bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Dobutamine on the Relationship between Oxygen Consumption and Delivery in Healthy Volunteers: Comparison with Sodium Nitroprusside
Authors: De Backer Daniel , Berre Jacques , Moraine Jean Jacques , Melot Christian , Vanfraechem Jacques , Vincent Jean-Louis
Published: August 2015

1. Dobutamine has been used to study the relationship between oxygen consumption (VO2) and oxygen delivery (DO2) in critically ill patients, but this has led to concerns that it could consistently increase VO2 in all patients. Although a direct thermogenic effect of the catecholamine has been primarily implicated in this increase in VO2, an increase in blood flow may contribute significantly by increasing the oxygen requirements of the heart and other organs such as the kidney and the liver. If this mechanism is predominant, it should also be observed when blood flow increases during the infusion of non-adrenergic agents. To separate the two mechanisms, we compared the effects of dobutamine with those of sodium nitroprusside on VO2/DO2 relationships in healthy volunteers.

2. Eight healthy volunteers received infusions of dobutamine at doses of 2, 4 and 6 μg min−1 kg−1 and nitroprusside at doses of 0.5, 1 and 2 μg min−1 kg−1 in an alternate order.

3. VO2 was determined by indirect calorimetry and cardiac output by electrical bioimpedance. Data were analysed by analysis of variance for repeated measurements and individual VO2/DO2 slopes were determined by linear regression.

4. VO2 increased more with dobutamine than with nitroprusside (from 138 ± 14 to 149 ± 20 ml min−1 m−2, P < 0.001, and from 131 ± 14 to 138 ± 17 ml min−1 m−2, P < 0.001, respectively). However, DO2 also increased more with dobutamine than with nitroprusside (from 531 ± 186 to 702 ± 274 ml min−1 m−2, P < 0.001, and from 523 ± 107 to 610 ± 122 ml min−1 m−2, P < 0.001, respectively). Individual VO2/DO2 slopes were similar with dobutamine and nitroprusside (6.5 ± 3.5 compared with 7.1 ± 4.6%, P not significant).

5. At the doses used, DO2 and VO2 increased more with dobutamine than with nitroprusside in healthy volunteers. However, the VO2/DO2 slopes were similar for both substances. Thus, an increase in VO2 is not exclusively observed with catecholamines. Studies of the effects of therapeutic interventions on oxygen-derived variables should report not only changes in VO2 but also VO2/DO2 slopes.
Autonomic Control of Skin Microvessels: Assessment by Power Spectrum of Photoplethysmographic Waves
Authors: Bernardi Luciano , Radaelli Alberto , Solda Pier Luigi , Coats Andrew J. S. , Reeder Martin , Calciati Alessandro , Garrard Christopher S. , Sleight Peter
Published: August 2015

1. Although it is well known that the microvessels of the skin constantly undergo spontaneous variations in volume, the significance of these rhythmic changes remains uncertain.

2. In 10 healthy males and in 15 patients in intensive care, we assessed the origin of the autonomic influences on spontaneous fluctuations in the microcirculation of the skin, obtained by an infra-red photoplethysmographic device; we used spectral analysis techniques to compare these fluctuations (which were recorded simultaneously in two sites) with those of blood pressure, in order to test the presence of autonomic control of any synchronous fluctuations in these different measurements from the cardiovascular system. In order to minimize mechanical fluctuations caused by occasional slow breaths, rather than nervously mediated fluctuations in skin blood flow, respiration was controlled at 15 breaths/min (0.25 Hz).

3. Spontaneous infra-red photoplethysmographic fluctuations were observed in different body areas (left index finger and left ear lobe, right and left index finger), and all were evident at 0.1 Hz, as well as respiration-related components at 0.25 Hz. Active standing increased the power of the 0.1 Hz fluctuations (sympathetic activity) in both blood pressure (from 62.7 ± 7.1 to 79.2 ± 3.7 normalized units, P<0.05) and IRP (finger: from 68.5 ± 6.4 to 86.9 ± 3.4 normalized units, P<0.05; ear: from 59.0 ± 5.9 to 88.1 ± 2.0, P<0.01). There was a high (>0.5) coherence between the fluctuations obtained in blood pressure, in IRP signals obtained simultaneously at the finger and at the ear, and in R—R interval. This synchronization between the oscillations in all these signals, which were unrelated to the respiratory frequency or to the pulse rate, suggests a common neural, non-local origin. The phase between IRP and blood pressure was positive in the 0.1 Hz region (+ 1.65 ± 0.41 radians, i.e. IRP was leading blood pressure, showing that 0.1 Hz fluctuations were not passively transmitted to the skin microvessels from large arteries) and negative in the 0.25 Hz region (−0.74 ± 0.19 radians, P<0.01 compared with phase in the 0.1 Hz region, i.e. IRP was lagging behind blood pressure, suggesting possible passive transmission to the skin microvessels of blood pressure fluctuations caused by respiration). Fluctuations at lower frequency were observed in all IRP recordings, suggesting a local origin for these. Intra-arterial and IRP fluctuations were compared in the 15 intensive care patients and gave similar results.

