bluuebunny/crossref_metadata_2025 huggingface dataset:
Intestinal permeability to polyethyleneglycol and sugars: a re-evaluation
Authors: LLOYD John B.
Published: August 2015

1.Previous studies have indicated that the permeability of polyethyleneglycol across the human intestine is anomalously high in comparison with the permeability of sugars with similar molecular mass. In consequence it has been proposed that two or more distinct mechanisms must exist for the translocation of these classes of molecule or, alternatively, that the molecular parameter determining rate of penetration is each molecule's minimum molecular dimension.

2.The notional hydrogen-bonding capacity of a molecule correlates well with oil–water partition coefficient and also, in a variety of experimental systems, with rate of passive diffusion across biological membranes. A molecule's hydrogen-bonding capacity is calculated by inspecting the structural formula and summing the individual theory-derived hydrogen-bonding capacities of the molecule's functional groups.

3.A classic set of intestinal permeability data that includes several ethyleneglycol oligomers and several sugars is re-analysed. A good correlation between permeability and hydrogen-bonding capacity is demonstrated. Specifically, there is no discontinuity between the polyethyleneglycols and the sugars. The data are compatible with a simple model in which all the molecules studied cross the intestine by passive diffusion across cellular membranes.
Usefulness of markers of cell proliferation in the management of pituitary adenomas
Authors: LOSA Marco , FRANZIN Alberto , MORTINI Pietro , TERRENI Maria Rosa , MANGILI Francesca , GIOVANELLI Massimo
Published: August 2015

1.Pituitary adenomas are benign and slow-growing tumours whose clinical manifestations depend mainly on the secretory activity of the adenomatous cells. Except for prolactinomas, surgical removal of the tumour is the therapy of choice.

2.Despite extensive research on their clinical and pathophysiological aspects, few studies have explored the oncological characteristics of these rare lesions. Among these, the growth fraction of pituitary adenomas has been determined by different methods, of which the most useful are those performed in archival material.

3.The results reported in the literature show that adrenocorticotropic hormone-secreting tumours seem to be characterized by a higher proliferation index than the other types of pituitary adenomas, despite their usually small tumour size.

4.In small series of patients radiotherapy and medical treatment with dopaminergic drugs and octreotide were associated with a lower proliferation index than untreated tumours. Tumour size was not correlated with the growth fraction of the pituitary tumours, whereas invasiveness was correlated in most studies.

5.From a clinical point of view, however, the more promising utilization of the proliferation index seems to be in predicting the potential of recurrence of the tumour, thus allowing a more rational approach to follow-up and further treatment of patients with pituitary adenomas.
Central cooling effects in patients with hypercholesterolaemia
Authors: LORENZO F. DE , MUKHERJEE M. , KADZIOLA Z. , SHERWOOD R. , KAKKAR V. V.
Published: August 2015

1.A prospective study has been carried out, and 68 patients with hypercholesterolaemia have been investigated to study the effects of central cooling on serum lipid levels.

2.Central cooling was obtained by the exposure of the whole body to cold water. All patients were trained to gradually reduce the water temperature from 22 to 14 ;°C and to increase the time of exposure from 5 to 20 ;min over a period of 90 days. The 33 male and 35 female patients were aged between 40 and 60 years at entry with total cholesterol of 6.0 ;mmol/l or greater and low-density lipoprotein (LDL)-cholesterol of 4.0 ;mmol/l or greater. Thyroid-stimulating hormone, free thyroxine (FT4), total T3, total cholesterol, LDL-cholesterol, high-density lipoprotein (HDL)-cholesterol, triacylglycerols and total fat mass (determined by dual-energy X-ray absorptiometry scan) were obtained at baseline and after 3 months treatment with hydrotherapy.

3.Central cooling obtained by hydrotherapy results in a median fall in tympanic temperature from 0.2 ;°C (P< 0.001) to 0.8 ;°C (P< 0.001). We have observed in these patients a significant reduction in total cholesterol (-0.2 ;mmol/l, P = 0.006) and LDL-cholesterol (-0.2 ;mmol/l, P = 0.004). Serum FT4 level was higher than baseline results in 30 of these hypercholesterolaemic patients (15.5 ;pmol/l to 17.3 ;pmol/l) and there was no significant change in serum thyroid-stimulating hormone and total T3.

4.In conclusion, in our patients with hypercholesterolaemia we have observed a significant reduction of total cholesterol and LDL-cholesterol after body temperature regulation.
Blood lead in U.K. children–time for a lower action level?
Authors: O'DONOHOE Jarlath , CHALKLEY Sylvia , RICHMOND John , BARLTROP Donald
Published: August 2015

1.Blood lead measurements in samples collected from 660 London schoolchildren during 1991 to 1992 suggest that the blood lead values in children in the U.K. are decreasing.

