bluuebunny/crossref_metadata_2025 huggingface dataset:
Accuracy of Breath-by-Breath Analysis of Flow-Volume Loop in Identifying Sleep-Induced Flow-Limited Breathing Cycles in Sleep Apnoea-Hypopnoea Syndrome
Authors: Sériès Frédéric , Marc Isabelle
Published: August 2015

1. Inspiratory flow limitation is involved in the pathophysiology of sleep-related breathing disorders. Since the definition of flow-limited cycle is based on a dissociation between flow and respiratory efforts, identification of inspiratory flow limitation requires upper airway or intrathoracic pressure measurements. We examined the accuracy of the analysis of the flow—volume loop of a tidal breath in identifying inspiratory flow limitation during sleep in ten patients with a sleep apnoea—hypopnoea syndrome.

2. Measurements were taken during continuous positive airway pressure trials. After data acquisition, the presence of inspiratory flow limitation was identified by the presence of an inspiratory plateau or decrease in inspiratory flow independently of the increase in inspiratory efforts. The flow—volume loop was reconstructed for each breathing cycle by plotting the instantaneous flow and the tidal volume. The instantaneous inspiratory and expiratory flows were measured at 50% of the respective portion of the tidal volume, and a breath-by-breath analysis of the midtidal volume—flow ratio (inspiratory/expiratory ratio) was obtained. The analysis of the flow—volume loop was compared with standard inspiratory flow limitation criteria using different values of the inspiratory/expiratory ratio threshold, below which breathing cycles were classified as flow-limited. With a lower limit of the normal inspiratory/expiratory ratio threshold of 0.97, the sensitivity and specificity of the method were both 76%. In each subject, the proportion of breathing cycles identified as flow-limited according to the inspiratory/expiratory ratio progressively decreased with an increasing positive pressure level.

3. We conclude that analysis of the flow—volume curve is accurate in identifying most of the inspiratory flow limitation breathings in sleep apnoea—hypopnoea syndrome.
Biosynthesis of Platelet-Activating Factor in Normal and Inflamed Human Colon Mucosa: Evidence for the Involvement of the Pathway of Platelet-Activating Factor Synthesis De Novo in Inflammatory Bowel Disease
Authors: Appleyard Caroline B. , Hillier Keith
Published: August 2015

1. Platelet-activating factor can be synthesized by two distinct biochemical pathways and is degraded by a number of enzymes, the first step of which is deacetylation by a specific acetyl hydrolase.

2. The biochemical pathway of platelet-activating factor synthesis de novo and the first step in platelet-activating factor degradation have been investigated for the first time in incubates of normal human colon mucosa and in inflamed mucosa from patients with inflammatory bowel disease.

3. In the presence of 100 μmol/l CDP-choline and 100 μmol/l hexadecyl acetyl glycerol, homogenates from inflamed mucosa synthesized significantly greater platelet-activating factor [851 ± 574 pmol/mg of protein (mean ± SEM) in 90 min incubation] than normal mucosa [105 ± 61 pmol/mg of protein in 90 min incubation] (P < 0.05).

4. Under the same conditions of assay, the percentage turnover to inactive lyso-platelet-activating factor was similar in inflamed mucosa (35.5 ± 9.4%) and normal mucosa (42.7 ± 8.5%) in 90 min (P > 0.05).

5. The identity of platelet-activating factor was confirmed by HPLC, by its mobility on TLC and by the ability of WEB 2170, a selective platelet-activating factor receptor antagonist, to block its platelet-aggregatory action.

6. These findings confirm the presence of the pathway for the synthesis de novo of the potently proinflammatory platelet-activating factor in human colon mucosa in inflammatory bowel disease.
Use of a Stable Copper Isotope (65Cu) in the Differential Diagnosis of Wilson's Disease
Authors: Lyon T. D. B. , Fell G. S. , Gaffney D. , McGaw B. A. , Russell R. I. , Park R. H. R. , Beattie A. D. , Curry G. , Crofton R. J. , Gunn I. , Sturniolo G. S. , D'inca R. , Patriarca M.
Published: August 2015

1. 65Cu/63Cu stable-isotope ratios have been measured in blood serum after oral administration of the stable isotope 65Cu. The incorporation of the isotope into the plasma protein pool was followed at various times for up to 3 days. The resulting patterns of enrichment in healthy control subjects, in Wilson's disease patients and in heterozygotes for the Wilson's disease gene, were similar in appearance to those found by others using copper radioactive isotopes. After an initially high enrichment at 2h after dosage, the Wilson's disease cases, in contrast to the control subjects, did not show a secondary rise in isotope enrichment of the plasma pool after 72 h, demonstrating a failure to incorporate copper into caeruloplasmin. The Wilson's disease heterozygotes had variable degrees of impairment of isotope incorporation, not always distinguished from those of control subjects.

2. The stability of the isotope also permits the copper tracer to be followed for a longer period. Ten healthy subjects were studied for over 40 days, allowing the biological half-time of an oral dose of copper to be determined (median 18.5 days, 95% confidence interval 14–26 days). Known heterozygotes for the Wilson's disease gene were found to have a significantly increased biological half-time for removal of copper from the plasma pool (median 43 days, 95% confidence interval 32–77 days).

