bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Atrial and Brain Natriuretic Peptides in Mitral Stenosis Treated by Valvulotomy
Authors: Tharaux Pierre-Louis , Dussaule Jean-Claude , Hubert-Brierre Jérôme , Vahanian Alec , Acar Jean , Ardaillou Raymond
Published: August 2015

1. In order to appreciate the effect of changes in left atrial pressure on plasma brain natriuretic peptide, 20 patients with mitral stenosis treated by percutaneous valvulotomy were studied 10 min before and 15 min after the first balloon inflation. They were also studied 24 h before and 48 h after the valvulotomy. At these times the effect of postural changes on brain natriuretic peptide secretion was examined. A group of 10 control subjects was also studied under basal conditions. In each case, plasma atrial natriuretic peptide was measured in parallel with plasma brain natriuretic peptide.

2. Similarly to plasma atrial natriuretic peptide, plasma brain natriuretic peptide was elevated in patients with mitral stenosis (32 ± 2.9 and 32 ± 2.8 pg/ml in the upright and supine position respectively versus 13.5 ± 0.5 and 13.8 ± 1.8 pg/ml in controls; P < 0.01). Changing from standing to lying did not modify plasma brain natriuretic peptide, whereas it produced an increase in plasma atrial natriuretic peptide in controls (13.3 ± 1.6 versus 24.8 ± 5.2 pg/ml; P < 0.01) and in patients 48 h after valvulotomy (52.5 ± 4.6 versus 66.9 ± 6.6 pg/ml; P < 0.01). Plasma brain natriuretic peptide also fell at this time (18.8 ± 1.1 and 19.1 ± 1.1 pg/ml in the upright and supine position respectively; P < 0.01) similarly to plasma atrial natriuretic peptide and cyclic GMP (P < 0.01). The acute left atrial mean pressure variation was significantly correlated with the parallel change in plasma atrial natriuretic peptide (P < 0.001) but not in plasma brain natriuretic peptide. Plasma brain natriuretic peptide measured 24 h before and 48 h after valvulotomy was not correlated with plasma cyclic GMP, contrary to plasma atrial natriuretic peptide (P < 0.001).

3. The results of the present study indicate that plasma brain natriuretic peptide depends on long-term but not on acute changes in left atrial pressure. This difference from atrial natriuretic peptide may result from both its preferential ventricular site of synthesis and its longer biological half-life.
Site of Action of Platelet-Activating Factor within the Mucosa of Rabbit Distal Colon
Authors: Travis S. P. L. , Crotty B. , Jewell D. P.
Published: August 2015

1. To determine how platelet-activating factor stimulates colonic anion secretion and increases epithelial permeability, epithelial sheets of rabbit distal colon excluding the submucosal neural plexus were mounted in Ussing chambers. The influence of specific inhibitors and 50 nmol/l platelet-activating factor on short-circuit current and transepithelial resistance was then investigated.

2. Pretreatment with 1 μmol/l indomethacin or 1 μmol/l doxantrazole abolished the biphasic stimulation of the short-circuit current and decrease in transepithelial resistance induced by platelet-activating factor. Addition of 10 μmol/l mepyramine attenuated the early phase and completely inhibited the late phase. Pretreatment with 1 μmol/l ranitidine, 0.1 μmol/l tetrodotoxin, 0.1 μmol/l ritanserin or a 5-lipoxygenase inhibitor (1 μmol/l MK886) had no effect.

3. To assess the influence of platelet-activating factor on epithelial function isolated from lamina propria elements, monolayers were cultured from a human colonic epithelial cell line (T-84).

4. The short-circuit current across monolayers mounted in Ussing chambers stimulated by 10 μmol/l ionomycin could be inhibited by pretreatment with ouabain or frusemide, consistent with the capacity for chloride secretion. Addition of platelet-activating factor (up to 500 nmol/l) had no effect on short-circuit current or transepithelial resistance. Receptor expression was examined with [3H]platelet-activating factor in isolated T-84 and HT-29 cells and found to be absent.

5. The influence of physiological concentrations of platelet-activating factor on colonic epithelial anion secretion and increased permeability in rabbit distal colon is indirect and consistent with mediation by prostaglandins released from mucosal mast cells. Other mediators, including histamine acting through H1 but not H2 receptors, may have a role. 5-Lipoxygenase metabolites or 5-HT2 receptors appear not to be involved and, contrary to previous reports, the influence of platelet-activating factor on colonic epithelial function is independent of the submucosal neural plexus.
Contractile Properties of the Quadriceps Muscle in Growth Hormone-Deficient Hypopituitary Adults
Authors: Rutherford Olga M. , Beshyah Salem A. , Schott Jonathan , Watkins Yvonne , Johnston Desmond G.
Published: August 2015

1. Growth hormone-deficient hypopituitary adults often complain of weakness and fatigue. The cause of the fatigue is unknown but could be an increased proportion of fast, fatiguable, type 2 fibres in the muscle. The aim of this study was to examine the contractile properties of the quadriceps muscle in a group of these patients compared with healthy controls. Changes in these properties were also examined in a small subset of the patients following growth hormone replacement.

2. Isometric strength, half-relaxation time from a twitch (t1/2) and the force—frequency relationship were measured using electrically evoked contractions in 14 growth hormone-deficient patients and 14 age- and sex-matched controls. Six patients were restudied following 6–24 month's replacement therapy with growth hormone (daily dose 0.04 ± 0.01 i.u./kg).