2.Geometric mean values for blood lead were 0.18 (range 0.05–0.71) ;μmol/l [3.7 (1.0–15.0) ;μg/dl]. Analysis of variance showed differences between ethnic groups, sex and schools. An age-matched subset of 148 children was compared with 136 children from an earlier study in 1986 and 1987. Trend analysis of the geometric mean lead values showed a negative slope (b = -0.484, P< 0.0001), with maximum values of 0.81, 1.00, 0.71 and 0.43 ;μmol/l (17, 21, 15 and 9 ;μg/dl) for the years 1986, 1987, 1991 and 1992 respectively.

3.It is recommended that children in the U.K. being investigated for anaemia, pica, recurrent abdominal pain or a high-risk environment should have blood lead values measured and that the action level for blood lead in children should be decreased from 1.19 ;μmol/l to 0.48 ;μmol/l (from 25 ;μg/dl to 10 ;μg/dl).

4.Guidance is offered to clinicians and other health professionals investigating excessive lead exposure.
Subjects with obstructive pulmonary disease tend to be chronically vasodilated
Authors: CASIGLIA Edoardo , PAVAN Lucia , MARCATO Luca , LEOPARDI Marco , PIZZIOL Alessandra , SALVADOR Paolo , ZUIN Renzo , PESSINA Achille C.
Published: August 2015

1.In 12 unselected outpatients with chronic obstructive pulmonary disease and six controls, arterial pH, Pao2, Paco2 and oxygen saturation (Sao2), forced expiratory volume in 1.0 ;s (FEV1.0) and vital capacity were measured. Subjects were grouped into those with or without obstruction based on the Tiffenau index. The Baseline Dyspnoea Index was employed to objectify the severity of dyspnoea and the Borg index to evaluate the subjective sensation. Blood pressure was measured with a sphygmomanometer; calf arterial flow both at rest and during reactive hyperaemia with a plethysmograph. Basal and minimal resistance were calculated.

2.FEV1.0 was 26% lower in patients with obstruction than in controls, and was also lower in patients with moderate-to-severe obstruction compared with those with mild or no obstruction. Arterial flow (75% greater in the patients with obstruction) progressively increased with increasing severity of obstruction, being 54% higher in those with mild obstruction than in those with no obstruction (P< 0.001), and 28% higher in moderate–severe than in mild obstruction (P< 0.005). In multiple regressions, F correlated inversely with FEV1.0, Pao2 and Sao2, and directly with Paco2. Basal resistance correlated positively with FEV1.0, Sao2 and the Tiffenau index, and inversely with Paco2 (r = -0.52, P = 0.02). Minimal resistance was significantly lower in obstructed than in non-obstructed subjects. Both basal and minimal resistance progressively decreased, although insignificantly, with worsening bronchial obstruction. Paco2 did not correlate with any haemodynamic parameter. Borg index correlated indirectly with FEV1.0 and basal resistance directly with arterial flow.

3.Patients with chronic obstructive pulmonary disease therefore tend to show chronic vasodilatation depending on hypoxia rather than Paco2. Other mechanisms could be involved in this phenomenon. The Borg index is a good indicator of oxygen desaturation and vasodilatation.
Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early Type 2 diabetes
Authors: TODD Jeannie F. , EDWARDS C. Mark B. , GHATEI Mohammad A. , MATHER Hugh M. , BLOOM Stephen R.
Published: August 2015

1.Glucagon-like peptide-1 (7-36) amide (GLP-1) is released into the circulation after meals and is the most potent physiological insulinotropic hormone in man. GLP-1 has the advantages over other therapeutic agents for Type 2 diabetes of also suppressing glucagon secretion and delaying gastric emptying. One of the initial abnormalities of Type 2 diabetes is the loss of the first-phase insulin response, leading to postprandial hyperglycaemia.

2.To investigate the therapeutic potential of GLP-1 in Type 2 diabetes, six patients were entered into a 6-week, double-blind crossover trial during which each received 3 weeks treatment with subcutaneous GLP-1 or saline, self-administered three times a day immediately before meals. A standard test meal was given at the beginning and end of each treatment period.

3.GLP-1 reduced plasma glucose area under the curve (AUC) after the standard test meal by 58% (AUC, 0–240 ;min: GLP-1 start of treatment, 196±141 ;mmol·min-1·l-1; saline start of treatment, 469±124 ;mmol·min-1·l-1; F = 16.4, P< 0.05). The plasma insulin excursions were significantly higher with GLP-1 compared with saline over the initial postprandial 30 ;min, the time period during which the GLP-1 concentration was considerably elevated. The plasma glucagon levels were significantly lower over the 240-min postprandial period with GLP-1 treatment. The beneficial effects of GLP-1 on plasma glucose, insulin and glucagon concentrations were fully maintained for the 3-week treatment period.