3. The incorporation of 65Cu in patients with diseases of the liver (other than Wilson's disease) was found to be similar to that in control subjects, aiding differential diagnosis.
Type I Collagen Biosynthesis by Skin Fibroblasts from Patients with Idiopathic Juvenile Osteoporosis
Authors: Pocock Andrew E. , Francis Martin J. O. , Smith Roger
Published: August 2015

1. Skin fibroblast lines were cultured from nine patients who had the features of idiopathic juvenile osteoporosis, six relatives, five unrelated control subjects and three unrelated patients with osteogenesis imperfecta type I. Some patients with idiopathic juvenile osteoporosis were adults whose previous osteoporosis was in remission. Two patients with idiopathic juvenile osteoporosis were siblings and one patient with idiopathic juvenile osteoporosis had a daughter with severe osteogenesis imperfecta (type III).

2. The ratio of type III to type I collagen, synthesized by fibroblasts, was increased in two of the patients with osteogenesis imperfecta type I and in the daughter with osteogenesis imperfecta type III, but was normal in all the other patients with idiopathic juvenile osteoporosis and the other relatives.

3. Radiolabelled collagen was digested by cyanogen bromide and separated on SDS-PAGE. Unreduced collagen peptides migrated normally, except those from both the two siblings with idiopathic juvenile osteoporosis. In these two lines, abnormal migration suggested the presence of collagen I mutations.

4. The secretion of synthesized collagen by these two idiopathic juvenile osteoporosis lines and two others was reduced to only 43–45% as compared with a line from a 13-year-old control subject, which was defined as 100%. The three osteogenesis imperfecta type I lines secreted 18–37%, the other five idiopathic juvenile osteoporosis lines secreted 57–75%, the relatives (including the daughter with severe osteogenesis imperfecta) secreted 49–115% and the controls secreted 69–102%.

5. We conclude that qualitative abnormalities of type I collagen associated with a reduction in total secreted collagen synthesis may occur in a minority of patients with idiopathic juvenile osteoporosis; these patients could represent a subset of patients with this disorder.
Lipopolysaccharide Induces Upregulation of Neutral Endopeptidase 24.11 on Human Neutrophils: Involvement of the CD14 Receptor
Authors: Fagny Christine , Marchant Arnaud , De Prez Eric , Goldman Michel , Deschodt-Lanckman Monique
Published: August 2015

1. As lipopolysaccharide is a major stimulator of neutrophil responses during Gram-negative bacterial infections, we studied its effect on the membrane expression of neutral endopeptidase 24.11/CD10 on neutrophils in a model of endotoxaemia in vitro. Lipopolysaccharide added to human whole-blood induced a marked and sustained CD10/neutral endopeptidase upregulation that was already detectable at 0.1 ng/ml and was maximal at a lipopolysaccharide concentration of 10 ng/ml.

2. We observed that neither tumour necrosis factor-α nor any newly synthesized protein was involved in the upregulation observed after 1 h incubation with 10 ng/ml lipopolysaccharide.

3. We further studied whether the lipopolysaccharide-induced CD10/neutral endopeptidase upregulation was mediated by lipopolysaccharide binding to the neutrophil CD14 receptor. Incubation of whole blood with an anti-CD14 monoclonal antibody before the addition of 0.1 ng/ml or 0.5 ng/ml lipopolysaccharide resulted in complete inhibition of CD10/neutral endopeptidase upregulation. In contrast, at a lipopolysaccharide concentration of 10 ng/ml, the anti-CD14 monoclonal antibody had an incomplete blocking effect.

4. The differential requirement for the CD14 receptor, depending on the lipopolysaccharide dose, was confirmed by the study of a patient suffering from paroxysmal nocturnal haemoglobinuria (in whom a complete defect in neutrophil CD14 expression was previously documented).

5. We finally confirmed these results using purified neutrophils, demonstrating that lipopolysaccharide-induced CD10/neutral endopeptidase upregulation depends on direct interaction with neutrophil CD14.
Compartmental Analysis of Colonic Transit Reveals Abnormalities in Constipated Patients with Normal Transit
Authors: Bouchoucha Michel , Devroede Ghislain , Renard Phillipe , Arhan Pierre , Barbier Jean-Phillipe , Cugnenc Paul-Henri
Published: August 2015

1. The aims of this study were to investigate if compartmental analysis can be used to analyse colonic transit measurements and to search for a relationship between transit time and the parameters deduced from this analysis. In addition, an attempt was made to determine if such analysis could reveal a functional abnormality in patients who complain of constipation but have normal colonic transit.

2. The subjects included 11 healthy controls, 10 patients with chronic diarrhoea and 55 constipated patients. Segmental and total colonic transit time were measured using a previously described method. Compartmental analysis was based on a three-compartment system, with k1, k2 and k3 being the coefficients of diffusion out of the right colon, the left colon and the rectosigmoid area respectively.

3. Patients complaining of constipation who had delayed transit time were the only subjects to have lower values of coefficient k1 than controls. k2 was lower than normal in all patients complaining of constipation, but this decrease was more marked in subjects with delayed colonic transit time than in subjects with normal colonic transit time. All patients complaining of constipation had lower values of k3 than control subjects.

4. This study shows that analysis of colonic transit time is feasible using a simple diffusion law, and that the results are correlated to clinical data. Moreover, this analysis permits detection of abnormalities in two groups of subjects: those who complain of constipation but are labelled as having normal colonic transit time and those who have chronic diarrhoea.
Regional Sympathetic Nervous Activation after a Large Meal in Humans
Authors: Cox Helen S. , Kaye David M. , Thompson Jane M. , Turner Andrea G. , Jennings Garry L. , Itsiopoulos Catherine , Esler Murray D.
Published: August 2015

1. To investigate the link between post-prandial thermogenesis and sympathetic nervous activation we have studied the effects of a single large meal on regional sympathetic nervous activity in healthy, lean subjects.