4. The skin microcirculation is thus not only under local control, but also reflects changes in sympathetic activity; the effect of these changes on the skin microcirculation can be easily evaluated by the spectral analysis of the IRP signal obtained simultaneously in multiple areas, in conjunction with the spectra of R—R interval and blood pressure.
Modulation of Multidrug Resistance Gene (mdr-1) with Antisense Oligodeoxynucleotides
Authors: Liu Chao , Qureshi Imran Ahmad , Ding Xun-Jie , Shan Yi-Fei , Huang Yi-Wei , Xie YI , Ji Mei-Rong
Published: August 2015

1. Multidrug resistance is the major obstacle to successful cancer chemotherapy. Circumventing multidrug resistance therefore represents a high priority for clinical anti-cancer treatment. Among many reversal strategies, antisense oligodeoxynucleotides may offer a molecular targeting tool for overcoming cellular multidrug resistance.

2. Two 17-mer phosphorothioate antisense oligomers, complementary to the 5′ end of the ATG initiator codon-containing region and loop-forming site (located at nucleotides 991–1007 from the first ATG codon) in mdr-1 cDNA sequence, were synthesized. The purpose was to study their effects on the function and expression of P-glycoprotein and mdr-1 gene.

3. The results showed that 10 μmol/l antisense oligomers could significantly inhibit the growth of multidrug resistant K562/Adm cells cultured in adriamycin-containing medium. No such effect was observed for parental (sensitive) K562/S cells. Intracellular daunorubicin accumulation increased greatly in the K562/Adm cells after they were treated with oligomers for 48 h and P-glycoprotein synthesis was strikingly reduced.

4. Further investigation with [α-32P]dCTP incorporation by the reverse transcriptase—polymerase chain reaction method revealed that antisense oligomers could result in a reduction in the level of mdr-1 mRNA, probably through hindering mdr-1 gene transcription.

5. The high reversal efficiency and specificity of antisense oligomers in regulating mdr-1 gene expression suggest a potential clinical application in gene therapy for drug resistant malignancies.
Neutrophil Adhesion Molecule Expression and Response to Stimulation with Bacterial Wall Products in Humans is Unaffected by Parenteral Nutrition
Authors: Plusa Mr S. M. , Webster N. , Primrose J. N.
Published: August 2015

1. Total parenteral nutrition is associated with a high incidence of septic complications. This may be partly due to neutrophil dysfunction induced by the parenteral nutrition.

2. Neutrophil adhesion molecule expression and the expression of CD11b in response to stimulation with formylmethionyl-leucyl-phenylalanine and lipopolysaccharide were determined before and after 24 h of lipid-containing parenteral nutrition. Eighteen adult patients referred for parenteral nutrition were studied.

3. There was no change in the expression of neutrophil l-selectin (CD62L), CD11a, CDllb, CD11c or CD15. Neutrophil response to stimulation with formylmethionyl-leucyl-phenylalanine and lipopolysaccharide as determined by CD11b expression was unaffected by parenteral nutrition.

4. This study has shown no evidence of parenteral nutrition-induced neutrophil dysfunction.
Negative Association between Erythrocyte Reduced Glutathione Concentration and Diabetic Complications
Authors: Thornalley P. J. , McLellan A. C. , Lo T. W. C. , Benn J. , Sönksen P. H.
Published: August 2015

1. Multiple logistic regression analysis of biochemical and clinical variables in diabetic patients was performed to identify those associated with the presence of diabetic complications (retinopathy, neuropathy and nephropathy).

2. The presence of diabetic complications correlated positively with duration of diabetes and patient age and negatively with the concentration of reduced glutathione in erythrocytes. Individually, retinopathy, neuropathy and nephropathy correlated with duration of diabetes, but retinopathy also correlated positively with haemoglobin A1c in diabetic patients. In insulin-dependent patients, the concentration of methylglyoxal was also in the logistic model for retinopathy and diabetic complications, but the logistic regression coefficient was not significant.

3. Multiple linear regression analysis indicated that erythrocyte reduced glutathione concentration correlated negatively with d-lactate concentration and positively with duration of diabetes in insulin-dependent patients and correlated negatively with glucose concentration in non-insulin-dependent diabetic patients.

4. In non-diabetic subjects, erythrocyte glyoxalase I activity correlated positively with methylglyoxal concentration. There was no similar correlation in diabetic patients. In insulin-dependent patients, methylglyoxal concentration correlated positively with duration of diabetes.

5. Glyoxal and methylglyoxal are detoxified by the glyoxalase system with reduced glutathione as co-factor. The concentration of reduced glutathione may be decreased by oxidative stress and by decreased in situ glutathione reductase activity in diabetes mellitus. A reduced concentration of reduced glutathione may predispose diabetic patients to oxidative damage and to α-oxoaldehyde-mediated glycation by decreasing the in situ glyoxalase I activity. Recent studies of vascular endothelial cells in vitro have suggested that α-oxoaldehydes detoxified by glyoxalase I are the major precursors of advanced glycation end products implicated in the development of diabetic complications. The role of these factors in the development of diabetic complications and the prospective prevention of diabetic complications by supplementation of reduced glutathione and/or α-oxoaldehyde-scavenging agents now deserve investigation.
Chromatographic Method for the Determination of Non-Transferrin-Bound Iron Suitable for Use on the Plasma and Bronchoalveolar Lavage Fluid of Preterm Babies
Authors: Kime Robert , Gibson Alan , Yong Wiston , Hider Robert , Powers Hilary
Published: August 2015

1. Non-protein-bound iron has been implicated in the aetiology of chronic lung disease of prematurity.

2. The modification of a method for the measurement of non-transferrin-bound iron in small volumes of plasma and bronchoalveolar lavage fluid from preterm babies is described.