4.We have demonstrated a significant improvement in postprandial glycaemic control with subcutaneous GLP-1 treatment. GLP-1 improves glycaemic control partially by restoring the first-phase insulin response and suppressing glucagon and is a potential treatment for Type 2 diabetes.
Absence of glutamine isotopic steady state: implications for the assessment of whole-body glutamine production rate
Authors: ACKER Bernadette A. C. VAN , HULSEWÉ Karel W. E. , WAGENMAKERS Anton J. M. , DEUTZ Nicolaas E. P. , KREEL Bernard K. VAN , HALLIDAY Dave , MATTHEWS Dwight E. , SOETERS Peter B. , MEYENFELDT Maarten F. VON
Published: August 2015

1.During infusion of [5-15N]glutamine in patients with gastrointestinal cancer we unexpectedly observed a gradual decrease in time of the appearance rate (Ra) of glutamine in plasma. Here we investigate whether the failure to achieve a plateau isotopic enrichment in plasma is, among other factors, due to incomplete equilibration of the glutamine tracer with the large intramuscular free glutamine pool.

2.Plasma and intramuscular glutamine enrichment were measured during 6–11 ;h infusions of L-[5-15N]glutamine and L-[1-13C]glutamine in post-absorptive patients admitted to hospital for elective abdominal surgery. L-[1-13C]Leucine and L-[ring-2H5]phenylalanine were infused to measure the proportion of glutamine appearing in plasma directly due to its release from protein.

3.The glutamine tracer entered muscle, but the rise in intramuscular glutamine enrichment was small, presumably as a result of the enormous size of the intramuscular glutamine pool and the limited speed of entry of glutamine into muscle. In each patient the intramuscular glutamine enrichment was lower than that in plasma (P < 0.001), and both increased with tracer infusion time (P < 0.001), indicating incomplete equilibration of the glutamine tracer.

4.A comparison of the results obtained by the two glutamine tracers indicated that recycling of the nitrogen label contributed to about 15% of the decrease in Ra.

5.There was a gradual reduction in the glutamine release from proteolysis, which contributed to 16–21% of the decline in Ra.

6.We conclude that slow equilibration of the glutamine tracer with the large muscle glutamine pool significantly contributes to the absence of isotopic steady state. Consequently, the appearance rate of glutamine in plasma measured during short tracer infusion periods (hours) considerably overestimates the whole-body glutamine flux.
Effect of interleukin-4 on pro-inflammatory cytokine production and the acute phase response in healthy individuals and in patients with cancer or multiple organ failure
Authors: WIGMORE Stephen J. , MAINGAY Jean P. , FEARON Kenneth C. H. , O'RIORDAIN Michael G. , ROSS James A.
Published: August 2015

1.This study investigates whether previously documented effects of interleukin-4 in down-regulating pro-inflammatory cytokine production by peripheral blood mononuclear cells (PBMCs) from healthy individuals would be reproducible in PBMCs isolated from patients with multiple organ failure (acute disease model) and gastrointestinal cancer (chronic disease model). The effects of interleukin-4 on the ability of PBMC supernatants to elicit an acute phase protein response from isolated human hepatocytes were also studied.

2.Incubation of PBMCs with interleukin-4 significantly reduced both spontaneous and lipopolysaccharide-induced production of tumour necrosis factor and lipopolysaccharide-induced interleukin-6 production, demonstrating that the PBMCs from patients with acute and chronic disease are not refractory to the effects of interleukin-4. The effects of interleukin-4 on the ability of PBMCs from the groups studied to elicit an acute phase response were complex and varied both between patient groups and individual acute phase proteins. Overall, interleukin-4 reduced the potential of PBMCs to stimulate production of the positive acute phase proteins C-reactive protein, α1-antichymotrypsin and α1-acid glycoprotein.

3.This work emphasizes the pleiotropic nature of cytokines and the complex regulatory mechanisms which exist. The study illustrates the difficulties in devising in vivo intervention strategies using cytokines such as interleukin-4.
Importance of glutamine metabolism in murine macrophages and human monocytes to L-arginine biosynthesis and rates of nitrite or urea production
Authors: MURPHY Colin , NEWSHOLME Philip
Published: August 2015

1.The intermediates of biochemical cycles are commonly utilized for biosynthetic processes; thus at least one intermediate must be replenished de novo to provide constant flux through the cycle. The utilization of l-arginine for NO synthesis in macrophages may thus reduce the concentration of intermediates of the urea cycle. It is possible that a glutamine-utilizing pathway exists in mononuclear phagocytes that may connect with the urea cycle.

2.In this paper we report that mouse peritoneal resident and Bacillus Calmette–Guerin (BCG)-activated macrophages and human monocytes are capable of utilizing glutamine at high rates, contain sufficient activity of the enzymes required to convert glutamine to citrulline (and subsequently citrulline to arginine) to account for observed rates of nitrite synthesis in the absence of extracellular l-arginine, and will release nitrite when exposed to intermediates of the proposed glutamine → arginine pathway.

3.The rate of nitrite production (in the absence of extracellular arginine) was reduced by culturing macrophages or monocytes in the presence of the glutaminase inhibitor 6-diazo 5-oxo norleucine.

4.The rate and extent of arginase secretion, glutamine utilization, nitrite production (basal and lipopolysaccharide-stimulated) and phosphate-dependent glutaminase activity from BCG-activated macrophages was increased compared with resident cells.