2. In nine male subjects, noradrenaline spillover was measured from the heart, kidney and liver using isotope dilution, both while fasting and after consumption of a high-energy liquid meal of composition 53% carbohydrate, 32% fat and 15% protein (energy value 2.64–3.51 MJ). Regional oxygen consumption, whole-body oxygen consumption and, in a subset of subjects, muscle sympathetic nerve firing (microneurography) were also measured.

3. Both whole-body oxygen consumption (P < 0.03) and total body spillover of noradrenaline (P < 0.01) rose after the meal, with peak increases of 24% and 56% respectively. Spillover of noradrenaline from the heart was unchanged, that from the hepatosplanchnic circulation increased marginally (0.377 nmol/min to 0.480 nmol/min, P = 0.09), while renal noradrenaline spillover more than doubled (0.440 nmol/min to 0.937 nmol/min, P < 0.05). Skeletal muscle sympathetic nerve activity (peroneal nerve) increased from 7.7 bursts/min at rest to peak at 17.9 bursts/min 60 min after the meal in the three subjects in whom stable recordings were obtained.

4. The meal increased oxygen consumption in the kidneys and liver significantly, from 11.5 ± 1.6 ml/min to 14.5 ± 1.1 ml/min and from 46 ± 7 ml/min to 57 ± 6 ml/min respectively (P < 0.05), but not in the heart.

5. Consumption of a large meal produces a substantial and relatively selective increase in sympathetic outflow to the kidneys and skeletal muscle. While resting regional oxygen consumptions and noradrenaline spillovers were related, the changes that occurred in each were unrelated, so that no direct relationship could be demonstrated between post-prandial thermogenesis and sympathetic activity.
t(8;21) Breakpoints are Clustered between Alternatively Spliced Exons of MTG8
Authors: Tighe Jane E. , Calabi Franco
Published: August 2015

1. The (8;21) translocation, which is consistently associated with a subgroup of acute myeloid leukaemia, involves two loci: runt on chromosome 21 and MTG8 on chromosome 8.

2. Breakpoints in runt fall within a single intron that is located immediately downstream of a phylogenetically conserved DNA-binding domain (the ‘runt box’).

3. We now show that most breakpoints on chromosome 8 fall within a region between two alternative 5′ MTG8 exons. Thus, we predict that chimaeric genes on both the derivative(8) and the derivative(21) chromosomes have the potential to be transcriptionally active.
Cutaneous Vasoconstrictor Response Induced by Inspiratory Gasp in Relation to Sex and Age
Authors: Lau Ying-Tung , Liu Chi-Feng , Tsai C. C.
Published: August 2015

1. Vasoconstrictor responses to inspiratory gasp were determined in fingertip skin by laser Doppler flowmetry in relation to age and gender of healthy adults. Variations of the responses were examined together with variations in body mass index and vital capacity.

2. In the absence of any significant difference in the baseline blood flow, the index of vasoconstrictor response (per cent change) induced by inspiratory gasp was higher in young males than in young females (71.4% versus 59.4%; P<0.05), and in the same direction as the change in vital capacity determined in the same laboratory setting. Similar parallel differences in the indexes of vasoconstrictor response and vital capacity existed between young and middle-aged males, suggesting that the differences observed were not due to gender or age per se.

3. Strong positive correlations between the index of the vasoconstrictor response and vital capacity in the same subject were found when young males and females were pooled together and when young and middle-aged males were pooled together. Furthermore, after graded inspiratory gasp, graded vasoconstrictor response was observed in the same subject, indicating a close relationship between the depth of inspiration (magnitude of stimulus) and the index of the vasoconstrictor response (reactivity).

4. We concluded that the index of the vasoconstrictor response induced by inspiratory gasp depends significantly on the magnitude of the vital capacity. These results provide a new approach for quantifying dynamic changes in skin blood flow and raise caveats about comparing differences in neurovascular functions using single measurements of vasoconstrictor response induced by inspiratory gasp as an index.
Contribution of Age and Intimal Lesion Morphology to Coronary Artery Wall Mechanics in Coronary Artery Disease
Authors: Kok Wouter E. M. , Peters Ron J. G. , Prins Martin H. , Piek Jan J. , Koch Karel T. , David George K. , Visser Cees A.
Published: August 2015

1. Atherosclerotic changes of the coronary vascular wall include localized plaque formation and diffuse hardening, both of which influence tensile strength of the inner vascular wall. Insight into the relation between age, the atherosclerotic process and vessel wall elasticity may contribute to the prevention of secondary vascular wall damage.

2. To evaluate the determinants of coronary artery wall elasticity, we studied a group of 34 patients, aged 54.6 ± 10.1 years, who underwent balloon angioplasty for coronary artery disease. With the use of 30 MHz intravascular ultrasound, a total of 127 cross-sections of coronary artery segments outside the balloon area were studied. The echographic appearance of the intima was classified as normal intimal thickening, fibrous lesions and calcified lesions. Fibrofatty lesions, which are believed to be rupture prone, were analysed separately. From the lumen area change, measured by semiautomated planimetry from digitized ultrasound images, and simultaneously measured aortic pressure change during the diastolic phase of the cardiac cycle, two elastic parameters were derived, pressure—strain modulus Ep and β-stiffness.

