serum ALP levels as the metabolism of these compounds is closely inter-related.
Whole Body Protein Metabolism in Human Pulmonary Tuberculosis and Undernutrition: Evidence for Anabolic Block in Tuberculosis
Authors: MacAllan Derek C. , McNurlan Margaret A. , Kurpad Anura V. , De Souza George , Shetty Prakash S. , Calder A. Graham , Griffin George E.
Published: August 2015

1. Differing patterns of protein metabolism are seen in wasting due to undernutrition and wasting due to chronic infection.

2. We investigated whole body energy and protein metabolism in nine subjects with pulmonary tuberculosis, six undernourished subjects (body mass index < 18.5 kg/m2) and seven control subjects from an Indian population. Fasting subjects were infused with l-[1-13C] leucine (2.3 μmol · h−1 · kg−1) for 8 h, 4 h fasted then 4 h fed. Leucine kinetics were derived from 13C-enrichment of leucine and α-ketoisocaproic acid in plasma and CO2 in breath.

3. Undernourished subjects, but not tuberculosis subjects, had higher rates of whole body protein turnover per unit lean body mass than controls [163.1 ± 9.4 and 148.6 ± 14.6 μmol compared with 142.8 ± 14.7 μmol leucine/h per kg, based on α-ketoisocaproic acid enrichment (P = 0.039)].

4. In response to feeding, protein oxidation increased in all groups. Tuberculosis subjects had the highest fed rates of oxidation (47.0 ± 10.5 compared with 37.1 ± 5.4 μmol · h−1 · kg−1 in controls), resulting in a less positive net protein balance in the fed phase (controls, 39.7 ± 6.2; undernourished subjects, 29.2 ± 10.6; tuberculosis subjects, 24.5 ± 93; P = 0.010). Thus fed-phase tuberculosis subjects oxidized a greater proportion of leucine flux (33.2%) than either of the other groups (controls, 24.0%; undernourished subjects, 24.0%; P = 0.017).

5. Tuberculosis did not increase fasting whole body protein turnover but impaired the anabolic response to feeding compared with control and undernourished subjects. Such ‘anabolic block’ may contribute to wasting in tuberculosis and may represent the mechanism by which some inflammatory states remain refractory to nutrition support.
Reflex Responses of Venous Capacitance Vessels in Patients with Hypertrophic Cardiomyopathy
Authors: Thomson Helen L. , Morris-Thurgood Jayne , Atherton John , McKenna William J , Frenneaux Michael P.
Published: August 2015

1. The aim of this study was to determine if there is impaired reflex venoconstriction in patients with hypertrophic cardiomyopathy and whether this is related to a history of syncope or exercise hypotension.

2. Thirty percent of patients with hypertrophic cardiomyopathy have exercise-induced hypotension associated with a failure of arteriolar constriction. Impaired venoconstriction could exacerbate this situation.

3. We evaluated 43 patients with hypertrophic cardiomyopathy and 24 controls. Nuclear venous plethysmography was used to measure forearm venous capacitance during lower body negative pressure, splenic venous volume changes during bicycle exercise and blood pressure responses to treadmill exercise. We assessed any association between abnormal reflex venous control and a history of syncope and exercise hypotension.

4. The percentage reduction in unstressed forearm venous volume during lower body negative pressure was similar in patients and controls (8.9 ± 7.1% versus 9.7 ± 5.9%, P not significant). Patients with a history of syncope demonstrated a less marked percentage reduction in volume than those without (−2.1 ± 6.9% versus −10.6 ± 6.0%, P = 0.001). In three patients with a history of syncope there was a paradoxical increase in forearm venous volume during lower body negative pressure. During exercise there was a substantially smaller decrease in splenic venous volume in patients compared with controls (−20.1 ± 14.0% and −42.6 ± 12.6% respectively, P = 0.0001). Furthermore, there was an association between attenuated splenic venoconstriction or venodilation and exercise hypotension in patients (P = 0.005).

5. Abnormal reflex control of venous capacitance beds in patients with hypertrophic cardiomyopathy was associated with both syncope and exercise hypotension.
Proximal Renal Tubular Peptide Catabolism, Ammonia Excretion and Tubular Injury in Patients with Proteinuria: Before and after Lisinopril
Authors: Rustom Rana , Grime J. Steve , Costigan Michael , Maltby Paul , Hughes Anthony , Shenkin Alan , Critchley Mair , Bone J. Michael
Published: August 2015

1. Progression to renal failure may be linked to the degree of proteinuria through tubulo-interstitial mechanisms. However, there are no data in man on the kinetics of proximal renal tubular protein catabolism or markers of tubular injury before and after lisinopril. We developed a method to allow such studies, and found increased tubular catabolism of 99mTc-labelled aprotinin (Trasylol) in patients with nephrotic range proteinuria which was associated with increased ammonia excretion.