5.We suggest that the elevated arginase secretion rates in activated macrophages would effectively increase the intracellular concentration of arginine available for conversion to NO via inducible nitric oxide synthase, the expression of which is known to increase on activation of macrophages or monocytes. Additionally, the rate of l-arginine biosynthesis from glutamine may be increased on immunostimulation of the macrophage.
Identification of oxidized low-density lipoprotein in human serum by NMR spectroscopy
Authors: JANKOWSKI J. , NOFER J.-R. , TEPEL M. , GRIEWEL B. , SCHLÜTER H. , ASSMANN G. , ZIDEK W.
Published: August 2015

1.In this study we compared the 500 MHz 1H-NMRs from native and oxidized low-density lipoproteins.

2.The measurements revealed a characteristic pattern of three resonances in spectra from oxidized, but not from native low-density liprotein at 1.17 p.p.m., 1.18 p.p.m. and 1.20 p.p.m. (relative to 3-trimethylsilyl-[2,2,3,3-2H4]-propionate).

3.A quantitative comparison between these resonances in sera from patients with coronary heart disease and healthy control subjects revealed that the intensity was significantly higher in patients with coronary heart disease (1.17 p.p.m.: 0.026±0.014 versus 0.015±0.019; 1.18 p.p.m.: 0.032±0.011 versus 0.017±0.021; 1.20 p.p.m.: 0.030±0.066 versus 0.010±0.005; P< 0.05 compared with healthy control subjects for each resonance).

4.Fractionation of sera from patients with coronary heart disease revealed that the resonances equal to those obtained from experimentally oxidized low-density lipoprotein are indeed caused by the low-density lipoprotein fraction of the sera.

5.When the NMRs from sera were calibrated with oxidized low-density lipoprotein prepared by Cu2+ oxidation, a concentration of 66.5±28.6 ;μg/ml and 36.3±23.7 ;μg/ml (P< 0.05) was estimated in patients with coronary heart disease and healthy subjects respectively. Elevated levels of oxidized low-density lipoprotein also occurred in those patients with normal serum concentrations of total low-density lipoprotein.

6.The study shows a simple method to measure oxidized low-density lipoprotein in human serum and may gain interest to assess the cardiovascular risk factor profiles more completely.
Evaluation of potential factors affecting the measurement of cerebrovascular reactivity by near-infrared spectroscopy
Authors: TOTARO Rocco , BARATTELLI Giovanna , QUARESIMA Valentina , CAROLEI Antonio , FERRARI Marco
Published: August 2015

1.Near-infrared (IR) spectroscopy is based on the relative transparency of skin, skull and brain to the light in the near-IR region (700–1100 ;nm) and on the oxygen-dependent tissue absorption changes of haemoglobin.

2.We evaluated the most relevant factors (reproducibility, venous return, age and sex) that might affect reliability of near-IR spectroscopy to test CO2 cerebrovascular reactivity.

3.Thirty-four healthy volunteers were enrolled in the study. The protocol consisted of a 3-min baseline, a 3-min hypercapnia (5% CO2 in air) and a 2-min recovery. Transcranial Doppler sonography measurements were simultaneously performed. The CO2 reactivity test was repeated on 27 subjects after 1 ;h to assess reproducibility. CO2 reactivity was also evaluated at different body positions (supine, 35° Trendelenburg and 35° reverse Trendelenburg), and over a gradual increase of the inspired CO2.

4.Changes in near-IR spectroscopy and transcranial Doppler sonography parameters were significantly correlated with variations of end-tidal CO2 (P< 0.005). A significant correlation between the reactivity indexes of near-IR spectroscopy parameters and flow velocity was also found (P< 0.01). A high reproducibility was also found for deoxyhaemoglobin (rI = 0.76), oxyhaemoglobin (rI = 0.68) and flow velocity (rI = 0.60) reactivity indexes. No significant differences between the reactivity indexes of different body positions were found (P> 0.05). The reactivity index of oxyhaemoglobin and deoxyhaemoglobin decreased (P< 0.05) and increased (P< 0.01) with age respectively.

5.We found that near-IR spectroscopy is a reliable and reproducible method for the evaluation of cerebrovascular reactivity and might be considered, after appropriate validation, for the assessment of patients with cerebrovascular disease.
Inhaled corticosteroid therapy reduces the early morning peak in cortisol and aldosterone
Authors: WILSON Andrew M. , SIMS Erika J. , STRUTHERS Allan D. , LIPWORTH Brian J.
Published: August 2015

1.As mineralocorticoid and adrenocorticoid activity are both under the diurnal control of adrenocorticotropic hormone secretion, we aimed to evaluate whether the normal circadian rhythm of cortisol and aldosterone secretion was suppressed by inhaled corticosteroid therapy.

2.Ten normotensive patients with mild–moderate asthma, mean age 24.0 (S.D. 9.8) years and mean arterial pressure 90.7 (9.8) mmHg, were studied in a double-blind, randomized crossover design comparing placebo with fluticasone propionate, 1000 ;μg administered twice daily at 08:00 ;h and 20:00 ;h. After 5 days of repeated dosing at steady state, measurements were made of plasma cortisol and aldosterone at midnight and 08:00 ;h.