3. In univariate analysis Ep and β-stiffness were determined by age, vessel size, intimal composition, severity of lumen obstruction and gender, but not by eccentricity of the lesion or a specific coronary artery. In multivariate linear analysis, increased vessel wall stiffness was independently determined by advanced age, larger vessel size, intimal composition, and to a lesser extent by female gender. Elastic parameters of fibrofatty lesions were not different from other fibrous lesions.

4. Coronary artery wall elasticity is independently determined by age, vessel size and intimal composition.
Effect of Water Restriction during Adaptation to a Low-Sodium Diet in Man
Authors: Sutters M. , Peart W. S.
Published: August 2015

1. Plasma sodium concentration may influence renal sodium excretion. We have examined the possibility that the fall in plasma sodium that occurs during salt restriction in man might be an important stimulus for renal sodium conservation.

2. In order to prevent the fall in plasma sodium that usually occurs during dietary salt restriction, we water restricted (200 ml/day) six normal subjects for the 2 days after the transition from 260 (high-sodium diet, day 3) to 20 mmol (low-sodium diet, days 4 and 5) sodium per day. In the control (hydrated) group water intake was held constant at 1800 ml/day.

3. Plasma sodium fell during the low-sodium diet in the hydrated group but remained constant in the dehydrated group (141.3 ± 0.2 to 140.2 ± 0.2 mmol/l versus 141.1 ± 0.3 to 141.3 ± 0.3 mmol/l). Plasma arginine vasopressin concentration was significantly higher and urine flow lower during the low-sodium diet in the dehydrated group (arginine vasopressin on day 5: hydrated group, 0.72 ± 0.1 pmol/l; dehydrated group, 2.18 ± 0.5 pmol/l). Weight fell by a similar amount in both groups (hydrated group, 1.23 ± 0.17 kg; dehydrated group, 1.45 ± 0.19 kg).

4. On the low-sodium diet there were no differences between groups in changes in plasma renin activity (hydrated group, 1.6 ± 0.24 to 4.78 ± 0.65 nmol angiotensin I h−1 ml−1; dehydrated group 1.57 ± 0.18 to 5.14 ± 0.56 nmol angiotensin I h−1 ml−1) or atrial natriuretic peptide (hydrated group, 23 ± 2.3 to 14.7 ± 1.6 pg/ml; dehydrated group, 26.8 ± 3.6 to 12.7 ± 1.3 pg/ml). Salivary aldosterone concentration increased further in the dehydrated study, but only on day 5.

5. Sodium excretion fell further in the dehydrated group over the first 16 h of the low-sodium diet on day 4 (hydrated group, 8.62 ± 0.76 mmol/h; dehydrated group, 6.57 ± 0.38 mmol/h). Creatinine clearance fell on day 5 (low sodium) in the dehydrated group but did not change significantly in the hydrated group (hydrated group, 152 ± 7 to 137 ± 7; dehydrated group, 157 ± 7 to 123 ± 7 ml/min).

6. We conclude that the fall in plasma sodium during salt restriction is not an important trigger for renal sodium conservation in man. The principal difference between studies was the elevation of arginine vasopressin in the dehydrated study. Differences in salivary aldosterone concentration occurred on day 5 only, too late to account for the differences in sodium excretion on day 4. Under the conditions of this study, our findings could be explained if physiological range elevation of arginine vasopressin has an antinatriuretic effect.
Postprandial Sympatho-Adrenal Activity: Its Relation to Metabolic and Cardiovascular Events and to Changes in Meal Frequency
Authors: Vaz Mario , Turner Andrea , Kingwell Bronwyn , Chin Jaye , Koff Elizabeth , Cox Helen , Jennings Garry , Esler Murray
Published: August 2015

1. Sympatho-adrenal activity was measured after the consumption of a 3.15 MJ mixed meal. Whole-body noradrenaline spillover rates, forearm plasma noradrenaline spillover and adrenaline secretion rates were derived using isotope dilution methodology. Heart rate and blood pressure spectral analysis measurements were also made. The relation of sympatho-adrenal activity to thermogenic and cardiovascular events was studied. Sympathetic nervous and thermogenic responses were measured for 120 min after the single 3.15 MJ meal and compared with those after three 1.05 MJ meals, given 30 min apart.

2. Whole-body and forearm plasma noradrenaline spillover, and the 0.1 Hz component of systolic pressure power all increased significantly postprandially, while the 0.1 Hz component of heart rate variability, an indirect index of cardiac sympathetic nervous activity, remained unaltered. Adrenaline secretion was unaltered postprandially. Whole-body plasma noradrenaline spillover and thermogenesis during the 120 min postprandial period were 37% and 36% higher after the single meal as compared with the multiple meals, although this was not statistically significant.

3. The sympathetic neural responses were delayed in relation to peak plasma insulin levels and sustained in the face of declining insulin levels. Energy expenditure increased significantly postprandially, but there was no direct quantitative relationship to plasma noradrenaline spillover. Forearm oxygen consumption did not increase postprandially despite significant increases in regional noradrenaline spillover. Thus, no close relation was demonstrated between postprandial sympathetic nervous activation and either insulin secretion or thermogenesis.
The Urinary F1 Activation Peptide of Human Prothrombin is a Potent Inhibitor of Calcium Oxalate Crystallization in Undiluted Human Urine in Vitro
Authors: Ryall Rosemary L. , Grover Phulwinder K. , Stapleton Alan M. F. , Barrell Dianne K. , Tang Yulu , Moritz Robert L. , Simpson Richard J.
Published: August 2015

1. The urinary F1 activation peptide of prothrombin is the predominant protein incorporated into calcium oxalate crystals precipitated from human urine. The aim of this study was to examine the effect of pure urinary prothrombin F1 on calcium oxalate crystallization in human urine.