3. The growth hormone-deficient patients had a significantly lower t1/2 than the controls (46.1 ± 6.1 ms versus 56.1 ± 10.5 ms respectively; P = 0.0072; mean ± SD). The 10/100% ratio was also significantly lower in growth-hormone-deficient patients (38.6 ± 9.9% versus 52.3 ± 8.0%; P = 0.0005), as was muscle strength (349 ± 99 N versus 493 ± 215 N; P = 0.036). Following growth hormone replacement, muscle strength increased significantly (P < 0.05). The 10/100% ratio also increased towards control values, but this change was not significant.

4. These results demonstrate that the relaxation times of the quadriceps are significantly shorter and that the force—frequency relationship shifted to the right in growth hormone-deficient patients, which is consistent with a greater proportion of type 2 fibres within the muscle. Preliminary data on a small group suggest that replacement with growth hormone results in a change in these properties towards that of controls.
Thrombin Does Not Alter Vascular Hyporeactivity in Models of Endotoxin-Induced Septic Shock in Rats
Authors: Martin Viviane , Wiesel Marie-Louise , Albert Anne , Beretz Alain
Published: August 2015

1. Hypotension and vascular hyporesponsiveness to vasoconstrictors are observed during endotoxic shock, and are associated with increased production of nitric oxide in the vascular wall. Disseminated intravascular coagulation is another feature of septicaemia. We hypothesized that thrombin generated during disseminated intravascular coagulation might modulate the changes in vascular tone induced by endotoxin.

2. Incubation of rat aortic rings for 4 h with α-thrombin (0.003–3.0 NIH units/ml) did not change their reactivity to noradrenaline. Incubation for 4 h with lipopolysaccharide increased the EC50 for noradrenaline, whereas co-incubation of thrombin (0.5 NIH units/ml) with lipopolysaccharide did not alter this hyporeactivity to noradrenaline.

3. In vivo in rats, lipopolysaccharide caused early (1 h) and late (4–6 h) hyporeactivity to noradrenaline. In rats infused with lipopolysaccharide and heparin (1 U min−1 kg−1, 0.4 ml/h) or hirudin (2.2 mg ml−1 kg−1, 0.8 ml/h), vasopressor responses to noradrenaline were not different from those after infusion of lipopolysaccharide alone. Aortic rings taken from rats receiving both anticoagulant treatment and lipopolysaccharide had the same sensitivity to noradrenaline as those obtained from rats receiving lipopolysaccharide alone.

4. Our results suggest that, in vivo, disseminated intravascular coagulation does not modify the early and late effects of lipopolysaccharide on arterial pressure and that, in vitro, thrombin neither induces hyporeactivity to noradrenaline nor modifies lipopolysaccharide-induced hyporeactivity. We propose that thrombin generated during disseminated intravascular coagulation in rats does not play a major role in the alterations of vascular tone observed during endotoxic shock.
Haemodynamic and Hormonal Responses to Cardiac Pacing in Humans: Influence of Different Stimulation Sequences and Rates
Authors: Berglund Hans , Edlund Anders , Theodorsson Elvar , Vallin Hans
Published: August 2015

1. To examine the effects of rate and pressure on release of vasoactive hormones, 10 healthy subjects were examined.

2. A standardized pacing protocol was used to achieve different haemodynamic responses at two predetermined heart rates. Haemodynamic variables, and plasma concentrations of atrial natriuretic peptide, arginine vasopressin, adrenaline and noradrenaline were measured.

3. Right atrioventricular pacing at a rate of 150 impulses/min resulted in disparate responses in right atrial pressure (slight decrease) and pulmonary capillary wedge pressure (increase). Change in arterial plasma concentration of atrial natriuretic peptide correlated to change in pulmonary capillary wedge pressure, and change in arterial plasma concentration of noradrenaline correlated to change in total systemic vascular resistance, whereas concentrations of adrenaline and arginine vasopressin did not alter significantly during the stimulation periods. A significant influence of rate in addition to the pressure related influence on plasma concentration of atrial natriuretic peptide was found. In contrast, an increase in rate in the absence of an increase in atrial pressures did not raise the plasma concentration of atrial natriuretic peptide. There was no significant relationship between change in atrial natriuretic peptide and noradrenaline.

4. These data support the concept of a rate dependence of atrial natriuretic peptide release in man. Increased atrial pressure and thus presumed atrial stretch seems to be a prerequisite for increased plasma concentration of atrial natriuretic peptide. In addition, these results highlight the importance of monitoring both left and right atrial pressure in clinical investigations assessing modulation of atrial natriuretic peptide release.
Haemodynamic Effects of Continuous Positive Airway Pressure in Humans with Normal and Impaired Left Ventricular Function
Authors: De Hoyos Alberto , Liu Peter P. , Benard Dean C. , Bradley T. Douglas
Published: August 2015

1. Continuous positive airway pressure increases intrathoracic pressure, thereby decreasing left ventricular preload and afterload. We hypothesized that there would be a dose-related alteration in cardiac and stroke volume indices in response to continuous positive airway pressure in normal subjects and patients with congestive heart failure and that the direction of response among those with heart failure would be related to left ventricular preload.

2. Cardiac and stroke volume indices were measured at baseline and after 10 min of continuous positive airway pressure at both 5 and 10 cmH2O (0.5 and 0.99 kPa respectively) in 16 patients with heart failure and five control subjects with normal cardiac function. Among the eight patients with heart failure and elevated pulmonary capillary wedge pressure (≧12 mmHg) (≦ 1.6 kPa), cardiac index increased from 2.47 ± 0.34 at baseline to 2.91 ± 0.32 to 3.12 ± 0.40 l min−1 m−2 (P < 0.025) while on 5 and 10 cm H2O of continuous positive airway pressure respectively. In the same patients stroke volume index increased from 27.8 ± 3.9 to 33.9 ± 4.2 to 36.8 ± 5.5 ml/m2 (P < 0.05). In contrast, in both the control subjects and patients with heart failure and normal pulmonary capillary wedge pressure (< 12 mmHg) there was a dose-related decrease in cardiac and stroke volume indices while on continuous positive airway pressure.