3.With placebo there was a significant (P< 0.05) difference between cortisol values at 08:00 ;h (588.6±83.8 ;nmol/l) and midnight (109.6±35.0 ;nmol/l), whereas after treatment with fluticasone propionate there was no significant difference between levels at 08:00 ;h (143.3±57.4 ;nmol/l) and midnight (64.3±22.3 ;nmol/l). For cortisol at 08:00 ;h there was also a significant (P< 0.05) difference between placebo and fluticasone propionate. The same pattern was observed for aldosterone. Plasma aldosterone levels at 08:00 ;h after treatment with placebo (129.6±30.9 ;nmol/l) were significantly different (P< 0.05) to those seen at midnight (40.4±6.2 ;nmol/l). After treatment with fluticasone propionate, there was no significant difference between levels at midnight (55.4±11.7 ;nmol/l) and 08:00 ;h (64.8±12.7 ;nmol/l).

4.These results show that inhaled corticosteroid therapy abolishes the circadian rhythm of aldosterone and cortisol secretion. This may have possible implications for patients taking inhaled corticosteroids in terms of the beneficial cardiac effects of suppressing early morning aldosterone.
Heart rate and flow velocity variability as determined from umbilical Doppler velocimetry at 10–20 weeks of gestation
Authors: URSEM Nicolette T. C. , STRUIJK Piet C. , HOP Wim C. J. , CLARK Edward B. , KELLER Bradley B. , WLADIMIROFF Juriy W.
Published: August 2015

1.The aim of this study was to define from umbilical artery flow velocity waveforms absolute peak systolic and time-averaged velocity, fetal heart rate, fetal heart rate variability and flow velocity variability, and the relation between fetal heart rate and velocity variables in early pregnancy.

2.A total of 108 women presenting with a normal pregnancy from 10 to 20 weeks of gestation consented to participate in a cross-sectional study design. Doppler ultrasound recordings were made from the free-floating loop of the umbilical cord.

3.Umbilical artery peak systolic and time-averaged velocity increased at 10–20 weeks, whereas fetal heart rate decreased at 10–15 weeks of gestation and plateaued thereafter. Umbilical artery peak systolic velocity variability and fetal heart rate variability increased at 10–20 and 15–20 weeks respectively.

4.The inverse relationship between umbilical artery flow velocity and fetal heart rate at 10–15 weeks of gestation suggests that the Frank–Starling mechanism regulates cardiovascular control as early as the late first and early second trimesters of pregnancy. A different underlying mechanism is suggested for the observed variability profiles in heart rate and umbilical artery peak systolic velocity. It is speculated that heart rate variability is mediated by maturation of the parasympathetic nervous system, whereas peak systolic velocity variability reflects the activation of a haemodynamic feedback mechanism.
Cardiovascular autonomic modulation and activity of carotid baroreceptors at altitude
Authors: BERNARDI Luciano , PASSINO Claudio , SPADACINI Giammario , CALCIATI Alessandro , ROBERGS Robert , GREENE Richard , MARTIGNONI Emilia , ANAND Inder , APPENZELLER Otto
Published: August 2015

1.To assess the effects of acute exposure to high altitude on baroreceptor function in man we evaluated the effects of baroreceptor activation on R–R interval and blood pressure control at high altitude. We measured the low-frequency (LF) and high-frequency (HF) components in R–R, non-invasive blood pressure and skin blood flow, and the effect of baroreceptor modulation by 0.1-Hz sinusoidal neck suction. Ten healthy sea-level natives and three high-altitude native, long-term sea-level residents were evaluated at sea level, upon arrival at 4970 ;m and 1 week later.

2.Compared with sea level, acute high altitude decreased R–R and increased blood pressure in all subjects [sea-level natives: R–R from 1002±45 to 775±57 ;ms, systolic blood pressure from 130±3 to 150±8 ;mmHg; high-altitude natives: R–R from 809±116 to 749±47 ;ms, systolic blood pressure from 110±12 to 125±11 ;mmHg (P< 0.05 for all)]. One week later systolic blood pressure was similar to values at sea level in all subjects, whereas R–R remained elevated in sea-level natives. The low-frequency power in R–R and systolic blood pressure increased in sea-level natives [R–R-LF from 47±8 to 65±10% (P< 0.05), systolic blood pressure-LF from 1.7±0.3 to 2.6±0.4 ln-mmHg2 (P< 0.05)], but not in high-altitude natives (R–R-LF from 32±13 to 38±19%, systolic blood pressure-LF from 1.9±0.5 to 1.7±0.8 ln-mmHg2). The R–R-HF decreased in sea-level natives but not in high-altitude natives, and no changes occurred in systolic blood pressure-HF. These changes remained evident 1 week later. Skin blood flow variability and its spectral components decreased markedly at high altitude in sea-level natives but showed no changes in high-altitude natives. Neck suction significantly increased the R–R- and systolic blood pressure-LF in all subjects at both sea level and high altitude.