2. Urinary prothrombin F1 was purified from demineralized calcium oxalate crystals precipitated from human urine, and its effects on calcium oxalate crystallization induced by addition of an oxalate load were tested in undiluted, ultrafiltered urine from healthy men, at final concentrations of 0 to 10 mg/l.

3. Urinary prothrombin F1 did not affect the amount of oxalate required to induce crystallization, but the volume of material deposited increased in proportion to increasing concentrations of urinary prothrombin F1. However, the mean particle size decreased in reverse order: this was confirmed by scanning electron microscopy, which showed it to be the result of a reduction in crystal aggregation rather than in the size of individual crystals. Analysis of 14C-oxalate data revealed a dose-dependent decrease in calcium oxalate deposition with an increase in urinary prothrombin F1 concentration, indicating that the increase in particle volume recorded by the Coulter Counter resulted from inclusion of urinary prothrombin F1 into the crystalline architecture, rather than increased deposition of calcium oxalate.

4. It was concluded that urinary prothrombin F1 may be an important macromolecular determinant of stone formation.
Septic Patients in Multiple Organ Failure Can Oxidize Infused Glucose, but Non-Oxidative Disposal (Storage) is Impaired
Authors: Green Ceri J. , Campbell I. T. , O'sullivan Ellen , Underhill S. , McLaren D. P. M. , Hipkin L. J. , MacDonald I. A. , Russell Jean
Published: August 2015

1. Patients suffering trauma and sepsis are insulin resistant, but no studies have specifically been made of patients suffering multiple organ failure.

2. We have studied exogenous glucose utilization in multiple organ failure using a combination of the hyperglycaemic glucose clamp and indirect calorimetry to quantify glucose utilization in multiple organ failure, partitioning it into oxidative and non-oxidative disposal (storage).

3. Fourteen septic patients with multiple organ failure were studied. APACHE II (Acute Physiological and Chronic Health Evaluation Mark II) scores on the day of the study ranged from 11 to 31 (median 16). Twenty percent d-glucose was infused and blood glucose was clamped at 12 mmol/l for 3 h. The results were compared with those obtained on seven healthy control subjects.

4. Glucose utilization and energy expenditure were similar in the two groups for the first 90 min of the clamp, after which glucose utilization and energy expenditure increased steadily in the control subjects but did not change in the patients. Respiratory exchange ratio rose in both groups; considered over the whole of the clamp period, respiratory exchange ratio was slightly lower in the patients than in the control subjects (P < 0.05) but not at any specific time point. Glucose oxidation rose in both groups but non-oxidative glucose disposal (storage) rose only in the control subjects. Glucose oxidation was slightly lower in the patients (P < 0.05) but not at any specific time point and there was no difference between the groups in the amount by which glucose oxidation increased. Non-oxidative disposal in the patients fell significantly (P < 0.01) over the course of the clamp and was significantly lower than in the control subjects (P < 0.01)

5. Growth hormone increased in response to glucose infusion in the patients but not in the control subjects.

6. Like patients suffering uncomplicated sepsis or trauma, patients with multiple organ failure are also insulin resistant. The defect appears to lie in an impairment of the ability to store glucose rather than oxidize it, and this may be due in part to the increase in growth hormone in patients with multiple organ failure.
Insulin-Like Growth Factor I is a Major Fibroblast Mitogen Produced by Primary Cultures of Human Airway Epithelial Cells
Authors: Cambrey A. D. , Kwon O. J. , Gray A. J. , Harrison N. K. , Yacoub M. , Barnes P.J. , Laurent G.J. , Chung K. F.
Published: August 2015

1. The ability of airway epithelial cells to produce insulin-like growth factor I may be important in the pathogenesis of subepithelial fibrosis observed in the airways of patients with asthma. We determined whether human airway epithelial cells are capable of producing polypeptide mediators that could induce fibroblast proliferative activity, in particular insulin-like growth factor I.

2. We examined 12 primary cultures of human airway epithelial cells grown to confluence on collagen gel-coated dishes. Using a colorimetric assay based on the uptake and subsequent release of Methylene Blue, increased proliferation of human fetal lung fibroblasts was detected in conditioned media from airway epithelial cells. The median stimulation of fibroblast proliferation was 49.9% (range 25.6 −113.3%) above control values (observed at 1:2 dilution of media).

3. A neutralizing antiserum to insulin-like growth factor I partly inhibited fibroblast proliferation induced by epithelial cell conditioned media by 52.2% (49.9–109%; n = 5).

4. Radioimmunoassay for insulin-like growth factor I in conditioned media demonstrated a median concentration of 54.1 ng/ml (32.4–96.8 ng/ml).

5. Insulin-like growth factor I mRNA was detected in epithelial cell monolayers by Northern blot analysis using an insulin-like growth factor I cDNA probe.

6. The insulin-like growth factor I gene is expressed in cultured human airway epithelial cells, which also secrete insulin-like growth factor I protein. Insulinlike growth factor I also accounts for the major mitogenic activity for fibroblasts of cultured human epithelial cell conditioned media. Insulin-like growth factor I may function in a paracrine manner to modulate fibroblast behaviour and may be involved in airway processes, such as those occurring in asthma.
Are Himalayan Sherpas Better Protected against Brain Damage Associated with Extreme Altitude Climbs?
Authors: Garrido Eduardo , Segura Ramón , Capdevila Antoni , Pujol Jesús , Javierre Casimiro , Li Ventura Josep
Published: August 2015

1. The potential risk of brain damage when low-landers attempt to climb the highest summits is a well-known fact. However, very little is known about what occurs to Himalayan natives, perfectly adapted to high altitude, when performing the same type of activity.