2. In this study, 10 patients with mild renal impairment (51Cr-EDTA clearance 63.7 ± 8.3 ml · min−1 · 1.73 m−2) and heavy proteinuria (8.2 ± 2.3 g/24 h) were given lisinopril (10–20 mg) for 6 weeks. Renal tubular catabolism of intravenous aprotinin was measured before and after lisinopril by renal imaging and urinary excretion of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Fresh timed urine collections were also analysed for ammonia excretion every fortnight from 6 weeks before treatment. Total urinary N-acetyl-β-d-glucosaminidase and the more tubulo-specific N-acetyl-β-d-glucosaminidase ‘A2’ isoenzyme were also measured.

3. After lisinopril proteinuria fell significantly as expected (from 9.5 ± 1.6 to 4.5 ± 1.0 g/24 h, P < 0.01). This was associated with a reduction in metabolism over 26 h (from 1.7 ± 0.1 to 1.2 ± 0.1% dose/h, P < 0.01) and in fractional degradation of aprotinin (from 0.08 ± 0.02 to 0.04 ± 0.007/h, P < 0.04). Ammonia excretion also fell significantly (from 1.2 ± 0.1 to 0.6 ± 0.1 mmol/h, P < 0.0001), as did both total urinary N-acetyl-β-d-glucosaminidase (P < 0.0001) and the N-acetyl-β-d-glucosaminidase ‘A2’ isoenzyme (P < 0.015). These observations after lisinopril treatment have not been described previously. There was no significant change in blood pressure nor in glomerular haemodynamics.
Genetics of Inflammatory Bowel Disease
Authors: Satsangi Jack , Parkes Miles , Jewell Derek P. , Bell John I.
Published: August 2015

1. The aetiology of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis, is uncertain. Studies of specific environmental factors and immune dysfunction have provided little insight into disease pathogenesis.

2. Concordance rates in twin pairs and siblings provide strong evidence that genetic factors are important in disease pathogenesis. In Oxford, information was obtained from 433 adult patients with Crohn's disease. Compared with the prevalence in the general population, the relative risks in siblings of patients with Crohn's disease calculated from these data were respectively 36.5 for Crohn's disease, 16.6 for ulcerative colitis and 24.7 for inflammatory bowel disease.

3. Clinical patterns of disease were compared in members of over 250 multiply affected families with inflammatory bowel disease. A high degree of concordance for many characteristics was noted (disease type, extent, extra-intestinal manifestations). However, in 77 affected parent—child pairs, the median age of onset in the parents was significantly higher than in offspring (P < 0.0001). These data reflect the results from other studies throughout the world, and are consistent with the phenomenon of genetic anticipation.

4. A detailed study investigating the contribution of the major histocompatibility complex was undertaken. Eighty-three affected sibling pairs were involved in a linkage analysis study; 348 patients with inflammatory bowel disease and 472 controls were involved in a detailed allelic association study. These data provide evidence that the major histocompatibility complex is an important determinant in ulcerative colitis, but not in Crohn's disease.

5. Cytokine genes are important candidate genes in inflammatory bowel disease. Allelic association study was performed to investigate the contribution of the gene encoding the interleukin-1 receptor antagonist and tumour necrosis factor-α. These data do not suggest that these genes encode important determinants of disease susceptibility in inflammatory bowel disease.

6. A two-stage genome-wide search for susceptibility loci in inflammatory bowel disease was performed involving 186 affected sibling pairs. The data provide strong evidence for the model of Crohn's disease and ulcerative colitis as related polygenic disorders. Loci on chromosomes 3, 7 and 12 were linked to inflammatory bowel disease overall, whereas loci on chromosomes 2 and 6 were linked only in ulcerative colitis. Linkage with chromosome 16 was noted in Crohn's disease only. Fine mapping of these susceptibility loci is in progress, and may lead to gene identification with attendant clinical benefits.
Elevated Heart Rate Variability in Physically Active Young and Older Adult Women
Authors: Davy Kevin P. , Desouza Christopher A. , Jones Pamela P. , Seals Douglas R.
Published: August 2015

1. Low heart rate variability is associated with an increased risk of cardiac sudden death, coronary heart disease and all-cause mortality. We have previously shown that physically active postmenopausal women demonstrate higher levels of heart rate variability and cardiac baroreflex sensitivity compared to their sedentary peers. The purpose of the present prospective study was to test the hypothesis that heart rate variability and cardiac baroreflex sensitivity would be reduced with age in sedentary but not physically active women. To accomplish this, we measured heart rate variability (both time and frequency domain) and spontaneous cardiac baroreflex sensitivity (SBRS, sequence method) in the sitting posture in 23 sedentary women [11 premenopausal and 12 postmenopausal (age, 28 ± 1 and 61 ± 2 years; Vo2max, 35.3 ± 1.4 and 21.7 ± 1.5 ml · min−1 · kg−1 respectively] and in 22 physically active women [12 premenopausal and 10 postmenopausal (age, 31 ± 1 and 59 ± 2 years; Vo2max, 52.5 ± 1.4 and 39.7 ± 1.8 ml · min−1 · kg−1)].