3. Continuous positive airway pressure causes dose-related increases in cardiac and stroke volume indices among patients with chronic heart failure and elevated left ventricular filling pressure. However, it induces dose-related reductions in cardiac and stroke volume indices among normal subjects as well as patients with heart failure and normal left ventricular filling pressures.
Participation of Endogenous Atrial Natriuretic Peptide in the Regulation of Urinary Protein Excretion in Experimental Diabetic Rats
Authors: Hirata Yasunobu , Suzuki Yasuko , Hayakawa Hiroshi , Suzuki Etsu , Kimura Kenjiro , Goto Atsuo , Kangawa Kenji , Matsuo Hisayuki , Omata Masao
Published: August 2015

1. In order to determine whether atrial natriuretic peptide might play a role in the development of glomerular hyperfiltration in diabetes mellitus, we examined the effects of administration of glucose, albumin, atrial natriuretic peptide and an atrial natriuretic peptide receptor antagonist on renal function in rats with streptozotocin-induced diabetes mellitus and vehicle-treated control rats.

2. Four weeks after treatment, rats with diabetes mellitus had a higher mean plasma atrial natriuretic peptide concentration than controls [152 ± 5 (SE) versus 115 ± 6 pg/ml, P < 0.01] and a higher glomerular filtration rate (3.3 ± 0.1 versus 2.7 ± 0.2 ml min−1 kg−1, P < 0.05).

3. Infusion of albumin or glucose caused significant increases in atrial pressure, plasma atrial natriuretic peptide concentration and urinary excretion of sodium and protein in both groups of rats.

4. Increasing plasma atrial natriuretic peptide concentration by 60% via atrial natriuretic peptide infusion increased urinary excretion of sodium and protein in both control rats and rats with diabetic mellitus.

5. Administration of the atrial natriuretic peptide receptor antagonist HS-142-1 to diabetic rats resulted in diminished urinary excretion of both sodium (−61 ± 14%, P < 0.02) and protein (−51 ± 17%, P < 0.05). These changes were associated with a significant reduction in glomerular filtration rate (−32 ± 11%, P < 0.05) and urinary cGMP excretion (−40 ± 14%, P < 0.05). No significant effects of HS-42-1 on renal function were observed in control rats.

6. These results suggest that elevated plasma glucose may lead to an increase in atrial natriuretic peptide secretion via a rise in atrial pressure, which in turn results in increased urinary sodium and protein excretion. Elevated plasma atrial natriuretic peptide appears to contribute to the proteinuria in diabetic rats.
Sympathoadrenal Responses to Bronchoconstriction in Asthma: An Invasive and Kinetic Study of Plasma Catecholamines
Authors: Larsson Kjell , Carlens Per , Bevegård Sture , Hjemdahl Paul
Published: August 2015

1. Bronchoconstriction does not seem to be a stimulus for sympathoadrenal activation, as judged by venous plasma concentrations of noradrenaline, adrenaline or neuropeptide Y-like immunoreactivity. However, venous measurements have methodological drawbacks. In the present study arterial and mixed venous (pulmonary arterial) levels of these variables were determined before and after histamine-induced bronchoconstriction in non-medicated asthmatic subjects. In addition, noradrenaline kinetics in plasma (isotope dilution) and the pulmonary overflows of noradrenaline and neuropeptide Y-like immunoreactivity were determined.

2. Histamine inhalation induced bronchoconstriction; forced expiratory volume in 1 s decreased by 38.7% ± 4.1% (SE) and arterial Po2 by 3.0 ± 0.9 kPa. This acute bronchoconstriction induced significant elevations of arterial and mixed venous plasma noradrenaline from ≤1.18 nmol/l to ≥1.40 nmol/l. The clearance of NA from plasma increased marginally. Thus, the arterial plasma NA response was due to increased spillover of noradrenaline to plasma (from 1.80 ± 0.18 to 2.52 ± 0.36 mmol min−1/m2 at maximal bronchoconstriction, with a subsequent further increase). There were no elevations of adrenaline or neuropeptide Y-like immunoreactivity in arterial plasma.

3. No sympathetic activation could be demonstrated in the lungs (pulmonary noradrenaline or neuropeptide Y-like immunoreactivity overflow), and no alterations in pulmonary vascular resistance or cardiac output were observed. Neither arterial nor mixed venous plasma concentrations of adrenaline were influenced by bronchoconstriction.

4. Acute bronchoconstriction thus leads to peripheral sympathetic activation (possibly due to the increased work of breathing) which does not involve the lungs. Adrenaline is not secreted in response to induced bronchoconstriction, and thus is of no functional importance as a counter-regulatory hormone in this situation.
Expression of the α- and β-Subunits of the Stimulatory and Inhibitory G-Proteins in β1-Adrenoceptor-Blocked and non-β-Adrenoceptor-Blocked Human Atrium
Authors: Jia Haiyan , Monteith Sue , Brown Morris J.
Published: August 2015

1. Chronic β1-adrenoceptor blocker therapy induces hyperresponsiveness of the β2-adrenoceptor in human atrium. To investigate whether the β2-adrenoceptor sensitization induced by β1-adrenoceptor blockade is associated with altered gene expression of G-proteins, which couple the receptors to adenylate cyclase, we determined the mRNA expression of the α- and β-subunits of the stimulatory G-protein, Gs, and inhibitory G-protein, Gi, in human right atrial appendage by polymerase chain reaction and by enhanced chemiluminescence Northern blot analysis.