2. Taking into account their long-life climbing experience at extreme altitudes, we examined seven of the most recognized Sherpas with the aim of performing a comprehensive neurological evaluation based on medical history, physical examination and magnetic resonance brain imaging. We compared them with one group of 21 lowland elite climbers who had ascended to altitudes of over 8000 m, and another control group of 21 healthy individuals who had never been exposed to high altitude.

3. While all of the lowland climbers presented psychoneurological symptoms during or after the expeditions, and 13 of them (61%) showed magnetic resonance abnormalities (signs of mild cortical atrophy and/or periventricular high-intensity signal areas in the white matter), only one Sherpa (14%) showed similar changes in the scans, presenting neurological symptoms at extreme altitude. The neurological examination was normal in all three groups, and no neuroimaging abnormalities were detected in the control group.

4. The significant differences, in both clinical and neuroimaging terms, suggest that Sherpa highlanders have better brain protection when exposed to extreme altitude. Although the key to protection against cerebral hypoxia cannot be established, it is possible that an increase in the usually short period of acclimatization could minimize brain damage in those low-landers who attempt the highest summits without supplementary oxygen.
Length-Specific Impairment of Skeletal Muscle Contractile Function after Eccentric Muscle Actions in Man
Authors: Saxton J. M. , Donnelly A. E.
Published: August 2015

1. The effects of maximum voluntary eccentric muscle actions on forearm flexor strength were studied at three different elbow joint angles (0.87, 1.57 and 2.79 rad) to examine whether subsequent impairment of contractile function is muscle length-specific.

2. A bout of 70 maximum voluntary eccentric muscle actions performed with the forearm flexors elicited delayed muscle soreness, efflux of creatine kinase into the blood, loss of elbow joint range of motion and a prolonged decline in maximum voluntary isometric contraction torque at the three elbow angles monitored (P < 0.01) in 30 subjects.

3. The relative decline in maximum voluntary isometric contraction torque after eccentric exercise differed between elbow angles (P < 0.01). The greatest decline in strength relative to baseline was observed at the most acute elbow angle of 0.87 rad, followed by 1.57 and 2.79 rad respectively. Superimposed electrical stimulation in a subgroup of eight subjects did not increase the torque elicited by the forearm flexors during maximum voluntary contraction tests at the most acute elbow angle (0.87 rad) at any time-point after eccentric exercise, suggesting the disproportionate loss of strength at short muscle length was not due to the inhibitory effects of muscle soreness.

4. Measures of arm circumference and ability to fully flex the elbow (in the same subgroup of eight subjects) suggested the greater decline in strength at the acute elbow angle was not due to the possible confounding influences of muscle swelling and/or impaired muscle shortening ability on strength measurements at short muscle length.

5. These data suggest a shift in the forearm flexor length—tension relationship could account for the disparate decline in strength between elbow angles after eccentric exercise. The disproportionate loss of strength at short muscle length suggests that eccentric exercise evoked a subtle increase in muscle length, perhaps attributable to the cumulative effects of regions of lengthened sarcomeres and/or series elastic elements.
Rheological and Microvascular Parameters in Diabetic Peripheral Neuropathy
Authors: Young M. J. , Bennett J. L. , Liderth S. A. , Veves A. , Boulton A. J. M. , Douglas J. T.
Published: August 2015

1. In order to determine whether rheological changes occur in neuropathic diabetic patients in the absence of smoking, proteinuria, retinopathy or other factors thought to influence haemorheology, three groups of subjects were studied; 24 non-diabetic control subjects (C), 24 non-neuropathic (D) and 24 neuropathic (N) diabetic patients. The groups were matched for age, sex, type and duration of diabetes. No patient or control was a current smoker. No patient had clinically detectable retinopathy or microalbuminuria. Neuropathy was defined as a peroneal conduction velocity < 40 ms−1. All subjects were tested resting semi-recumbent after a light breakfast.

2. There were no significant differences in rheological or microvascular parameters between uncomplicated diabetic patients and non-diabetic control subjects, although peroneal nerve motor conduction velocity was significantly reduced in otherwise uncomplicated diabetic patients [C 51.7 ± 6.0 ms−1 (mean ± SD) versus D 45.1 ± 5.2 ms−1 (P<0.05 C versus D)].

3. Transcutaneous oxygen and laser Doppler flux measured at 44°C were higher in control subjects than in neuropathic diabetic patients [C 76 ± 16 mmHg versus D 71 ± 10 mmHg versus N 63 ± 9 mmHg, and C 72 ± 40 flow units versus D 64 ± 41 flow units versus N 50 ± 26 flow units respectively (both P not significant C versus D, P<0.05 N versus C).

4. Erythrocyte aggregation, plasma viscosity and plasma fibrinogen were all significantly higher in the neuropathic diabetic patients compared with non-diabetic control subjects (all P<0.05 N versus C). Erythrocyte filtration was not significantly different between groups but was lower in diabetic patients. Whole-blood viscosity (corrected to 45% haematocrit) was significantly higher at both high (100 s−1) and low (1 s−1) shear rates in neuropathic diabetic patients than in non-diabetic control subjects (both P not significant C versus D, P<0.05 N versus C). There were no significant differences in whole-blood viscosity at a shear rate of 0.01 s−1.