2. The S.D. of the R—R interval (time domain) was reduced (P < 0.05) with age in both sedentary (52 ± 6 versus 33 ± 4 ms) and physically active women (72 ± 8 versus 49 ± 9 ms). The high-frequency power (3740 ± 1527 versus 915 ± 188 and 9516 ± 2849 versus 2803 ± 1083 ms2/Hz), total power of heart rate variability and SBRS (11 ± 2 versus 7 ± 2 and 19 ± 3 versus 13 ± 2 ms/mmHg) also demonstrated similar age-related reductions in sedentary and physically active women, respectively (all P < 0.05). The S.D. of the R—R interval, high-frequency and total power of heart rate variability, and SBRS were higher (all P < 0.05) in the physically active compared with the sedentary women at any age. There was no significant influence of age or physical activity status on the low-frequency power of heart rate variability. In addition, no significant differences in any of the time or frequency domain measures of heart rate variability or SBRS were observed in users compared with non-users of hormone replacement therapy.

3. The results of the present study suggest that heart rate variability and cardiac baroreflex sensitivity decline similarly with age in healthy sedentary and physically active women. However, physically active women demonstrate higher levels of heart rate variability and cardiac baroreflex sensitivity compared with their sedentary peers, regardless of age.
Increased Plasma Adrenomedullin Concentrations during Cardiac Surgery
Authors: Nishikimi Toshio , Hayashi Yukio , Iribu Gentaro , Takishita Shuichi , Kosakai Yoshio , Minamino Naoto , Miyata Atsuro , Matsuo Hisayuki , Kuro Masakazu , Kangawa Kenji
Published: August 2015

1. Adrenomedullin (AM), a potent hypotensive peptide, was originally isolated from human phaeochromocytoma. Plasma AM concentrations are elevated in hypertension, heart failure and renal failure in proportion to the severity of the disease. This study was performed to investigate the pathophysiological significance of AM during cardiac surgery.

2. Serial blood samples were obtained from patients undergoing cardiac surgery and plasma AM concentrations were determined by specific radioimmunoassay.

3. Plasma AM concentrations did not increase with anaesthesia or surgery (n = 9). Plasma AM concentrations gradually increased during cardiopulmonary bypass and after pulmonary reperfusion. After pulmonary reperfusion, plasma AM concentrations increased further. In addition, we measured plasma AM concentrations in the pulmonary vein (n = 8) and coronary sinus (n = 8) to examine the contribution of the lungs and heart to the increase in circulating AM concentrations after cardiopulmonary bypass. However, no significant differences were seen in plasma AM concentrations of the pulmonary vein or the coronary sinus and the aorta. Peak AM concentrations during cardiac surgery correlated with duration of surgery. Elevated plasma AM levels during and after surgery began to decline next day after surgery and returned to normal levels 7 days after surgery.

4. These results demonstrate that plasma AM concentrations increase during cardiac surgery and that the duration of surgery may be related to the changes in AM concentrations. Taken together with recent findings that vascular endothelial cells and vascular smooth muscle cells actively produce AM, these results suggest that plasma AM during cardiac surgery may act as a vasodilatory hormone.
Serum Leptin Level: Possible Association with Haematopoiesis in Adolescents, Independent of Body Mass Index and Serum Insulin
Authors: Hirose Hiroshi , Saito Ikuo , Kawai Toshihide , Nakamura Keiko , Maruyama Hiroshi , Saruta Takao
Published: August 2015

1. The obese gene product leptin, secreted exclusively from adipocytes, was discovered to serve as a satiety factor and to play an important role in regulating body weight. In adults, the serum leptin level reportedly increases with the degree of obesity. Leptin receptors are expressed in various tissues, and recent in vitro studies suggest a role for leptin in haematopoiesis.

2. The present study was designed to clarify the relationship between serum leptin and body mass index, peripheral blood cell counts, serum cholesterol, high-density lipoprotein-cholesterol, insulin and Cortisol levels in 299 Japanese male adolescents aged 15–16 years.

3. With simple linear correlation, log [serum leptin] showed a strong correlation with body mass index (r = 0.56), log [insulin] (r = 0.36) and leucocyte count (r = 0.22) (P < 0.001 for all). There were also correlations with systolic blood pressure, erythrocyte count, haematocrit and high-density lipoprotein-cholesterol (P < 0.01 for all). Even after adjustment for body mass index and log [insulin], log [leptin] correlated with leucocyte (P = 0.004) and erythrocyte (P = 0.057) counts. Stepwise multiple regression analyses revealed log [leptin] to correlate significantly with body mass index, log [insulin] and the leucocyte count (P < 0.005 for all, r2 = 0.399).