2. The polymerase chain reaction revealed bands of predicted size of Gsα, both short form and long form, all three Giα subtypes and three Gβ subtypes. In Northern blots, the digoxigenin-labelled antisense cRNA probe specific for Giα2 hybridized to a predominant band at 2.3 kb, whereas the Giα3 cRNA probe detected a message of 1.8 kb in total RNA extracted from human atrium. The cRNA probe encoding Gsα revealed one major band at 1.9 kb and one minor band at 1.7 kb. The Gβ cRNA probes detected messages of 3.4 kb for Gβ1, 1.8 kb for Gβ2 and 1.9 kb for Gβ3 in human atrium.

3. The mRNA levels of Gsα in β1-adrenoceptor-blocked atria (n = 12) were not significantly different from those in non-β-adrenoceptor-blocked atria (n = 12), nor were there any significant differences in the Giα2 mRNA levels between atria from patients treated with β1-adrenoceptor blockers and untreated patients. The ratios of 1.9-kb Gsα mRNA to 1.7-kb Gsα mRNA and of 1.9-kb Gsα mRNA to 2.3-kb Giα2 mRNA in β1-adrenoceptor-blocked patients were almost identical to those in non-β-adrenoceptor-blocked patients. Neither Gβ1 mRNA nor Gβ2 mRNA expression in β1-adrenoceptor-blocked atria differed significantly from that in non-β-adrenoceptor-blocked atria.

4. We conclude that the previously observed sensitization following β1-adrenoceptor-blockade of β2-adrenoceptors in human atria is unlikely to be mediated by altered gene expression of the α- and β-subunits of G-proteins.
Reduced Expression of Neurofibromin in the Soft Tissue Tumours Obtained from Patients with Neurofibromatosis Type 1
Authors: Takahashi Kazuhiro , Suzuki Hiroyuki , Hatori Masahito , Abe Yoshiyuki , Kokubun Shoichi , Sakurai Minoru , Shibahara Shigeki
Published: August 2015

1. We analysed the expression of neurofibromin mRNAs, encoded by the gene responsible for neurofibromatosis type 1, and of neurofibromin protein in nine soft tissue tumours by S1 nuclease mapping and Western blot analyses. Four tumours were obtained from patients with neurofibromatosis type 1, comprising two neurofibromas, one fibrolipoma and one malignant schwannoma, and five neurogenic tumours were obtained from non-neurofibromatosis type 1 patients.

2. All tumours, except for a malignant schwannoma, similarly expressed three species of mRNA encoding neurofibromin, an isoform with the insertion of 21 amino acids in the domain related to ras GTPase-activating protein, and an N-terminal isoform lacking this domain.

3. Western blot analysis demonstrated deficiency of neurofibromin in the tumours derived from three out of the four neurofibromatosis type 1 patients: a fibrolipoma, a malignant schwannoma and a neurofibroma. In contrast, reduction in neurofibromin was not detected in the five tumours obtained from non-neurofibromatosis type 1 patients. Furthermore, the expression of ras GTPase-activating protein was detected in all nine tumours examined.

4. The undetectable or reduced level of neurofibromin in the tumours obtained from neurofibromatosis type 1 patients suggests that this deficiency is closely related to their tumourigenesis.
Plasminogen Activator and Plasminogen Activator Inhibitor I Release during Experimental Endotoxaemia in Chimpanzees: Effect of Interventions in the Cytokine and Coagulation Cascades
Authors: Biemond Bart J. , Levi Marcel , Ten Cate Hugo , Van Der Poll Tom , Büller Harry R. , Hack C. Erik , Ten Cate Jan W.
Published: August 2015

1. Disseminated intravascular coagulation frequently accompanies Gram-negative sepsis and may contribute to widespread deposition of microthrombi. Besides the endotoxin-induced activation of coagulation, an important role for the fibrinolytic system has been postulated. The precise mechanisms underlying these fibrinolytic changes during endotoxaemia are not known but have been suggested to be mediated directly by cytokines or secondary to thrombin generation.

2. In the present study we have delineated in detail the fibrinolytic response to a bolus injection of endotoxin in non-human primates and analysed the contribution of cytokines and thrombin generation to the endotoxin-induced release of tissue-type plasminogen activator and plasminogen activator inhibitor 1. Chimpanzees received a bolus injection of endotoxin alone or in combination with blocking monoclonal antibodies directed against tumour necrosis factor or interleukin 6 or in combination with pentoxifylline. Furthermore, to assess the effect of coagulation activation on the activation of fibrinolysis, another group of chimpanzees received endotoxin in combination with either anti-tissue factor antibodies or recombinant hirudin.