3.High altitude induces sympathetic activation in sea-level natives which is partially counteracted by active baroreflex. Despite long-term acclimatization at sea level, high-altitude natives also maintain active baroreflex at high altitude but with lower sympathetic activation, indicating a persisting high-altitude adaptation which may be genetic or due to baroreflex activity not completely lost by at least 1 year's sea-level residence.
Augmented effects of methionine and cholesterol in decreasing the elastic lamina while thickening the aortic wall in the rat aorta
Authors: ZULLI Anthony , BUXTON Brian F. , DOOLAN Laurie , LIU James J.
Published: August 2015

1.Patients with an elevated plasma level of either homocysteine or cholesterol are at increased risk of cardiovascular disease. Both methionine, the precursor of homocysteine, and cholesterol are found primarily in the same foods; therefore we investigated the effect of methionine feeding alone, cholesterol feeding alone, and both, on the thickness of the aortic wall and the aortic elastic lamina of normotensive animals.

2.Twenty normotensive rats were divided into four groups of five animals. The following diet was administered for 15 weeks: normal chow; normal chow supplemented with 2% methionine; normal chow supplemented with 2% cholesterol; normal chow supplemented with 2% methionine+2% cholesterol.

3.The results showed a 3-fold decrease (P< 0.003) in the aortic elastic lamina in the 2% methionine group and a 2.5-fold decrease in the 2% cholesterol group compared with the normal chow group. There was a 9-fold (P< 0.0003) decrease in the 2% methionine+2% cholesterol group compared with the normal chow group. Furthermore, feeding with methionine plus cholesterol significantly increased aortic wall thickness compared with the methionine group, cholesterol group or control.

4.These results demonstrate an augmented effect of cholesterol plus methionine in the deterioration of the aortic elastic lamina, and furthermore, the combination of these two agents increases the thickness of the aortic wall. The results indicate a more important role for these two agents in combination than for either agent alone.
Lack of interaction of hyperpnoea with methacholine and histamine in asthma
Authors: SOMPRADEEKUL Suree , HEJAL Rana , McLANE Melissa , LENNER K. A. , NELSON J. A. , McFADDEN E. R.
Published: August 2015

1.The thermal precipitants of asthma (exercise and hyperventilation) appear to have a unique pathogenesis that does not alter bronchial responsiveness. In the present work, we tested whether hyperpnoea interacts with other constrictor stimuli.

2.To provide data on this issue, we exposed 17 subjects with asthma to isocapnic hyperventilation of frigid air (HV), methacholine (METH) and histamine (HIS) alone and in combination.

3.With HV (mean ventilation = 55.6±7.7 litres/min), METH (2.20±0.7 ;mmol/l) and HIS (10.35±5.04 ;mmol/l) alone, the decrements in forced expiratory volume in 1 ;s (FEV1) from baseline were 27.4±3.4, 27.4±3.8 and 32.4±3% respectively (n = 9). Giving the agonists simultaneously did not produce additive effects (ΔFEV1 HV+METH = 32.8±3.6%; HV+HIS = 28.7±5.1%). None of the individual or combined responses was significantly different from each other. Changing the sequence of the experiments and giving METH at the height of the HV-induced bronchial narrowing, instead of during hyperpnoea, did not alter the findings (n = 8). The maximum fall in FEV1 after both bronchoconstrictors in this experiment (ΔFEV1 = 32.3±4.3%) was not significantly different from either alone (HV = 22.8±1.0%; METH = 27.3±1.9%). When METH and HIS were administered together, however (n = 5), a positive interaction ensued (METH = 1.53±0.56 ;mmol/l, ΔFEV1 = 15.6±4.6%; HIS = 4.77±2.07 ;mmol/l, ΔFEV1 = 18.8±3.1%; METH+HIS ΔFEV1 = 33.4±5.2%; P< 0.001 compared with the individual effects).

4.These results indicate that HV does not interact with stimuli that directly or indirectly modulate airway calibre. It is unclear if this effect represents protection conferred from increased bronchial blood flow or derives from differences in effector mechanisms between the thermal and pharmacological agonists.
Relationship between arterial baroreflex, cardiopulmonary vagal reflex and renal natriuretic response to saline in conscious rabbits
Authors: MAYBAUM Nadine , GORODETSKY Elena , WEINSTOCK Marta
Published: August 2015

1. We have previously shown that normotensive rabbits with a genetic impairment in arterial baroreflex sensitivity showed a delayed sodium excretion and failed to increase their renal blood flow in response to a saline infusion that did not alter blood pressure. These renal haemodynamic and excretory abnormalities were abolished by renal denervation. The present study determined the sensitivity of the cardiopulmonary baroreceptors and the renal response to a mild saline infusion in normotensive rabbits varying widely in their arterial baroreflex sensitivity.