5. In summary, there were no significant differences in rheological or microvascular parameters between matched groups of uncomplicated diabetic patients and control subjects, but erythrocyte aggregation, fibrinogen and plasma and corrected whole-blood viscosity were all significantly different in neuropathic diabetic patients compared with control subjects, as were assessments of microvascular flow. These results suggest that haemorheological changes are associated with disturbances of microvascular flow and diabetic peripheral neuropathy in the absence of other diabetic complications.
Influence of Treatment with Beclomethasone, Cromoglycate and Theophylline on Perception of Bronchoconstriction in Patients with Bronchial Asthma
Authors: Higgs C. M. B. , Laszlo G.
Published: August 2015

1. Perception of asthma by patients can be assessed from the relationship between symptom scores and peak expiratory flows. This study was designed to investigate the possibility that medication can affect perception of the sensation of asthma independently of changes in lung function.

2. Twelve subjects whose asthma was inadequately controlled by inhaled bronchodilator alone were studied during four different drug treatments over 3 months. Subjective self-assessment of asthma was scored on a 10 cm visual analogue scale and followed by three consecutive measurements of peak expiratory flow, using a coded electronic peak flow meter. This was recorded not less than three times daily on diary cards. Observations were recorded during the second week of each of four treatments:(i) a run-in period using only inhaled salbutamol as required, (ii) inhaled beclomethasone, (iii) inhaled cromoglycate and (iv) oral theophylline at a dose adjusted to achieve blood levels of 10–20 mg/l. Inhaled salbutamol was permitted during the other treatments as required. Changes in the slope and position of the regression lines of asthma scores on PEF were used to measure changes in perception of asthma on each treatment. Dynamic lung volumes were measured in the clinic before the study and after each treatment period.

3. In the group as a whole, theophylline improved lung function (mean peak flow and dynamic lung volumes) without affecting mean visual analogue scores, beclomethasone improved mean visual analogue scores with much less effect on lung function, while cromoglycate had a small though consistent effect on both.

4. Perception of asthma, measured by the relationship between peak flow rate and visual analogue scores, was unaffected by cromoglycate. On theophylline, perception of asthma was heightened in five subjects despite a definite improvement in their peak flow. On beclomethasone, perception of asthma was reduced in most subjects, often with no discernible improvement in mean peak flow or dynamic spirometry.

5. Perception of bronchoconstriction in asthma can be affected by drugs independently of control of the condition. Theophylline may produce a paradoxical increase in awareness of asthma in some individuals. With beclomethasone therapy a reduction in symptoms of asthma may occur without any improvement in tests of air flow.
Excessive Gravitational Blood Pooling Caused by Impaired Venous Tone is the Predominant Non-Cardiac Mechanism of Orthostatic Intolerance
Authors: Streeten David H. P. , Scullard Thomas F.
Published: August 2015

1. In a group of 40 patients with orthostatic intolerance due to hypotension and/or tachycardia, we have compared the pathogenetic roles of impaired contractility of the arterioles and the veins by measuring contractile responsiveness of the arterioles, reflected by increases in diastolic blood pressure and of the veins reflected by measurements of reduction in venous diameter during intravenous noradrenaline infusions.

2. Compared with 27 healthy subjects, patients with diffuse autonomic insufficiency showed striking supersensitivity in diastolic blood pressure (six out of eight) and venous constrictive responses (seven out of eight patients) to noradrenaline, consistent with impaired arteriolar and venous innervation.

3. In contrast, the patients with hyperadrenergic orthostatic hypotension (n =16) and orthostatic tachycardia (n = 16) showed diastolic blood pressure responses to noradrenaline that were almost invariably within the 95% confidence limits of the changes in normal subjects but supersensitive constrictive responses of foot veins in 22 of 32 subjects and subnormal venous responses in two individuals. The rate of noradrenaline infusion calculated to cause 50% of maximal venous constriction (the ED50) was significantly lower in the patients [mean (SEM) 6.8 (1.9) ng/min] than in the normal subjects [mean (SEM) 23.2 (3.0) ng/min, P<0.025].

4. The finding of significantly supersensitive foot vein constrictive responses to noradrenaline infusion in the patients of all three groups and supersensitive blood pressure responses exclusively in the patients with diffuse autonomic insufficiency indicates that venous pooling in the legs was the predominant pathogenetic mechanism of orthostatic intolerance in all three types of patients studied.

5. Correction of the orthostatic hypotension and/or tachycardia by external compression in virtually all patients confirmed this conclusion.
Role for the Endogenous Natriuretic Peptide System in the Control of Basal Coronary Vascular Tone in Dogs
Authors: Supaporn Thanom , Wennberg Paul W. , Wei Chi-Ming , Kinoshita Masahiko , Matsuda Yuzuru , Burnett John C.
Published: August 2015

1. While the natriuretic peptides (atrial, brain and C-type) mediate potent endothelium-independent vasorelaxing actions in vitro, the role of the endogenous natriuretic peptide system in vascular regulation in vivo remains unclear.

2. HS-142-1 is a novel natriuretic peptide receptor antagonist derived from a fungus named Aureobasidium sp. which selectively blocks particulate guanylate cyclase-linked natriuretic peptide A and B receptors that bind atrial, brain and C-type natriuretic peptide, and thus attenuates the generation of cGMP.

3. To characterize the vascular actions of the endogenous natriuretic peptide system in the control of basal coronary and systemic haemodynamics, six normal male mongrel anaesthetized dogs were studied while a second group of five dogs served as a control. HS-142-1 was given as an intravenous bolus at 3 mg/kg and was studied over five 20 min periods.