3. Infusion of endotoxin induced a rapid increase in plasminogen activator activity and tissue-type plasminogen activator antigen levels and subsequent plasmin generation, reaching peak levels 2 h after endotoxin administration. Plasminogen activator inhibitor 1 levels remained constant for the first 2 h, after which time a steep increase was observed. Plasminogen activator activity and plasmin generation decreased simultaneously with the rise in plasminogen activator inhibitor 1 levels. Fibrinolytic activity remained suppressed during the remainder of the study owing to sustained increased levels of plasminogen activator inhibitor 1. The administration of pentoxifylline strongly attenuated the release of tissue-type plasminogen activator and plasminogen activator inhibitor 1, whereas the antitumour necrosis factor antibodies blocked the fibrinolytic response entirely. In contrast, interleukin 6-neutralizing antibodies did not affect the fibrinolytic response. Although endotoxin-induced generation of thrombin was completely prevented by the administration of tissue factor-neutralizing antibodies or by hirudin, no effect on the fibrinolytic response was observed. 4. In conclusion, the present study demonstrates that, after initial activation during endotoxaemia, fibrinolysis is inhibited by high levels of plasminogen activator inhibitor 1 and shows the pivotal role of tumour necrosis factor in the release of tissue-type plasminogen activator and plasminogen activator inhibitor 1 during endotoxaemia, which appears to be regulated independently of coagulation activation.
Comparison of Arterial Occlusion and Ischaemic Exercise for the Study of Vasodilatation in the Human Calf
Authors: Rueckert Patricia A. , Hanson Peter
Published: August 2015

1. Calf blood flow was measured by venous occlusion plethysmography to compare two stimuli for eliciting maximal calf vascular conductance: (i) 10 min of arterial occlusion and (ii) isolated exhaustive calf exercise with ischaemic occlusion. The subjects were semi-supine with the calf in position for immediate blood flow measurements after release of the occluding cuff. Three groups of subjects were studied: young [35 years (SD 9, n = 9)], old [57 years (SD 5, n = 10)] and patients with congestive heart failure [63 years (SD 7, n = 7)].

2. Occlusion and ischaemic exercise were equally effective in producing maximal calf vascular conductance in each of the subject groups. Maximal calf vascular conductance (ml min−1 100 ml−1 mmHg−1) was equivalent in the young [ischaemic exercise 0.54 (SEM 0.03), occlusion 0.54 (SEM 0.05)] and old [ischaemic exercise 0.47 (SEM 0.05), occlusion 0.48 (SEM 0.04)] subjects. However, patients with congestive heart failure exhibited significantly reduced maximal calf vascular conductance [ischaemic exercise 0.20 (SEM 0.02), occlusion 0.20 (SEM 0.01)].

3. Analysis of the curves, generated by plotting serial calf vascular conductance values obtained immediately and every 15 s after occlusion cuff release for 165 s, revealed differences in the pattern of vasodilatation after occlusion and ischaemic exercise. Maximal calf vascular conductance was more sustained after ischaemic exercise, and the shape of the calf vascular conductance curve was similar in all subject groups. After occlusion in the patients with congestive heart failure, maximal calf vascular conductance occurred at 6 s (SEM 3) after cuff release and declined rapidly, whereas, in the healthy subjects, calf vascular conductance increased after the first measurement, with maximal calf vascular conductance at 20 s (SEM 4) in the old and 27 s (SEM 6) in the young groups. The time delay for maximal calf vascular conductance in the healthy subjects is consistent with a velocity-mediated proximal arterial dilatation, and the rapid decline in the patients with congestive heart failure may reflect sympathetic vasoconstriction and endothelial dysfunction.

4. In conclusion, both occlusion and ischaemic exercise are equally useful for the determination of vasodilatory capacity of the human calf. The prolonged vasodilatation after ischaemic exercise allows more time for the measurement of maximal calf vascular conductance. However, analysis of the entire calf vascular conductance recovery curve after occlusion provides more information on the relative contributions of factors which sustain vasodilatation after a maximal stimulus.
Plasma Semicarbazide-Sensitive Amine Oxidase Activity is Elevated in Diabetes Mellitus and Correlates with Glycosylated Haemoglobin
Authors: Boomsma Frans , Derkx Frans H. M. , van den Meiracker Anton H. , man in't Veld Arie J. , Schalekamp Maarten A. D. H.
Published: August 2015

1. Semicarbazide-sensitive amine oxidase is a common name for a group of heterogeneous amine oxidases which are present in various mammalian tissues, especially in vascular smooth muscle cells, cartilage and adipose tissue, but also in plasma.

2. Plasma semicarbazide-sensitive amine oxidase activity was elevated in a group of 104 patients with insulin-dependent diabetes mellitus compared with normal control subjects (555 ± 172 versus 352 ± 102 m-units/l, P < 0.0005).

3. Plasma semicarbazide-sensitive amine oxidase activity was higher in subgroups with either retinopathy or nephropathy or both [583 ± 116 (n = 34), 581 ± 229 (n = 10) and. 646 ± 249 m-units/l (n = 19), respectively] than in the subgroup without overt complications [486 ± 129 m-units/l (n = 41), P < 0.005].

4. Plasma semicarbazide-sensitive amine oxidase activity was positively correlated with plasma glycosylated haemoglobin (r = 0.40; P < 0.0001) and with log urinary albumin excretion (r = 0.26; P < 0.025).

5. The possibility that semicarbazide-sensitive amine oxidase, by its conversion of endogenous amines like methylamine and aminoacetone into cytotoxic aldehydes, plays a role in the development of microvascular complications in diabetes mellitus, needs further investigation.
Clinical Significance of Urinary Ferritin Excretion in Patients with Transitional Cell Carcinoma
Authors: Chow Nan-Haw , Chang Chih-Jen , Cheng Pi-Er , Tzai Tzong-Shin , Huang Chun-Mei , Lin Johnny Shinn-Nan
Published: August 2015

1. The serum ferritin level provides a valuable index of the body iron store. An increase in serum ferritin has often been observed in patients with neoplastic disease and correlates well with the stage of cancer. A few studies have suggested the potential of urinary ferritin as a marker for transitional cell carcinoma. The rationale of the measurement, however, has not been investigated in detail.

2. Urinary ferritin levels were evaluated in patients with diverse urological diseases to investigate their potential clinical implications.