2. Sensitivity of cardiopulmonary baroreceptors was assessed from the slope of the relationship of the change in both blood pressure and heart rate and the dose of phenylbiguanide, a stimulator of vagal afferents.

3. The change in renal blood flow and lithium and sodium excretion was measured in response to saline, infused at a rate of 0.11 ml·min-1·kg-1 into the ear vein. Urine was collected via a urethral catheter and renal blood flow was measured by para-aminohippurate clearance.

4. A significant correlation was found between the magnitude of the gain of the cardiac arterial baroreflex and the sensitivity of the cardiopulmonary baroreceptor response to phenylbiguanide. The latter was significantly correlated to renal blood flow and lithium clearance 60–90 min after the start of the saline infusion.

5. It was also found that in some normotensive rabbits there was a blunting of cardiovascular regulation as indicated by a reduced sensitivity of cardiopulmonary and arterial baroreceptors. This may explain their abnormal haemodynamic and natriuretic response to salt.
Variation in the apparent sensitivity of the insulin-mediated inhibition of proteolysis to amino acid supply determines the efficiency of protein utilization
Authors: FEREDAY Amelia , GIBSON Neil R. , COX Malcolm , PACY Paul J. , MILLWARD D. Joe
Published: August 2015

1. The variability between normal individuals in the efficiency of postprandial protein utilization (PPU), a determinant of the apparent protein requirement, was examined in relation to the relative responses of protein synthesis and proteolysis to protein feeding by means of [1–13C]leucine turnover and balance studies.

2. Twenty-five healthy adults were infused intravenously with l-[1-13C]leucine continuously for 9 h. This was started in the postabsorptive state (PA, 3 h) and followed by low-protein feeding (LP, 3 h), and then by isoenergetic high-protein feeding (HP, 3 h). This allowed protein intake to be varied against a constant postprandial insulin level so that the extent of any amino-acid-mediated responses which were additional to those exerted by insulin could be investigated. Leucine oxidation, O, and balance (intake-oxidation), protein synthesis, S, and degradation, D, were calculated from plasma [1-13C]α-ketoisocaproic acid enrichment and 13CO2 excretion.

3. PPUprotein, calculated as change in leucine balance/change in intake (HP-LP), varied from 0.58 to 0.99 (mean = 0.81±0.10), independently of age or sex. PPUprotein varied directly with the inhibition of D and inversely with the increase in leucine concentration and stimulation of O and S.

4. Efficient PPU, as demonstrated by the top quintile of individuals categorized in terms of PPUprotein, involves maximal inhibition of D by protein feeding with minimal increases in free amino acid concentrations, O and S. Lesser inhibition of D and greater stimulation of S and O characterized the lower, less efficient quintile. This indicates that the efficiency of protein utilization in individuals, and a component of their apparent protein requirement, is determined by the sensitivity of the insulin-mediated inhibition of proteolysis to amino acid supply.
Increased plasma levels of adrenomedullin in patients with pulmonary hypertension
Authors: KAKISHITA Mikio , NISHIKIMI Toshio , OKANO Yoshiaki , SATOH Toru , KYOTANI Shingo , NAGAYA Noritoshi , FUKUSHIMA Kengo , NAKANISHI Norifumi , TAKISHITA Shuichi , MIYATA Atsuro , KANGAWA Kenji , MATSUO Hisayuki , KUNIEDA Takeyoshi
Published: August 2015

Adrenomedullin, a potent hypotensive peptide, reduces blood pressure and pulmonary vascular resistance, and increases pulmonary blood flow. The mRNA for adrenomedullin and its receptor is highly expressed in the lung, suggesting a regulatory role for adrenomedullin in the pulmonary circulation. To investigate the clinical significance of adrenomedullin in patients with pulmonary hypertension, we studied the relationship between plasma levels of adrenomedullin and pulmonary haemodynamics. Venous, arterial and pulmonary arterial blood samples were obtained during cardiac catheterization and plasma levels of adrenomedullin were measured by specific radioimmunoassay in 33 consecutive patients with severe pulmonary hypertension (12 cases of primary pulmonary hypertension, 21 with chronic thromboembolic pulmonary hypertension; age 49±16 years, mean pulmonary arterial pressure 50±15 mmHg). In addition, plasma levels of adrenomedullin were measured before and after acute nitric oxide inhalation. The changes in plasma adrenomedullin during the follow-up period of 10.3±4.3 months were also evaluated (n ;= ;5). Sixty-two healthy subjects served as the control group. Adrenomedullin was measured in an antecubital vein in the controls. Plasma levels of adrenomedullin were significantly higher in the patients with pulmonary hypertension than in the control subjects (10.1±8.7 versus 4.9±1.1 pmol/l, P< 0.01). Plasma levels of adrenomedullin, expressed as their natural logarithm, were significantly correlated with mean right atrial pressure (r ;= ;0.71, P< 0.01), stroke volume (r ;=-0.63, P< 0.01), total pulmonary resistance (r ;= ;0.60, P< 0.01), mean pulmonary arterial pressure (r ;= ;0.37, P< 0.05), and the natural logarithm of plasma atrial natriuretic peptide (r ;= ;0.63, P< 0.01). Plasma levels of adrenomedullin did not change significantly after nitric oxide inhalation, but significantly increased in association with the elevation of the total pulmonary resistance during the long-term follow-up period. These results suggest that plasma levels of adrenomedullin increase in proportion to the extent of pulmonary hypertension.
α-Lipoic acid reduces expression of vascular cell adhesion molecule-1 and endothelial adhesion of human monocytes after stimulation with advanced glycation end products
Authors: KUNT Thomas , FORST Thomas , WILHELM Axel , TRITSCHLER Hans , PFUETZNER Andreas , HARZER Oliver , ENGELBACH Martin , ZSCHAEBITZ Albrecht , STOFFT Eckart , BEYER Juergen
Published: August 2015