3. The assay runs with a good degree of precision and a lower limit of detection of 0.02 μmol/l.

4. Non-transferrin-bound iron was detected in 50% of plasma samples and 11% of bronchoalveolar lavage fluid samples collected over the first week of life from babies born prematurely.
HPLC Glycosaminoglycan Analysis in Patients with Graves' Disease
Authors: Hansen CH , Fraiture B. , Rouhi R. , Otto E. , Förster G. , Kahaly G.
Published: August 2015

1. Orbital accumulation of hydrophilic, interstitial glycosaminoglycans (GAGs) and subsequent expansion of retrobulbar tissue lead to the clinical manifestation of exophthalmos in patients with Graves' eye disease.

2. A highly specific method to determine the concentration and biochemical composition of different GAGs was developed in order to obtain a sensitive test system for the activity of the disease. By means of this method, GAG excretion in 24 h urine collections of 56 patients and 21 controls was analysed by precipitation with cetylpyridinium chloride and potassium acetate in ethanol, followed by sequential enzymic hydrolysis with chondroitin AC lyase, chondroitin ABC lyase and hyaluronate lyase, with HPLC analysis of the resulting α,β-unsaturated disaccharides by anion-exchange chromatography.

3. Concentrations of GAG, chondroitin sulphate A (CA), dermatan sulphate (DS) and hyaluronic acid (HA) were determined in patients and controls, with high recovery rates [72.2 ± 5.3%, mean ± SEM; detection limit, 4.2 μg/l (0.01 μmol/l)], revealing marked differences in urinary concentrations of total GAG and HA, as well as an elevation of CA in patients compared with controls.

4. Method sensitivity was 0.86 for patients with active Graves' eye disease, and 0.87 for patients with untreated ophthalmopathy, whereas specificity was 1.0 for patients with inactive disease. Patients with increased GAG concentration responded well to steroids and/or orbital irradiation (before therapy: GAG, 111.49 ± 40.32; CA, 59.58 ± 21.34; DS, 25.05 ± 8.12; HA, 26.88 ± 11.63 mg/24 h; during therapy: GAG, 54.22 ± 10.94; CA, 20.52 ± 4.58; DS, 17.65 ± 3.46; HA, 16.05 ± 3.69 mg/24 h), whereas GAG excretion increased markedly 2–3 months after stopping prednisone therapy in patients with still active eye disease (GAG, 109.9 ± 10.51; CA, 63.8 ± 7.34; DS, 24.1 ± 5.07; HA, 22.0 ± 6.28 mg/24 h).

5. This sensitive method determines the nature of renally excreted GAGs, reflecting the aberrant synthesis pattern of fibroblasts in patients with Graves' disease.
The Antibody Response in Human Autoimmune Thyroid Disease
Authors: McIntosh Richard S. , Asghar M. Suhail , Weetman Anthony P.
Published: August 2015

1. The analysis of the antibody response in autoimmune thyroid disease has followed several historical trends. It was the investigation of thyroid-reactive antibody that allowed the initial characterization of the three principle thyroid autoantigens, thyroglobulin, thyroid peroxidase and the thyroid stimulating hormone receptor.

2. Analysis can be grouped under two broad areas: analysis of the physiological and pathological effects of the antibody, and analysis of the structure of the antibodies themselves. This review will focus on the latter.

3. Within recent years there has been a great increase in knowledge of thyroid-reactive antibody structure, principally through the adoption of phage display combinatorial library methodologies. While this latter technique has established some general principles for antibodies to thyroglobin and especially thyroid peroxidase, there is still a substantial gap in our knowledge of the antibody response to the thyroid stimulating hormone receptor.

4. Thyroid peroxidase antibodies have a relatively restricted V-region usage, and there is a correlation between the V-regions used and the epitope on thyroid peroxidase bound. In particular the Vκ light chain, Vκl(O12), is associated with reactivity to one epitope.

5. The purpose of this review is to bring together the latest results concerning the molecular analysis of the antibody response in autoimmune thyroid disease, to highlight areas of ignorance and conflict, and to discuss the methods adopted to circumvent the problems associated with analysis of the antibody response.
Elevated Plasma and Urinary Endothelin-I Levels in Human Salt-Sensitive Hypertension
Authors: Ferri Claudio , Bellini Cesare , Desideri Giovambattista , Mazzocchi Clarita , De Siati Luca , Santucci Anna
Published: August 2015

1. The behaviour of the potent vasoconstrictive endothelium-derived peptide endothelin-1 was evaluated in salt-sensitive hypertension.

2. Circulating and urinary endothelin-1 levels were evaluated in 30 men (mean age 44.6 ± 3.1 years) with uncomplicated essential hypertension after three consecutive 2-week periods on an intermediate (120 mmol), low (20 mmol) and high (240 mmol) NaCl diet. On the same occasions, blood pressure was measured to identify salt-sensitive patients (n = 16), i.e. those patients showing a mean blood pressure increase > 10 mmHg when switching from a low to a high NaCl diet, and salt-resistant patients (n = 14), i.e. those who did not show such mean blood-pressure variations.

3. Plasma endothelin-1 levels were higher (P < 0.005) in salt-sensitive than in salt-resistant hypertensive patients after intermediate-, low- and high-NaCl diets. Urinary endothelin-1 excretion was similar in both groups after an intermediate-NaCl diet, whereas it was significantly higher in salt-sensitive than in salt-resistant hypertensive subjects after low (P < 0.002) and high (P < 0.007) NaCl diets. High NaCl intake induced a significant increase in plasma endothelin-1 levels (P < 0.002) as compared with intermediate and low NaCl diet levels in salt-sensitive patients, but did not in salt-resistant subjects. No significant NaCl intake-related variations of urinary endothelin-1 excretion were observed in either group.