4. To our knowledge, this is the first clinical study to show the possible association of serum leptin level with blood cell counts, independent of body mass index and serum insulin. We conclude that these data further support a role for leptin in haematopoiesis.
Bronchial reactivity and intracellular magnesium: a possible mechanism for the bronchodilating effects of magnesium in asthma
Authors: DOMINGUEZ Ligia J. , BARBAGALLO Mario , LORENZO Gabriele Di , DRAGO Agata , SCOLA Santi , MORICI Giuseppina , CARUSO Calogero
Published: August 2015

1.Increased bronchial smooth muscle contractility with consequent bronchial hyperreactivity are characteristic physiopathological events of asthma. Since magnesium intervenes in calcium transport mechanisms and intracellular phosphorylation reactions, it constitutes an important determinant of the contraction/relaxation state of bronchial smooth muscle. In the present study we investigated the relationship between bronchial reactivity, assessed by methacholine-provocation test, and magnesium concentrations both at extracellular and intracellular levels measured by spectrophotometry. Twenty-two patients with mild-to-moderate asthma and 38 non-asthmatic subjects with allergic rhinitis (24 allergic to Parietaria pollen and 14 allergic to Grasspollen) were recruited to the study. Exclusion criteria included renal failure, hepatic diseases, heart failure and arterial hypertension.

2.The salient finding of our study is that there is a strong positive correlation between bronchial reactivity and the level of intracellular magnesium (r = 0.72, P< 0.0001), both when the groups are analysed separately or together. Intracellular magnesium concentrations in the group of patients with asthma were significantly lower (1.8±0.01 mmol/l; n = 22) when compared with levels in rhinitis subjects allergic to Parietaria(1.9±0.01 mmol/l; n = 24, P< 0.05), and with levels in rhinitis subjects allergic to Grass pollen (2.0±0.03;mmol/l; n = 14, P< 0.05). Serum levels of the ion were similar in all groups.

3.We conclude that the level of intracellular magnesium may be an important determinant of bronchial hyperreactivity, as supported by the significant positive correlation between these two parameters in allergic patients with known bronchial hyperresponsiveness. This finding, in addition to reports of the bronchodilating effects of magnesium administration in patients with asthma, confirms the proposed role of this ion in the pathogenesis and treatment of asthma.
Respiratory correlates of muscle sympathetic nerve activity in heart failure
Authors: NAUGHTON Matthew T. , FLORAS John S. , RAHMAN M. Atiar , JAMAL Munir , BRADLEY T. Douglas
Published: August 2015

1.Sympathetic activation in congestive heart failure indicates a poor prognosis. Haemodynamic correlates of increased sympathetic nerve traffic to muscle (MSNA) and to the heart have been well characterized, but these account for only 50 to 60% of the variance in sympathetic activity between patients.

2.In healthy subjects, breathing pattern modulates MSNA and positive airway pressure consistently increases MSNA. However, in patients with heart failure, the influence of spontaneous breathing pattern and of short-term application of nasal continuous positive airway pressure on MSNA have not been described.

3.Spontaneous breathing frequency, tidal volume, end-expiratory lung volume, Pco2 and MSNA were recorded, along with blood pressure, heart rate and stroke volume in 14 men with congestive heart failure of idiopathic or ischaemic origin (left ventricular ejection fraction < 35%). Measurements were made during baseline rest, followed by 45 ;min of either nasal continuous positive airway pressure applied at 10 ;cmH2O (n = 9), or spontaneous breathing, in the absence of nasal continuous positive airway pressure (time control; n = 6).

4.At baseline, there was a significant positive correlation between MSNA burst frequency and breathing frequency (r = 0.758, P = 0.001), and an inverse correlation between MSNA burst incidence and tidal volume (r = -0.705, P = 0.005). These relationships were independent of left ventricular ejection fraction, stroke volume or cardiac output.

5.Nasal continuous positive airway pressure increased end-expiratory lung volume, but had no effect on breathing frequency, tidal volume or MSNA.

6.In patients with congestive heart failure, there is a significant independent and previously unrecognized correlation between spontaneous breathing pattern and MSNA; patients with rapid shallow breathing exhibit the highest degree of sympathetic activation. In distinct contrast to healthy subjects, the short-term application of nasal continuous positive airway pressure at 10 ;cmH2O does not increase MSNA in congestive heart failure.
Inhibition of renal 11β-hydroxysteroid dehydrogenase in vivo by carbenoxolone in the rat and its relationship to sodium excretion
Authors: SEWELL K. J. , SHIRLEY D. G. , MICHAEL A. E. , THOMPSON A. , NORGATE D. P. , UNWIN R. J.
Published: August 2015

1.The type 2 isoform of 11β-hydroxysteroid dehydrogenase, an enzyme which converts cortisol or corticosterone to inactive 11-ketosteroid metabolites, is thought to be responsible for preventing access of endogenous glucocorticoids to mineralocorticoid receptors in the distal nephron; although direct in vivo evidence for this is still lacking. We have examined whether graded inhibition of renal 11β-hydroxysteroid dehydrogenase activities in vivo results in corresponding changes in urinary electrolyte excretion due to exposure of mineralocorticoid receptors to circulating endogenous glucocorticoids.