4. No significant difference after HS-142-1 was observed in mean arterial pressure, heart rate, cardiac output, right atrial pressure, pulmonary capillary wedge pressure or systemic vascular resistance compared with control. In contrast, a significant increase in coronary vascular resistance and decrease in coronary blood flow were observed which were different from the baseline values and the responses of the control group.

5. These studies demonstrate that HS-142-1 produces vasoconstriction in the coronary circulation. We conclude that the endogenous natriuretic peptide system, which is of cardiac and endothelial cell origin, is an important regulator of basal coronary vascular tone.
Chemical Characterization and Quantification of Proteoglycans in Human Post-Burn Hypertrophic and Mature Scars
Authors: Scott P. G. , Dodd C. M. , Tredget E. E. , Ghahary A. , Rahemtulla F.
Published: August 2015

1. Samples of normal skin from four patients, post-burn hypertrophic scar from five patients and post-burn mature scar from six patients were analysed for hydroxyproline, water and uronic acid and extracted with guanidinium chloride to yield the proteoglycan pool. A large chondroitin sulphate proteoglycan and biglycan were purified from one hypertrophic scar biopsy and decorin from a normal skin biopsy, by ion-exchange chromatography, gel-filtration and hydrophobic interaction chromatography. These purified proteoglycans were used in an inhibition ELISA assay to estimate the quantities of each in the tissue samples.

2. Samples of post-burn hypertrophic scar had on average 30% less hydroxyproline, 12% more water and 2.4 times as much uronic acid as normal skin. These differences were all statistically significant, whereas the small differences between mature scars and normal skin were not. The content of decorin in hypertrophic scars was only 25% of that in normal skin whereas the large chondroitin sulphate proteoglycan and biglycan were each about 6-fold higher. The mature scars had slightly elevated levels of large chondroitin sulphate proteoglycan and biglycan and a reduced content of decorin compared with normal skin but these differences were not statistically significant.

3. The results suggest that aberrant proteoglycan metabolism is a significant factor contributing to the altered physical properties of hypertrophic scars and that maturation of post-burn scars is dependent on a return of the relative proportions and concentrations of proteoglycans to those characteristic of normal dermis.
Interstitial Glycerol Concentration in Human Skeletal Muscle and Adipose Tissue is Close to the Concentration in Blood
Authors: Samra Jaswinder S. , Ravell Cate L. , Giles Sarah L. , Arner Peter , Frayn Keith N.
Published: August 2015

1. The suggestion that the interstitial glycerol concentration in both adipose tissue and skeletal muscle is around 3 mmol/l (Maggs DG, Jacob R, Rife F, et al. J Clin Invest 1995; 96: 370–7), rather than close to the blood concentration as previously supposed, was tested by independent methods.

2. Free glycerol was infused, as part of a triacylglycerol emulsion, into six normal subjects and the arteriovenous difference for glycerol across the forearm was measured. In addition the relative interstitial glycerol concentration in subcutaneous adipose tissue was assessed simultaneously in four of the subjects by microdialysis.

3. During glycerol infusion the arterialized glycerol concentration rose from 52 ± 5 μmol/l to 250–300 μmol/l (P < 0.001) in a square wave fashion. The net arteriovenous difference for glycerol across the forearm changed from negative (output) to positive (uptake) (P < 0.01). In subcutaneous adipose tissue the interstitial glycerol concentration rose during glycerol infusion (P < 0.001).

4. These observations are most easily explained by the movement of glycerol from plasma to interstitial fluid down a concentration gradient. We conclude that the interstitial glycerol concentration in skeletal muscle and adipose tissue is closer to the arterial concentration than to 3 mmol/l.
Superficial Hand Vein Responses to NG-Monomethyl-l-Arginine in Post-Partum and Non-Pregnant Women
Authors: Ford G. A. , Robson S. C. , Mahdy Z. A.
Published: August 2015

1. During human pregnancy marked vasodilatation occurs in arterial and venous vascular beds. The mechanisms responsible for this change remain unclear. The contribution of increased nitric oxide activity to vasodilatation associated with pregnancy was determined by examining superficial hand vein responses to NG-monomethyl-l-arginine, an inhibitor of nitric oxide synthase, in post-partum women 24–48 h after delivery when vasodilatation remains at levels present during the third trimester.

2. Seventeen healthy women, 24–48 h post partum, and 13 healthy non-pregnant women were studied. Eight of the post-partum women underwent repeat studies 12–16 weeks after delivery.

3. NG-monomethyl-l-arginine (100 nmol/min) resulted in venoconstriction in non-constricted veins (baseline, 0%; 5 min, 26 ± 9%; 10 min, 14 ± 8%; 15 min, 8 ± 7%; means ± SEM) and noradrenaline-constricted veins (5 min, 30 ± 7%; 10 min, 24 ± 10%; 15 min, 14 ± 11%). No constrictor response to NG-monomethyl-l-arginine was present in the same women 12 weeks post partum (5 min, 1 ± 4%; 10 min, 0 ± 3%; 15 min, 1 ± 4%) or in the non-pregnant control subjects in non-constricted (5 min, 2 ± 3%; 10 min, 4 ± 3%; 15 min, 2 ± 2%) or noradrenaline-constricted veins (Smin, − 2 ± 7%; 10 min, 1 ± 9%; 15 min, − 5 ± 7%).

4. These findings indicate that nitric oxide activity is increased in the immediate post-partum period in venous vasculature, and support the hypothesis that increased nitric oxide activity may be responsible for the vasodilatation observed during normal pregnancy.