4. Salt-sensitive hypertensives are characterized by increased levels of endothelin-1 in both plasma and urine. This fact suggests that blood-pressure sensitivity to NaCl intake could be associated with an increased risk of developing both renal and cardiovascular damage.
Plasma Leptin, Energy Intake and Hunger following Total Hip Replacement Surgery
Authors: Stratton Rebecca J. , Dewit Odile , Crowe Elaine , Jennings Graham , Villar Richard N. , Elia Marinos
Published: August 2015

1. This study aimed to investigate the possible role of leptin in post-traumatic anorexia by making pre- and post-operative (0–8 days) measurements of circulating leptin concentrations in six patients undergoing elective total hip replacement for osteoarthritis.

2. Mean daily hunger rating (four categories) and food intake (assessed by food record charts) were measured pre-operatively, as well as post-operatively for the first 5 days (days 0–5). Leptin concentrations, circulating metabolites [glucose, non-esterified fatty acids, glutamine and 3-hydroxy-butyrate] and insulin and cortisol concentrations were measured pre-operatively (day 0) and post-operatively (days 1, 2, 3, 5 and 8).

3. Mean leptin concentrations were significantly increased only on day 1 (56% increase compared with pre-operative values, P < 0.009), whereas food intake (only 0.6 MJ on day 0) and hunger (5/6 patients ‘not hungry’ on day 0) only gradually improved over the next few days. (The energy intake over the first 5 days was 56% of the pre-operative value.)

4. Circulating insulin and cortisol concentrations were elevated on day 1 compared with pre-operative values on day 0 (P<0.05). Of the measured metabolites implicated in the control of food intake, circulating non-esterified fatty acids and 3-hydroxybutyrate were not significantly altered in the post-operative period, but significant hyper-glycaemia was noted on day 1 compared with day 0 pre-operatively (8.8 compared with 6.4 mmol/l glucose; P < 0.01).

5. It is concluded that circulating leptin is involved in the early (<24 h) acute-phase response after moderately severe surgical trauma (characterized biochemically by a substantial acute-phase protein response, hypoalbuminaemia, hyperglycaemia and hypoglutaminaemia). Therefore, leptin may be implicated in post-traumatic anorexia, although other factors are likely to be involved, especially after the first 24 h when circulating leptin concentrations are no longer elevated.
Different Dietary Calcium Intake and Relative Supersaturation of Calcium Oxalate in the Urine of Patients Forming Renal Stones
Authors: Messa Piergiorgio , Marangella Martino , Paganin Luisa , Codardini Mara , Cruciatti Aldo , Turrin Daniela , Filiberto Zattoni , Mioni Giuseppe
Published: August 2015

1. Dietary calcium restriction, an efficient practice in reducing urinary calcium excretion, has been reported to induce either an increase or no change in oxalate excretion, questioning its use in hypercalciuric stone-forming patients. In addition, calcium restriction has been previously demonstrated to induce other urinary changes which might influence the relative supersaturation of calcium oxalate. So the overall effect of calcium deprivation on the relative supersaturation of calcium oxalate is unpredictable.

2. The aim of the study was to evaluate the effect of dietary calcium restriction on the relative supersaturation of calcium oxalate in the urine of stone-forming patients utilizing a computer methodology which takes into account the main soluble complex species of oxalate.

3. We studied 34 stone-forming patients on both a free-choice diet, whose Ca and oxalate content (24 and 1.2 mmol respectively) was assessed by dietary inquiry, and after 30 days on a prescribed low-calcium and normal oxalate diet (11 and 1.1 mmol respectively). Under both conditions, the excretion of the main urinary parameters related to dietary composition, electrolytes, oxalate and daily citrate urinary excretion, were measured. The relative supersaturation of calcium oxalate was calculated by means of an iterative computer method which takes into account the main soluble complex species on which the solubility of calcium oxalate is dependent. In addition, intact parathyroid hormone and 1,25-dihydroxyvitamin D blood levels were also evaluated. In 13 of the patients intestinal calcium absorption was evaluated during both a free- and a low-calcium diet, utilizing kinetics methodology.

4. The low-calcium diet induced, together with an expected reduction of calcium excretion, a marked increase in oxalate urinary output. This finding was independent of the presence or otherwise of hypercalciuria and of the serum levels of parathyroid hormone and vitamin D. Intestinal calcium absorption was also stimulated by calcium deprivation and its levels were well correlated with oxalate excretion. Minor changes in magnesium and citrate excretion were also observed. The overall effect on the relative supersaturation of calcium oxalate consisted in a substantial increase in this parameter during the low-calcium diet.

5. In conclusion, our data reinforce the concept that dietary calcium restriction has potentially deleterious effects on lithogenesis, by increasing the relative supersaturation of calcium oxalate.
Angiotensin-Converting Enzyme Gene Polymorphism and Cardiovascular Disease
Authors: Butler R. , Morris A. D. , Struthers A. D.
Published: August 2015

1. The crucial role played by the renin-angiotensin—aldosterone system in the cardiovascular system and the immense therapeutic potential of angiotensin-converting enzyme inhibitors and, more recently, angiotensin II receptor blocking agents, in both heart failure and post-myocardial infarction is becoming increasingly evident. Polymorphisms within the genes controlling this enzyme system are candidates for the elucidation of the pathogenesis of cardiovascular disease and this link is both intriguing and provocative. Recently, an association between a polymorphism of the angiotensin-converting enzyme gene and phenotypic expression of cardiovascular disease, namely myocardial infarction, was reported. Since then, several small case-controlled studies have confirmed an association with manifestations of ischaemic heart disease or various other cardiac end-points. However, in a large prospective study the angiotensin-converting enzyme gene conferred no appreciable risk.