2.Anaesthetized rats were infused intravenously with vehicle alone or with one of three doses of carbenoxolone: 0.06, 0.6 or 6 ;mg/h. After measurement of renal electrolyte excretion, the kidneys were snap-frozen in liquid nitrogen and 11β-hydroxysteroid dehydrogenase activities were measured directly by enzyme assay in the presence of NAD+ or NADP+.

3.A dose-dependent inhibition of renal 11β-hydroxysteroid dehydrogenase activities was observed: the low, intermediate and high doses of carbenoxolone causing approximately 50%, 80% and > 90% inhibition respectively. Only with the high dose was an effect on renal function observed (decreased fractional Na+ excretion and urinary Na+/K+ ratio).

4.The poor correlation between the extent of inhibition of renal 11β-hydroxysteroid dehydrogenase and altered urinary Na+ excretion, apparent at the lower doses of carbenoxolone, suggests either that 11β-hydroxysteroid dehydrogenase has considerable functional reserve, or that it may not be the only mechanism determining mineralocorticoid receptor specificity in the distal nephron.
Comparative effects of dilator drugs on human penile dorsal artery and deep dorsal vein
Authors: SEGARRA G. , MEDINA P. , ACUÑA A. , DOMENECH C. , MARTÍNEZ LEÓN J. B. , VILA J. M. , LLUCH S.
Published: August 2015

The present study was designed to characterize the response of human penile dorsal artery and deep dorsal vein to dilator drugs used in the diagnosis and treatment of erectile dysfunction with special emphasis on the effects on sympathetic neurotransmission. Ring segments of penile dorsal artery and deep dorsal vein were obtained from 20 multi-organ donors during procurement of organs for transplantation. The rings (3 ;mm long) were suspended in organ bath chambers for isometric recording of tension. We then studied the relaxant responses to prostaglandin E1 (PGE1), vasoactive intestinal peptide (VIP), papaverine (PV), sodium nitroprusside (SNP) and linsidomine chlorhydrate (SIN-1), and analysed the effects of these drugs on contractions induced by stimulation of perivascular sympathetic nerves. In artery and vein rings contracted by noradrenaline, all the drugs tested caused concentration-dependent relaxation. The order of potencies in terms of IC50 values (concentration of agonist causing 50% of the maximal relaxation) was PGE1 = VIP > SNP > SIN-1 = PV. Both arteries and veins contracted to electrical field stimulation (15 ;V, 0.5–2 ;Hz, 0.2 ;ms duration for 15 ;s) in a frequency-dependent manner. All relaxant drugs caused concentration-dependent inhibition of neurogenic contractions; the relative order of potencies was PGE1 > VIP > SNP > SIN-1 = PV. It is concluded that inhibition of sympathetic activity constitutes an effective relaxing mechanism in penile dorsal artery and vein. Modulation of sympathetic activity together with the direct effects on smooth muscle should be considered to evaluate adequately the efficacy of relaxant drugs to increase human penile blood supply.
Serial changes in sarcoplasmic reticulum gene expression in volume-overloaded cardiac hypertrophy in the rat: effect of an angiotensin II receptor antagonist
Authors: HASHIDA Hidetoshi , HAMADA Mareomi , HIWADA Kunio
Published: August 2015

This study was designed to clarify whether gene expression in the cardiac sarcoplasmic reticulum [sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, ryanodine receptor and calsequestrin] changes in accordance with left ventricular functional alterations in the volume-overloaded heart. Further, the effect of the angiotensin II type 1 receptor antagonist, TCV-116, on the expression of these genes was also evaluated. Left ventricular fractional shortening was significantly increased at 7 days, had returned to control levels at 21 days, and had significantly decreased at 35 days after the shunt operation, compared with sham-operated rats. The level of SERCA mRNA was significantly decreased at both 21 days and 35 days after the shunt operation. The levels of ryanodine receptor and phospholamban mRNAs were significantly decreased at 35 days in shunt-operated rats. The decrease in the SERCA mRNA level preceded the development of cardiac dysfunction. The levels of SERCA and ryanodine receptor mRNAs were correlated positively with left ventricular fractional shortening (r = 0.73, P< 0.0001 and r = 0.61, P< 0.01 respectively). Attenuation of the decrease in left ventricular fractional shortening occurred on treatment with TCV-116. After the treatment with TCV-116, the levels of SERCA and phospholamban mRNAs were restored to the respective values in sham-operated rats. Ryanodine receptor mRNA levels remained unchanged after treatment with TCV-116. These results indicate that the down-regulation of SERCA and ryanodine receptor mRNA levels may be related to cardiac dysfunction in the volume-overloaded heart. In addition, treatment with an angiotensin II receptor antagonist may restore the altered sarcoplasmic reticulum mRNA levels to control levels, and this may result in attenuation of the functional impairment in the volume-overloaded heart.
Changes in muscle strength in women following the menopause: a longitudinal assessment of the efficacy of hormone replacement therapy
Authors: GREEVES Julie P. , CABLE Nigel T. , REILLY Thomas , KINGSLAND Charles
Published: August 2015