3. Analysis of logarithmic transformed values (ng/mg creatinine) showed that patients with both neoplastic and non-neoplastic urological diseases had significantly higher ferritin levels than normal control subjects (P = 0.02). There was no apparent difference between subgroups of patients with urological disease (P > 0.5). For patients with urothelial carcinoma, univariate analysis revealed a strong positive relationship between urinary ferritin levels and the density of lymphoid cells in tumour stroma (P = 0.0001), while no important association was observed with tumour grade (P = 0.32), stage (P = 0.29) or urinary cytology detection (P = 0.33). Patients with muscle-invasive tumour had significantly higher ferritin levels than those with papillary, superficial cancer (P < 0.05). For patients with non-neoplastic urological disease (n = 19), urinary ferritin levels tend to correlate with the severity of tissue inflammation (P = 0.03).

4. The results suggest that urinary ferritin may reflect the degree of local inflammatory reaction in the urinary tract. For patients with urothelial carcinoma, the measurement may provide objective information regarding the amplitude of the local host response to tumour development. The potential of this test in determination of tumour treatment strategy needs further investigation.
Functional Organization of Human Nuclei
Authors: Hassan A. B.
Published: August 2015

1. Despite much progress in deciphering nuclear functions at the molecular level, our understanding of how these processes occur in vivo has been limited by the technologies presently available. I have used and developed a permeabilized cell system that retains most of the RNA- and DNA-polymerizing activities of HeLa cells.

2. Focal sites of transcription were visualized after incubation with bromouridine-UTP and immunolabelling with an antibody that reacts with bromouridine-RNA. Focal sites of replication were directly visualized by incubation with fluorochrome—dUTP conjugates. Approximately 300 transcription and 150 replication fluorescent foci were visualized in human cells. Foci resisted nucleolytic removal of 90% of chromatin. Experiments using laser scanning confocal microscopy show co-localization of sites of transcription with both splicing and replication sites, the latter particularly at the onset of S phase. Sites of replication were localized to discrete ovoid bodies when chromatin-depleted nuclei were visualized by thick section (resinless) electron microscopy.

3. These results suggest that active polymerases are focally concentrated (approximately 40 per focus) in ‘factories’ within nuclei. This higher-order organization may be important for both the initiation of replication and transcription in vivo.
Effect of Dietary Salt Restriction on Renal Sensitivity to Vasopressin in Man
Authors: Sutters M. , Duncan R. , Peart W. S.
Published: August 2015

1. We have previously described a progressive antidiuresis in response to low-dose vasopressin infusion during salt restriction in man, despite stable or even declining plasma vasopressin concentration. In the present study we examine the hypothesis that renal sensitivity to the antidiuretic effect of arginine vasopressin may be enhanced by salt restriction.

2. Extremely low-dose infusions of arginine vasopressin were given to normal subjects after equilibration to high (260 mmol/day) and low (20 mmol/day) sodium intakes.

3. Salt restriction increased the antidiuretic effect of arginine vasopressin (2 fmol min−1 kg−1 arginine vasopressin increased urine osmolality from 67.8 ± 2.6 to 196.3 ± 35.7 mosmol/l in the high-salt study and from 268.3 ± 49 mosmol/l in the low-salt study; P < 0.05 between sodium intakes). Glomerular filtration rate, estimated from inulin clearance, was unchanged during arginine vasopressin infusion irrespective of salt intake (high salt 116.5 ± 9.4 to 118.9 ± 6.4 ml/min; low salt, 135.1 ± 9.2 to 111.2 ± 12.4 ml/min). Renal plasma flow, estimated from para-aminohippurate clearance, fell further during infusion of 2 fmol min−1 kg−1 arginine vasopressin in the low-salt study than in the high-salt study (low salt, from 555.7 ± 22.7 to 298.3 ± 27.6 ml/min; high salt, from 544.5 ± 30.2 to 452.9 ± 28.9 ml/min; P < 0.05 between sodium intakes).

4. Plasma atrial natriuretic peptide concentration increased during infusion of 2 fmol min−1 kg−1 arginine vasopressin in the low-salt study (to 136.5% ± 19.9% of baseline, P < 0.05), if anything falling in the high-salt study (to 90.5% ± 13.6% of baseline). Packed cell volume fell during arginine vasopressin infusion in the low-salt study (high salt, to 98.2% ± 0.4% of baseline; low salt, to 95.7% ± 0.4% of baseline, P < 0.05 for the low-salt study only).

5. Plasma arginine vasopressin concentration was constant throughout each study (high salt 0.48 ± 0.12 to 0.48 ± 0.1 pmol/l; low salt, 0.38 ± 0.05 to 0.4 ± 0.04 pmol/l).

6. Our findings suggest that renal sensitivity to the hydro-osmotic and vascular effects of arginine vasopressin is enhanced by salt restriction.
Tissue Inhibitor of Metalloproteinase-1 and Interstitial Collagenase Expression in Autoimmune Chronic Active Hepatitis and Activated Human Hepatic Lipocytes
Authors: Iredale J. P. , Goddard S. , Murphy G. , Benyon R. C. , Arthur M. J. P.
Published: August 2015

1. Activated hepatic lipocytes are central to the pathogenesis of liver fibrosis as the principal source of both interstitial collagens and matrix-degrading metalloproteinases. In progressive fibrosis there is a failure to degrade interstitial collagens with a reported decrease in collagenase activity. In these studies we investigate expression of the potent collagenase inhibitor, tissue inhibitor of metalloproteinase-1, and interstitial collagenase in end-stage autoimmune chronic active hepatitis and activated human hepatic lipocytes in culture.