2. Our aim was to review the evidence that links polymorphisms of the angiotensin-converting enzyme gene with cardiovascular disease. We searched the Medline database (1990–1997) using the key words myocardial infarction, ischaemic heart disease, angiotensin-converting enzyme and polymorphisms and performed a search of the reference citation of relevant articles. We selected clinical studies on cardiovascular disease related to the angiotensin-converting enzyme genotype

3. Taken together, the available evidence supports the notion that the DD-angiotensin-converting enzyme genotype adversely influences specific cardiovascular diseases but appears to do so in specific geographical areas and in particular patient subgroups. It is not yet known whether it does this through an interaction with other genes or by as yet unexplained biochemical mechanisms.

4. We should regard the current data with the angiotensin-converting enzyme genotype as an intriguing clue in the pathogenesis of cardiovascular disease. However, the main factor against this potential benefit is that the impact of the DD genotype appears to be small and its clinical manifestations rather heterogeneous.
Genetic Susceptibility to the Development of Autoimmune Disease
Authors: Heward Joanne , Gough Stephen C. L.
Published: August 2015

1. Autoimmune diseases are common conditions which appear to develop in genetically susceptible individuals, with expression of disease being modified by permissive and protective environments. Familial clustering and data from twin studies provided the impetus for the search for putative loci. Both the candidate gene approach in population-based case-control studies and entire genome screening in families have helped identify susceptibility genes in a number of autoimmune diseases.

2. After the first genome screen in type 1 (insulin-dependent) diabetes mellitus it seems likely that most autoimmune diseases are polygenic with no single gene being either necessary or sufficient for disease development. Of the organ-specific autoimmune diseases, genome screens have now been completed in insulin-dependent diabetes mellitus and multiple sclerosis. Furthermore, the clustering of autoimmune diseases within the same individuals suggests that the same genes may be involved in the different diseases. This is supported by data showing that both HLA (human leucocyte antigen) and CTLA-4 (cytotoxic T-lymphocyte-associated-4) appear to be involved in the development of insulin-dependent diabetes mellitus and Graves' disease.

3. Genome screens have also been completed in some of the non-organ-specific autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis. Many candidate genes have also been investigated although these are predominantly in population-based case-control studies.

4. Substantial progress has been made in recent years towards the identification of susceptibility loci in autoimmune diseases. The inconsistencies seen between case-control studies may largely be due to genetic mismatching between cases and controls in small datasets. Family-based association studies are being increasingly used to confirm genetic linkages and help with fine mapping strategies. It will, however, require a combination of biology and genetics, as has been necessary with the major histocompatibility complex in insulin-dependent diabetes mellitus, to identify primary aetiological mutations.
Increased l-arginine Transport in Human Erythrocytes in Chronic Heart Failure
Authors: Hanssen H. , Brunini T. M. C. , Conway M. , Banning A. P. , Roberts N. B. , Mann G. E. , Ellory J. C. , Ribeiro A. C. Mendes
Published: August 2015

1. Transport of l-arginine was investigated under zero-trans conditions in human erythrocytes from healthy donors and patients with heart failure.

2. Saturable influx of l-arginine was mediated by the classical cationic amino acid transport systems y+ and y+L.

3. The Vmax for l-arginine transport via system y+ increased from 292 to 490 μmol h−-1 l−-1 of cells in heart failure.

4. With system y+ inhibited by N-ethylmaleimide (0.2 mmol/l), the Vmax for the transport of l-arginine via system y+L was unaffected in erythrocytes from patients with heart failure.

5. The inhibition of l-arginine and l-leucine influx by NG-monomethyl-l-arginine was similar in erythrocytes from control and heart failure patients.

6. Plasma l-arginine levels were reduced in patients with heart failure (59 μmol/l) compared with controls (125 μmol/l). Plasma from patients with heart failure also contained the endogenous l-arginine analogue NG-monomethyl-l-arginine, which was undetectable in plasma from controls.

7. Intracellular concentrations of l-arginine and NG-monomethyl-l-arginine were significantly elevated in erythrocytes from patients with heart failure compared with controls, consistent with an increased transport capacity for l-arginine and NG-monomethyl-l-arginine.

8. The present study provides the first evidence that system y+ mediates the increased transport of l-arginine in human erythrocytes from patients with chronic heart failure. These findings are similar to our previous results obtained in patients with chronic renal failure. Since both pathologies seem to present with an increased synthesis of nitric oxide, studies of l-arginine transport in erythrocytes may provide a valuable paradigm to study abnormalities of the l-arginine-nitric oxide signalling pathway.
Hypotensive and Regional Haemodynamic Effects of Exercise, Fasted and after Food, in Human Sympathetic Denervation
Authors: Puvi-Rajasingham Sharmini , Smith Gareth D. P. , Akinola Adeola , Mathias Christopher J.
Published: August 2015

1. In human sympathetic denervation due to primary autonomic failure, food and exercise in combination may produce a cumulative blood pressure lowering effect due to simultaneous splanchnic and skeletal muscle dilatation unopposed by corrective cardiovascular reflexes. We studied 12 patients with autonomic failure during and after 9 min of supine exercise, when fasted and after a liquid meal. Standing blood pressure was also measured before and after exercise.