The effects of hormone deficiency at the menopause on muscle strength was examined in 10 healthy middle-aged women (1-3 years post-menopause) in a longitudinal trial over 39 weeks. Performance was compared with that of age-matched females (n = 11) taking a course of hormone replacement therapy (HRT). Muscle strength of the quadriceps was measured isometrically at 90° of knee flexion and at angular velocities of 1.05, 2.09 and 3.13 rad/s using an isokinetic dynamometer. Hand grip strength was assessed by means of a portable dynamometer. Measurements were taken every 13 weeks for 39 weeks. Significant decreases in isometric strength (-10%) and dynamic leg strength at 1.05 rad/s (-9%) were found in the post-menopausal women over 39 weeks. There was no change in strength in the HRT group. There were also no changes in leg strength at higher angular velocities or in grip strength for either the post-menopausal group or those taking HRT. While HRT preserved muscle strength, there was no evidence of a strengthening effect on skeletal muscle within this short period of treatment. A rapid loss of leg strength occurs post-menopausally in hormone-depleted women. HRT may offer protection against muscle weakness, although the hormone responsible for regulating strength is not evident using this model.
Pulsatile secretion of atrial natriuretic peptide and brain natriuretic peptide in healthy humans
Authors: PEDERSEN Erling B. , PEDERSEN Henrik B. , JENSEN Kaare T.
Published: August 2015

Both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are involved in sodium and water homoeostasis in healthy humans. The plasma concentrations of the natriuretic peptides can be used to differentiate between dyspnoea of cardiac and pulmonary origin, and the degree of elevation of the peptide levels in the plasma in heart failure is a measure of the severity of the disease. However, the patterns of secretion of ANP and BNP are not clear either in healthy humans or in patients. The purpose of the present study was to test the hypotheses that both ANP and BNP are secreted in pulses in healthy humans, and that this phenomenon can be revealed by determination of ANP and BNP in peripheral venous blood samples. In 12 healthy subjects, blood samples were drawn every 2 min through an intravenously inserted plastic needle over a period of 2 h. Plasma concentrations of ANP and BNP were determined by RIAs, and the results were analysed for pulsatile behaviour by Fourier transformation. Pulsatile secretion of ANP was seen in 10 out of 12 subjects [ν = 0.028 min-1 (median; range 0.013–0.047 min-1), i.e. a pulse of ANP with an interval of 36 min (range 21–77 min)]. Pulsatile secretion of BNP was seen in nine out of 12 patients [ν = 0.021 min-1 (range 0.013–0.042 min-1), i.e. a pulse of BNP with an interval of 48 min (range 24–77 min)]. The main conclusion is that the secretion patterns of both ANP and BNP are pulsatile in most healthy humans. Consequently, it is important to study whether pulsatile secretion also occurs in heart failure in order to obtain the most informative predictive values both in the differential diagnosis of dyspnoea and in the evaluation of the severity of the disease.
Contribution of non-cardiomyocyte apoptosis to cardiac remodelling that occurs in the transition from compensated hypertrophy to heart failure in spontaneously hypertensive rats
Authors: IKEDA Shuntaro , HAMADA Mareomi , HIWADA Kunio
Published: August 2015

Various alterations in molecular and cellular events have been considered as possibly contributing to the cardiac remodelling that occurs during the transition from compensated hypertrophy to heart failure. The aim of the present study is to clarify (1) whether cardiac apoptosis occurs during the transition from compensated hypertrophy to decompensated heart failure, and (2) whether expression of the genes encoding Bax (an apoptosis inducer) and Bcl-xL and Bcl-2 (apoptosis inhibitors) is altered during this transition. We used 12-month-old and 20-month-old male spontaneously hypertensive rats (SHR12 and SHR20 respectively) and age-matched Wistar–Kyoto rats (WKY12 and WKY20 respectively). These rats were killed after measurement of haemodynamic parameters by transthoracic echocardiography and use of a tipmanometer via the right carotid artery. The expression of bcl-2, bcl-xL and bax was analysed by Northern blotting. Samples were also fixed in 4% paraformaldehyde for in situ nick end-labelling (TUNEL) methods and immunohistochemistry. SHR12 had well compensated left ventricular hypertrophy with normal fractional shortening and normal end-systolic wall stress. In contrast, the hearts of SHR20 developed decompensated dilatation, with a decrease in fractional shortening and an increase in end-systolic wall stress. TUNEL-positive cells were seen exclusively in the hearts of SHR20. The major cell types that showed TUNEL-positive nuclei were non-cardiomyocytes. The expression of bax remained unchanged during the transition to heart failure. However, there was increased expression of bcl-xL in the failing stage, whereas the expression of bcl-2 remained unchanged. Immunohistochemical studies revealed that Bcl-xL protein was up-regulated in the hearts of SHR20. In conclusion, non-cardiomyocyte apoptosis may play a contributory role in the remodelling that occurs in the transition from compensatory hypertrophy to decompensated heart failure. In addition, it is suggested that enhanced expression of bcl-xL plays an important role in the preservation of cardiomyocytes during this transition.
Cardiac peptide stability, aprotinin and room temperature: importance for assessing cardiac function in clinical practice
Authors: BUCKLEY Martin G. , MARCUS Neil J. , YACOUB Magdi H.
Published: August 2015

Brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and N-terminal ANP are good research indices of the severity of heart failure. The stability of these peptides at room temperature has become an important factor in assessing their use as indicators of cardiac function in routine clinical practice. Inhibitors such as aprotinin are routinely added in the blood collection process, but may provide no benefit in sample collection and routine clinical practice. We assessed the stability of BNP, ANP and N-terminal ANP in blood samples collected in either the presence or the absence of the protease inhibitor aprotinin. Blood, either with or without aprotinin, was processed immediately (initial; 0 h) and after blood samples had been left for 3 h, 2 days or 3 days at room temperature. These times were chosen to reflect processing in a hospital outpatient clinic (2–3 h), or when posted from general practice (2–3 days). Initial plasma BNP, ANP and N-terminal ANP levels in the absence of aprotinin were 28.2±5.4, 44.2±7.9 and 1997±608 pg/ml respectively, and were not significantly different from initial values in the presence of aprotinin (29.0±5.9, 45.2±8.0 and 2009±579 pg/ml respectively). After 3 h at room temperature, there was a significant fall in ANP in the absence of aprotinin (36.7±7.9 pg/ml; P< 0.005), but not in the presence of aprotinin (41.2±7.6 pg/ml). Both BNP and N-terminal ANP were unchanged in either the absence (BNP, 27.6±5.5 pg/ml; N-terminal ANP, 2099±613 pg/ml) or the presence (BNP, 29.4±5.6 pg/ml; N-terminal ANP, 1988±600 pg/ml) of aprotinin. After 2 days at room temperature, ANP had fallen significantly in both the absence (16.9±3.4 pg/ml) and the presence (24.0±5.0 pg/ml) of aprotinin compared with initial values, and there was a significant difference in ANP levels in the absence and presence of aprotinin (P< 0.001). ANP levels had decreased further after 3 days at room temperature, to 11.9±3.4 pg/ml (no aprotinin) and 20.3±5.0 pg/ml (aprotinin added); these values were significantly different (P = 0.002). In contrast, there was no change in the levels of BNP or N-terminal ANP after 2 or 3 days at room temperature, in either the absence or the presence of aprotinin. These studies indicate that aprotinin adds little benefit to the stability of cardiac peptides at room temperature. Blood samples for BNP and N-terminal ANP measurement used as a test of heart function in hospital clinics and by general practitioners in the community could be taken into blood tubes containing only EDTA as anticoagulant and without the additional step of adding the routinely used inhibitor aprotinin.
Changes in vitreous concentrations of human hepatocyte growth factor (hHGF) in proliferative diabetic retinopathy: implications for intraocular hHGF production
Authors: NISHIMURA Masato , IKEDA Tsunehiko , USHIYAMA Masaji , KINOSHITA Shigeru , YOSHIMURA Manabu
Published: August 2015

We measured human hepatocyte growth factor (hHGF) concentrations in the original vitreous and in the artificial vitreous after vitrectomy in 13 patients with proliferative diabetic retinopathy (PDR) undergoing repeated pars plana vitrectomy, in order to investigate whether the vitreous hHGF concentration is related to the recurrence of PDR after vitrectomy as well as to the original occurrence of PDR. We also examined the relationship between vitreous concentrations of hHGF and transforming growth factor-β2 (TGF-β2), the predominant TGF-β isoform in the vitreous, in 14 patients with PDR. For the original vitreous, mean hHGF concentrations were higher (P< 0.05) in that from patients with severe PDR (vitreous haemorrhage, fibrovascular proliferation and tractional retinal detachment) than in that from patients with vitreous haemorrhage alone. In the artificial vitreous, mean vitreous hHGF concentrations were higher (P< 0.05) in that from patients with severe PDR than in that from patients with vitreous haemorrhage alone or with vitreous haemorrhage plus fibrovascular proliferation. No correlation was found between the hHGF concentration in the artificial vitreous and time between vitrectomies. Vitreous hHGF concentrations were directly proportional to vitreous concentrations of latent TGF-β2 (r =0.831; P = 0.0002), but inversely proportional to vitreous concentrations of active TGF-β2 (r = 0.495; P = 0.072), which inhibits hHGF production. A decreased conversion of latent into active TGF-β2 in ocular disorders such as PDR is likely to result in an increased concentration of hHGF in the vitreous. Thus intraocular hHGF may be involved in pathological mechanisms causing not only the occurrence, but also the recurrence, of PDR.
Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children
Authors: DOYLE L. W. , FORD G. W. , DAVIS N. M. , CALLANAN C.
Published: August 2015