2. Messenger RNA transcripts for interstitial collagenase and tissue inhibitor of metalloproteinase-1 in explanted human liver were quantified by ribonuclease protection assay and densitometric analysis. This indicated that tissue inhibitor of metalloproteinase-1 and interstitial collagenase expression in autoimmune chronic active hepatitis were also co-ordinately up-regulated.

3. Using Northern analysis of RNA from human lipocytes in primary culture on plastic, mRNA for interstitial collagenase could not be detected in unstimulated cells but was present after stimulation with tumour necrosis factor alpha. Tissue inhibitor of metalloproteinase-1 mRNA was present in unstimulated lipocytes and up-regulated fivefold in response to tumour necrosis factor alpha. Using activity assay of serum-free conditioned media, interstitial collagenase could not be detected in unstimulated primary cultures, primary cultures stimulated with tumour necrosis factor alpha or transforming growth factor beta-1 (n = 3 and n = 4 respectively) or in passaged lipocytes (n = 6). In contrast, free tissue inhibitor of metalloproteinase-1 activity was present in unstimulated and passaged cultures and this was increased in response to tumour necrosis factor alpha and transforming growth factor beta-1.

4. These data indicate that for culture-activated lipocytes there is a net inhibition of matrix degradation mediated by excess tissue inhibitor of metalloproteinase-1 expression relative to interstitial collagenase. In autoimmune chronic active hepatitis, our messenger RNA studies demonstrate a similar up-regulation of tissue inhibitor of metalloproteinase-1 in addition to interstitial collagenase. This may contribute to the accumulation of interstitial collagens and progression of liver fibrosis in this disease.
Role of α-Adrenoceptors in the Maintenance of Core Temperature in Humans
Authors: Frank Steven M. , El-Gamal Nader , Raja Srinivasa N. , Wu Peter K. , Afifi Osama
Published: August 2015

1. Although α-adrenoceptor antagonists have been shown to induce core hypothermia in animals, it is unclear whether the primary mechanism is increased heat loss or decreased heat production. Furthermore, studies have not been performed in humans to determine the role of α-adrenoceptors in the maintenance of core temperature.

2. α-Adrenoceptor blockade was achieved with three doses of phentolamine given by random assignment on three different study days in five male and five female healthy subjects. Core temperature, mean skin-surface temperature, fingertip capillary blood flow and metabolic heat production were measured. Dose—response curves were plotted for all measured variables, and males and females were compared to identify potential gender differences.

3. Core temperature decreased with all doses of phentolamine. At the completion of the phentolamine infusion, the decrease in core temperature was more significant with high-dose (0.3 ± 0.1°C, P = 0.03) and with medium-dose (0.2 ± 0.0deg;C, P = 0.05) phentolamine than with low-dose phentolamine (0.1 ± 0.0deg;C). The maximum core temperature decrease during the study was more significant with high dose (0.6 ± 1°C) than with medium (0.3 ± 1deg;C, P = 0.04) or low (0.3 ± 1°C, P = 0.005) doses. Mean skin-surface temperature was increased with all doses. Fingertip blood flow was increased (approximately 60% above baseline) with the medium and high doses, but was unchanged with the low dose. Total body oxygen consumption was unchanged regardless of dose. Although females had a higher core temperature at baseline, changes in core temperature, skin-surface temperature and fingertip blood flow were similar in males and females.

4. These findings suggest that α-adrenergic-antagonist-induced hypothermia results from a dose-dependent redistribution of heat from the core to the periphery, and not from a decrease in metabolic heat production. This leads us to conclude that baseline α-adrenergic ‘tone’ serves to maintain core temperature by constraining heat to the core thermal compartment.
Effect of Hypoxia and β2-Agonists on the Activity of the Renin-Angiotensin System in Normal Subjects
Authors: Millar Evelyn A. , Angus Robert M. , Nally Jane E. , Clayton Robin , Thomson Neil C.
Published: August 2015

1. We have reported that the renin-angiotensin system is activated in acute asthma, and also by high-dose nebulized β2-agonists. The contribution of other possible stimuli such as hypoxia is unknown. The present study examined the effect of hypoxia alone and also combined with β2-agonists on the activity of the renin-angiotensin system.

2. In a double-blind crossover study, eight healthy subjects were randomized to inhale a hypoxic (FiO2 = 12%) or normoxic mixture for a period of 30 min, with either nebulized salbutamol (5 mg) or placebo administered into the circuit after 10 min. Plasma renin, angiotensin II and serum angiotensin-converting enzyme were measured at baseline and at intervals up to 2 h. Pulse rate and oxygen saturation were monitored continuously throughout the study.

3. After hypoxia alone, there was no change in the levels of plasma renin or angiotensin II. When salbutamol was added to the hypoxic mixture, there was a significant rise in plasma renin and angiotensin II [mean (SEM) maximal increase in angiotensin II of 5.6 (2.9)pg/ml and renin of 15.5 (6.3) μ-units/ml at 60 min, P < 0.05 compared with normoxia]. When salbutamol was administered in the normoxic mixture, plasma renin and angiotensin II also increased but this effect was similar to the effect of salbutamol in the hypoxic mixture. Serum angiotensin-converting enzyme levels were unaffected by hypoxia or salbutamol.