2. When fasted, blood pressure fell during exercise from 162 ± 7/92 ± 4 to 129 ± 9/70 ± 5 mmHg (mean arterial pressure by 22 ± 5%), P < 0.0005. After the meal, blood pressure fell from 159 ± 8/88 ± 6 to 129 ± 6/70 ± 4 mmHg (mean arterial pressure by 22 ± 3%), P < 0.0001, and further during exercise to 123 ± 6/61 ± 3 mmHg (mean arterial pressure by 9 ± 3%), P < 0.01. The stroke distance—heart rate product, an index of cardiac output, did not change after the meal. During exercise, changes in the stroke distance—heart rate product were greater when fasted.

3. Resting forearm and calf vascular resistance were higher when fasted. Calf vascular resistance fell further after exercise when fasted. Resting superior mesenteric artery vascular resistance was lower when fed; 0.19 ± 0.02 compared with 032 ± 0.06, P < 0.05. After exercise, superior mesenteric artery vascular resistance had risen by 82%, to 0.53 ± 0.12, P < 0.05 (fasted) and by 47%, to 0.29 ± 0.05, P < 0.05 (fed).

4. On standing, absolute levels of blood pressure were higher when fasted [83 ± 7/52 ± 7 compared with 71 ± 2/41 ± 3 (fed), each P < 0.05]. Subjects were more symptomatic on standing post-exercise when fed.

5. In human sympathetic denervation, exercise in the fed state lowered blood pressure further than when fasted and worsened symptoms of postural hypotension.
Does Total Antioxidant Status Relate to Outcome in Very Preterm Infants?
Authors: Drury Josephine A. , Nycyk Julie A. , Baines Malcolm , Cooke Richard W. I.
Published: August 2015

1. In healthy humans, a balance exists between oxygen-derived free-radical production and their removal by antioxidants. In preterm infants inadequate antioxidant defences may contribute to the pathogenesis of some of the complications of prematurity.

2. Plasma total antioxidant status and malondialdehyde concentration were measured during the first 11 days of life in 25 infants to determine whether increased lipid peroxidation is associated with low extracellular antioxidant status. In a second group of infants, total antioxidant status was quantified within 12 h of birth, and subsequently on days 4 and 10 to investigate the hypothesis that adverse neonatal outcome is associated with low antioxidant status.

3. There may be a weak negative correlation between the total antioxidant status of infants and the lipid peroxidation marker malondialdehyde in plasma (r = −0.24, P = 0.056, n = 89) during the first 11 days of life. In the second group of infants, total antioxidant status was found to be significantly related to plasma urate and bilirubin levels, but not to adverse neonatal outcomes such as chronic lung disease, intraventricular haemorrhage, retinopathy of prematurity or death.

4. If adverse neonatal outcomes are due to inadequate antioxidant defences, these are likely to be intracellular or localized rather than general extracellular deficiencies.
Bone Mineral Changes during Pregnancy and Lactation: A Longitudinal Cohort Study
Authors: Kolthoff Niels , Eiken PIA , Kristensen Bent , Nielsen Stig Pors
Published: August 2015

1. The influence of pregnancy, lactation and weaning on bone mineral density in healthy women was investigated during a 2 year prospective study of 59 pregnant and lactating women from the 18th week of gestation.

2. Bone mineral density was measured by dual energy X-ray absorptiometry at the non-dominant radius ultra distally and more proximally in the 18th and 37th weeks of gestation, and 0, 3, 6, 12 and 18 months after delivery. Measurements of bone mineral density of the lumbar spine, the proximal femur and the whole body were performed at all dates after delivery.

3. Reappearance of menstruation after delivery averaged 6.1 months; mean lactating period was 8.7 months. During pregnancy and lactation bone mineral density tended to decrease, but different measuring sites showed different patterns of bone mineral density changes. The reduction in the ultra distal radius during pregnancy amounted to 2%, and no further changes were observed here during lactation. After delivery, reduction in mean bone mineral density was most pronounced in the spine (5.2% in 3 months), but the fall in bone mass tended to revert after resumption of menstruation. Bone mineral density was still reduced by 3.3% after 12 months in women with menstruation resumption later than 8 months after delivery. No significant reduction was observed 18 months after delivery. No association with calcium intake, weight changes or initial bone mineral density was observed. High calcium intake did not protect against bone mineral loss in the spine and the femur.

4. Thus it can be concluded that bone loss during pregnancy and lactation took place mainly from the trabecular skeleton. Resumption of menstruation tended to result in a regain of bone mass towards baseline.
Skeletal Progenitor Cells and Ageing Human Populations
Authors: Oreffo Richard O. C. , Bord Stéphanie , Triffitt James T.
Published: August 2015

1. Stem and progenitor cells present within bone marrow give rise to colony forming units-fibroblastic (CFU-F) which can differentiate into fibroblastic, osteogenic, myogenic, adipogenic and reticular cells. The decrease in skeletal bone formation and rate of fracture repair observed with ageing and in osteoporosis has been suggested to be due to a decrease in numbers of these progenitors, but human studies are limited.