Antenatal corticosteroid therapy substantially improves the survival rate of preterm infants, with few side effects. Higher blood pressure in adulthood has been described in several animal species after exposure to antenatal corticosteroids, but there are no similar reports in humans. The objective of the present study was to determine the relationship between exposure to antenatal corticosteroid therapy and blood pressure at 14 years of age. This was a cohort study of 210 preterm survivors with birthweights of < 1501 g born in the Royal Women's Hospital, Melbourne, between 1 January 1977 and 31 March 1982. Blood pressure was measured in 177 subjects (84.3%) at 14 years of age with a standard mercury sphygmomanometer. Children exposed to antenatal corticosteroids (n = 89) had higher systolic and diastolic blood pressures than those not exposed to corticosteroids (n = 88) [mean difference (95% confidence interval) (mmHg): systolic, 4.1 (0.1–8.0); diastolic, 2.8 (0.05–5.6)]. However, few had blood pressure in the hypertensive range. It is concluded that antenatal corticosteroid therapy is associated with higher systolic and diastolic blood pressures in adolescence, and might lead to clinical hypertension in survivors well beyond birth.
Role of nitric oxide in airway remodelling
Authors: GABAZZA Esteban C. , TAGUCHI Osamu , TAMAKI Shigenori , MURASHIMA Shuichi , KOBAYASHI Hiroyasu , YASUI Hiroki , KOBAYASHI Tetsu , HATAJI Osamu , ADACHI Yukihiko
Published: August 2015

Airway remodelling, which is manifested by thickening of bronchial wall, is an important causative factor of bronchial hyper-responsiveness in asthma. The pathophysiological mechanism of airway remodelling is not clear. In the present study we evaluated the relationship between nitric oxide (NO) generation and airway wall thickening in patients with chronic asthma. As a marker of NO production, the levels of nitrite/nitrate were measured in induced sputum, and bronchial wall thickening was measured by high-resolution computed tomography. Sputum concentrations of nitrite/nitrate were significantly increased in asthmatic patients compared with controls. The ratio of airway wall thickness to lumen diameter was significantly correlated with the sputum concentration of nitrite/nitrate. Although statistical correlation does not prove causation, this finding suggests that NO may play a key role in the pathogenesis of airway remodelling.
Resveratrol induces vasorelaxation of mesenteric and uterine arteries from female guinea-pigs
Authors: NADERALI Ebrahim K. , DOYLE Patrick J. , WILLIAMS Gareth
Published: August 2015

Naturally occurring hydroxystilbenes have been shown to induce vasorelaxation. Here, we studied the mechanism of resveratrol-induced vasorelaxation in different types of blood vessels, namely mesenteric (resistance) and main uterine (conductance) arteries, from female guinea-pigs on day 7 and day 15 of the oestrous cycle. Resveratrol (5–70 µmol/l) induced concentration-dependent relaxation of both mesenteric and uterine arteries preconstricted with either noradrenaline (NA; 10 µmol/l) or KCl (125 mmol/l). Resveratrol was 2-fold more potent in inducing relaxation of mesenteric arteries than of uterine arteries. Its effects on uterine arteries from both day-7 and day-15 guinea-pigs were similar, irrespective of the constrictor used, but it was significantly (P < 0.01) more potent in inducing relaxation of mesenteric arteries contracted with NA compared with those constricted with KCl. In day-7 arteries precontracted with NA, NG-nitro-l-arginine methyl ester (l-NAME; 10 µmol/l) had no effects on the time course of resveratrol-induced vasorelaxation in either mesenteric or uterine arteries. However, indomethacin (50 µmol/l) significantly (P < 0.05) potentiated resveratrol's effect on mesenteric, but not uterine, arteries. Indomethacin had no effect on resveratrol-induced vasorelaxation of arteries contracted with KCl, whereas l-NAME significantly (P < 0.05) reduced the effects of resveratrol on uterine, but not on mesenteric, arteries. In day-15 arteries, l-NAME significantly (P < 0.01) attenuated the effects of resveratrol on mesenteric arteries contracted with NA. Indomethacin had no effect on resveratrol activity. This study indicates that: (a) the effect of resveratrol on resistance arteries is greater than that on conductance arteries; (b) the effects of resveratrol are not mediated via prostanoids, but NO may play a role; and (c) the stage of the oestrous cycle has no influence on resveratrol-induced vasorelaxation.