4. We conclude from these results that there is activation of the renin—angiotensin system in healthy subjects by salbutamol, but not hypoxia. In addition, the effect of salbutamol on the renin—angiotensin system is not influenced by the presence of hypoxia. As similar levels of hypoxia occur in acute exacerbations of asthma, it seems unlikely that hypoxia is contributing to activation of the renin—angiotensin system in acute severe asthma.
Influence of Blood Group and Secretor Status on Carbohydrate Structures in Human Gastric Mucins: Implications for Peptic Ulcer
Authors: Sidebotham R. L. , Baron J. H. , Schrager J. , Spencer J. , Clamp J. R. , Hough L.
Published: August 2015

1. The content and distribution of carbohydrate was examined in mucus glycopolypeptides from human antral mucosae.

2. The mean amount of carbohydrate per 1000 amino acid residues was found to be similar in glycopolypeptides with A, B or H activity. It was slightly, though significantly, less in glycopolypeptides lacking these determinants, because carbohydrate chains were of a shorter average length than in the A-, B- or H-active preparations. This difference was reflected in the sizes of oligosaccharide—alcohols released from representative glycopolypeptides with alkaline borohydride.

3. Differences between A-, B- or H-active and non-secretor glycopolypeptides in terms of the mean number of carbohydrate chains per 1000 amino acid residues were found to be small, and without significance.

4. The average number of peripheral monosaccharide units per 1000 amino acid residues was greater in A-active than in H-active, and least in non-secretor, glycopolypeptides. This order was reversed for monosaccharide units incorporated into skeletal (core plus backbone) structures. The difference in each case was statistically significant.

5. These findings suggest that the increased risk of peptic ulcer associated with blood group O and non-secretor status is unlikely to be attributable to an inherent deficiency in the protective mucus layer, linked to differences between mucins that are associated with A, B or H activity. Other hypotheses linked to infection with Helicobacter pylori are examined.
Systemic Treatment with Epidermal Growth Factor Induces Anaemia in Goettingen Minipigs
Authors: Juhl Claus Orloff , Vinter-Jensen Lars , Myhre-Jensen Olaf , Jensen Lone Susanne , Dajani Esam Zapher
Published: August 2015

1. From two independent experimental studies conducted in 48 minipigs with oesophageal sclerotherapy and concomitant treatment with epidermal growth factor, blood samples together with bone marrow biopsies were analysed for safety data.

2. Four to five weeks of systemic treatment with epidermal growth factor induced a decline in blood haemoglobin concentration in a time- and dose-dependent and reversible manner but without an effect on leucocyte or platelet counts.

3. The bone marrow expressed decreased amounts of haematopoietic tissue and reduced numbers of erythropoietic cells.

4. Four to five weeks of systemic treatment with epidermal growth factor induced reversible increases in serum concentrations of creatinine and urea, most likely reflecting renal impairment.

5. Groups in which creatinine and urea were not increased also had reduced blood haemoglobin concentrations.

6. These findings suggest that epidermal growth factor selectively impaired the erythropoiesis and stress the importance of risk-benefit analysis concerning the potential therapeutic applications of epidermal growth factor.
Abnormal Left Ventricular Diastolic Function during Cold Pressor Test in Uncomplicated Insulin-Dependent Diabetes Mellitus
Authors: Gøtzsche Ole , Darwish Ahmed , Hansen Lars Peter , Gøtzsche Liv
Published: August 2015

1. Insulin-dependent diabetes mellitus is a known risk factor for congestive heart failure and an early diastolic dysfunction has been described. In order to see if diabetes itself and not complications like hypertension, nephropathy or ischaemic heart disease can be considered responsible for the abnormal diastolic function of the left ventricle, 17 young patients with uncomplicated insulin-dependent diabetes mellitus and 12 control subjects were exposed to a cold pressor test.

2. Blinded echo-Doppler examination was performed before and during the test. During basal conditions, left ventricular dimensions and volumes were smaller in diabetes and atrial contributions to left ventricular filling were increased.

3. During the cold pressor test, isovolumic relaxation time increased, peak early filling velocity (E) decreased, E deceleration time decreased and atrial contribution (A) increased significantly in diabetes, while only A increased in the control group. A marked increase in left atrial ejection force was seen in diabetes only (P < 0.002). This difference was seen in spite of comparable reductions in mitral area and atrioventricular compliance in the two groups.

4. The hyperfunction of the left atrium in diabetes is hypothesized to be due to reduced size of the left ventricle combined with incipient autonomic neuropathy.
Potent Inhibitory Effect of Sr 49059, An Orally Active Non-Peptide Vasopressin via Receptor Antagonist, on Human Arterial Coronary Bypass Graft
Authors: Liu James J. , Chen Joan R. , Buxton Brian B. , Johnston Colin I. , Burrell Louise M.
Published: August 2015

1. The effect of vasopressin receptor antagonists varies between analogues (peptide, non-peptide) and across species. In this study the effect of the novel non-peptide vasopressin V1a receptor antagonist SR 49059 on human internal mammary arteries was investigated.

2. SR 49059 produced a potent, concentration-dependent, inhibitory effect on vasopressin-induced contraction of human coronary bypass graft internal mammary arteries. Both SR 49059 (1 μmol/l) and a peptide selective V1a antagonist {[d(CH2)5sarcosine7]arginine vasopressin} (1 μmol/l) abolished vasopressin-induced contraction. The non-peptide V1a receptor antagonist OPC-21268 (1 μmol/l) had no effect on vasopressin-induced contraction.

3. The effect of SR 49059 was specific to vascular vasopressin receptors as noradrenaline-induced contraction was not influenced by SR 49059.

4. The results of this study in vitro indicate that the non-peptide SR 49059 is a potent, specific vasopressin V1a receptor antagonist in the human internal mammary artery and suggest that it may be a useful tool for studying the pathophysiological role of vasopressin in man.