2. We have tested the potential to form CFU-F in a total of 99 patients undergoing corrective surgery (16 controls, 14–48 years of age) or hip arthroplasty for osteoarthritis (57 patients, 28–87 years of age) or osteoporosis (26 patients, 69–97 years of age). Total colony number, alkaline phosphatase-positive colony number and colony size were determined.

3. No decrease in colony forming efficiency under the culture conditions used was observed in all populations examined irrespective of age, disease or gender, as determined by the lack of correlation between colony formation and age.

3. Examination of colony sizes showed a significant reduction in colony size with age in osteoarthritis and in control populations indicating a change in cellular proliferative potential with age.

4. Examination of number and percentage of alkaline phosphatase-positive CFU-F showed a significant decrease in osteoporotic patients compared with controls and osteoarthritis patients, indicating altered differentiation potential.

5. These results suggest that the reduction in bone mass with ageing may be due to reduction of the proliferative capacity of progenitor cells or their responsiveness to biological factors leading to alteration in subsequent differentiation. The maintenance of CFU-F number and alkaline phosphatase activity in these osteoarthritis patients may, in part, explain the inverse relationship observed for the preservation of bone mass between generalized osteoarthritis and primary osteoporosis.
How Does Treatment Influence Endocrine Mechanisms in Acute Severe Heart Failure? Effects on Cardiac Natriuretic Peptides, the Renin System, Neuropeptide Y and Catecholamines
Authors: Missouris Constantinos G. , Grouzmann Eric , Buckley Martin G. , Barron Jeffrey , MacGregor Graham A. , Singer Donald R.J.
Published: August 2015

1. Hormones involved in cardiovascular regulation are influenced by drug treatment. It is therefore difficult to study endocrine mechanisms in heart failure as most patients are already on treatment by the time they reach hospital.

2. We studied nine hospital in-patients before and after treatment of acute New York Heart Association class IV heart failure.

3. Before treatment, plasma brain and atrial natriuretic peptides were markedly elevated (BNP 121 ± 26 pg/ml, ANP 163 ± 33 pg/ml; normal range: BNP 3.9 ± 0.3 pg/ml, ANP 8.6 ± 0.8 pg/ml) and correlated positively with serum creatinine and left ventricular end-diastolic diameter and negatively with ejection fraction. Eight patients improved and one died.

4. With improvement plasma ANP and BNP fell. Initial renin activity was within the normal range but increased on treatment. Plasma neuropeptide Y and adrenaline remained normal before and after treatment in the eight patients who improved. Initial plasma noradrenaline was in the normal range in four of these patients and just above normal in a further four. In the patient who died, initial plasma neuropeptide Y and catecholamines were very high.

5. Plasma BNP emerged as complementary to ANP as a dynamic index in severe heart failure; however, renal function is also an important determinant of plasma BNP and ANP. There is little evidence for activation of the circulating renin—angiotensin—aldosterone system or neuropeptide Y before treatment of acute heart failure.
Deep Venous Thrombosis: A Prospective 3-Month Follow-up Using Duplex Scanning and Strain-Gauge Plethysmography
Authors: Janssen M. C. H. , Wollersheim H. , Haenen J. H. , van Asten W. N. J. C. , Thien TH.
Published: August 2015

1. The purpose of the study was to evaluate the degree of thrombus regression, development of valvular insufficiency, impaired calf muscle pump function and clinical symptoms after a period of acute deep venous thrombosis.

2. Seventy patients with acute deep venous thrombosis, diagnosed by duplex scanning or venography, received treatment with heparin and oral coumarin derivatives according to a standard protocol. All patients wore graduated compression stockings during the whole study period. Duplex scanning was performed at diagnosis and 1 and 3 months later to measure thrombus mass and reflux. The supine venous pump function test was used to assess calf muscle pump function.

3. Three months follow-up was completed in 60 patients. In total 218 (28%) out of 780 vein segments were initially thrombosed and 134 (17%) could not be traced. A statistically significant reduction of thrombus mass was recorded throughout the study period. Total resolution of thrombosis in all vein segments occurred in 25% of the patients within 1 month and in 40% in 3 months. There was no difference in regression between the various proximal vein segments. Distal segments showed more regression than proximal segments. Reflux occurred in 27% of the initially thrombosed veins and in 15% of the patent veins. Patients who showed total resolution after 1 month had a significantly higher calf muscle pump function than patients without total resolution (70%pf vs 61%pf, P < 0.05). Patients with reflux in two or more segments had a significantly lower calf muscle pump function than patients with reflux in less than two segments (58%pf vs 69%pf, P < 0.05).

4. Using duplex scanning and the supine venous pump function test 3 months after an acute deep venous thrombosis, overall haemodynamic abnormalities and local site of valve incompetence could readily be identified. Patients with haemodynamic abnormalities might be at risk to develop the post-thrombotic syndrome. There was no difference in thrombus regression between the various proximal vein segments. Reflux was significantly more often seen in initially thrombosed veins. Thirty-five percent of the patients developed an abnormal calf muscle pump function after 3 months. Patients with early resolution of thrombus had a higher calf muscle pump function after 3 months.
Autonomic modulation of heart rate and blood pressure in hypertensive subjects with symptoms of anxiety
Authors: PICCIRILLO Gianfranco , ELVIRA Santagada , VIOLA Emanuela , BUCCA Carmela , DURANTE Michele , RAGANATO Paolo , MARIGLIANO Vincenzo
Published: August 2015

1.The influence of anxiety symptoms on autonomic nervous system cardiovascular control has never been studied in hypertensive subjects. This study was designed to verify the presence of sympathetic hyperactivity in hypertension associated with anxiety symptoms.

2.Neuroautonomic cardiovascular control was evaluated using short-time power spectral analysis of RR and arterial pressure variability at baseline and after the head-up tilt test. The two spectral components principally influenced by the autonomic nervous system are the low-frequency (LF) component, mainly though not exclusively due to sympathetic modulation, and the high-frequency (HF) component, due to parasympathetic activity. The ratio of LF to HF powers (LF:HF) provides an index of the sympathovagal sinus balance.

3.We studied 33 hypertensive subjects (mean age 47±1 years; M:F = 19:14) and 37 normotensive control subjects (mean age: 47±2 years; M:F = 20:17) divided into four subgroups: hypertensive subjects who scored 2 or more on a 5-item anxiety symptom scale, hypertensive subjects who scored 0, normotensive controls who scored 2 or more and normotensive controls who scored 0. LF:HF and LF during rest were significantly higher (P< 0.05) in hypertensive and normotensive groups with an anxiety score of 2 or more compared with the two groups who scored 0. HF of systolic blood pressure was significantly lower in the hypertensive group who scored 2 or more than in the hypertensive group who scored 0 (P< 0.05). Tilt in both hypertensive groups reporting anxiety symptoms left the indexes of sympathetic modulation unchanged. Tilt in hypertensive subjects reporting anxiety symptoms also induced a significant fall in arterial pressure (P< 0.05). The mean left ventricular mass index was significantly higher in the hypertensive subjects who had anxiety scores of 2 or more than in those scoring 0 (144.7±3.0 versus 133.4±2.31, P< 0.05).

4.In conclusion, normotensive and hypertensive subjects reporting anxiety symptoms showed increased sympathetic modulation of heart rate at rest. Higher anxiety scores seem to be associated with the development of left ventricular hypertrophy.
Gender differences in fat oxidation and sympathetic nervous system activity at rest and during submaximal exercise in older individuals
Authors: TOTH Michael J. , GARDNER Andrew W. , ARCIERO Paul J. , CALLES-ESCANDON Jorge , POEHLMAN Eric T.
Published: August 2015

1.Gender differences in fat oxidation at rest and during exercise may contribute to higher body fat in women. We examined gender differences in fat oxidation at rest and during submaximal exercise and their relationship to sympathetic nervous system activity, free fatty acid availability, body composition and aerobic capacity in older volunteers.

2.We measured free fatty acid kinetics using [14C]palmitate, absolute (μmol/min) and relative (respiratory quotient) rates of fat oxidation by indirect calorimetry and sympathetic nervous system activity from noradrenaline kinetics using [3H]noradrenaline in 12 older men (70±4 years) and 12 older women (66±4 years) at rest and during 30 min of submaximal exercise (45% of peak oxygen consumption).

3.At rest, men oxidized more fat than women on both an absolute (88±19 versus 51±15 μmol/min; P< 0.01) and relative (respiratory quotient: 0.80±0.04 versus 0.85±0.04; P< 0.01) basis. These differences were not related to noradrenaline appearance rate, free fatty acid concentration, body composition or aerobic capacity. During exercise, fat oxidation was higher (P< 0.05 to P< 0.01) in men on an absolute level, but respiratory quotient did not differ. Higher absolute fat oxidation in men during exercise was explained by their higher absolute workload. Plasma free fatty acids and free fatty acid rate of appearance did not differ between men and women during exercise despite higher (P< 0.05 to P< 0.01) plasma noradrenaline concentrations in men.

4.We conclude that: (i) resting fat oxidation is higher in older men compared with older women independent of differences in noradrenaline appearance rate, free fatty acid availability, body composition or aerobic capacity, and (ii) despite higher plasma noradrenaline concentrations during submaximal exercise, no gender differences in free fatty acid appearance rate or fat oxidation were found. These results suggest a sex dimorphism in post-absorptive fat metabolism in the elderly.
Effect of propylthiouracil-induced hypothyroidism on the onset of skeletal muscle necrosis in dystrophin-deficient mdx mice
Authors: McARDLE Anne , HELLIWELL Timothy R. , BECKETT Geoffrey J. , CATAPANO Mariana , DAVIS Anthony , JACKSON Malcolm J.
Published: August 2015

1.Duchenne and Becker muscular dystrophies are X-linked disorders caused by defects in muscle dystrophin. The mdx mouse is an animal model for Duchenne muscular dystrophy which has a point mutation in the dystrophin gene, resulting in little (< 3%) or no expression of dystrophin in muscle. Mdx mice show a characteristic pattern of muscle necrosis and regeneration. Muscles are normal until the third postnatal week when widespread necrosis commences. This is followed by muscle regeneration, with the persistence of centrally nucleated fibres.

2.This work has examined the hypothesis that the onset of this muscle necrosis is associated with postnatal maturation of the thyroid endocrine system and that pharmacological inhibition of thyroid hormone synthesis delays the onset of muscle necrosis.

3.Serum T4 and T3 concentrations of mice were found to rise immediately before the onset of muscle necrosis in the mdx mouse, and induction of hypothyroidism by treatment of animals with propylthiouracil was found to delay the onset of muscle necrosis.

4.The results provide the first demonstration of experimental delay of muscle necrosis by manipulation of the endocrine system in muscle lacking dystrophin, and provide a novel insight into the way in which a lack of dystrophin interacts with postnatal development to precipitate muscle necrosis in the mdx mouse.