Advanced glycation end products (AGEs) have been identified as relevant mediators of late diabetic complications such as atherosclerotic disease. The endothelial migration of monocytes is one of the first steps in atherogenesis and monocyte–endothelial interaction itself is linked to the expression of adhesion molecules like vascular cell adhesion molecule-1 (VCAM-1). Recently, stimulation of VCAM-1 by AGEs has been demonstrated. Since endothelial stimulation by AGEs is followed by generation of oxygen free radicals with subsequent activation of nuclear transcription factor κB, we investigated the influence of α-lipoic acid on the expression of VCAM-1 and monocyte adherence to endothelial cells in vitro by means of cell-associated chemiluminescence assays and quantitative reverse transcriptase polymerase chain reaction using a constructed recombinant RNA standard. We found that α-lipoic acid was able to decrease the number of VCAM-1 transcripts from 41.0±11.2 to 9.5±4.7 RNA copies per cell in AGE-stimulated cell cultures. Furthermore, expression of VCAM-1 was suppressed in a time- and dose-dependent manner by α-lipoic acid as shown by chemiluminescence endothelial cell assay. Pretreatment of endothelial cells with 0.5 ;mM or 5 ;mM α-lipoic acid reduced AGE-induced endothelial binding of monocytes from 22.5±2.9% to 18.3±1.9% and 13.8±1.8% respectively. Thus, we suggest that extracellularly administered α-lipoic acid reduces AGE-albumin-induced endothelial expression of VCAM-1 and monocyte binding to endothelium in vitro. These in vitro results may contribute to the understanding of a potential antioxidative treatment of atherosclerosis.
Relationship of serum levels of interleukin-6, soluble interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase protein response in advanced pancreatic cancer
Authors: BARBER Matthew D. , FEARON Kenneth C. H. , ROSS James A.
Published: August 2015

The level of the acute-phase response is a major predictor of survival in patients with advanced pancreatic cancer. This study examines the association between the acute-phase protein response, as determined by serum C-reactive protein, and serum levels of interleukin-6, soluble interleukin-6 receptor and the soluble tumour necrosis factor receptors in patients with pancreatic cancer. Thirty-four blood samples were collected from 13 patients with advanced pancreatic cancer. Samples were also collected from six healthy subjects. Levels of C-reactive protein, interleukin-6, soluble interleukin-6 receptor and soluble tumour necrosis factor receptors 55 and 75 were measured by indirect ELISA. Serum levels of C-reactive protein, interleukin-6 and soluble tumour necrosis factor receptors 55 and 75 were significantly higher in cancer patients than in controls. Levels of serum soluble interleukin-6 receptor were not significantly different between the two groups. In cancer patients, a significant positive association was found between the level of the acute-phase protein response and serum levels of interleukin-6, soluble tumour necrosis factor receptor 55 and soluble tumour necrosis factor receptor 75. No association was found between levels of soluble interleukin-6 receptor and any other factor. There is no significant relationship between the level of soluble interleukin-6 receptor and the acute-phase protein response in vivo and the biological role of soluble interleukin-6 receptor in the chronic inflammatory component of cachexia remains unclear.
Macrophage-mediated lysis of a β-cell line, tumour necrosis factor-α release from bacillus Calmette–Gue´rin (BCG)-activated murine macrophages and interleukin-8 release from human monocytes are dependent on extracellular glutamine concentration and glutamine metabolism
Authors: MURPHY Colin , NEWSHOLME Philip
Published: August 2015

Macrophages and monocytes are cells with a large capacity for cytokine production. Cytokines produced by these cells are not preformed and released upon stimulation, but must be transcribed and translated. Although much is known concerning the regulation of the latter processes at the molecular level, the role of exogenous amino acids in the secretory process has not been actively investigated. Glutamine is utilized by macrophages at a much faster rate than any other amino acid. The role for high rates of glutamine utilization in macrophages or monocytes is not fully understood. We demonstrate here that the rates of lipopolysaccharide-stimulated tumour necrosis factor-α secretion from bacillus Calmette–Guérin (BCG)-activated murine peritoneal macrophages and lipopolysaccharide-stimulated interleukin-8 production from human monocytes are dependent upon extracellular glutamine concentration. We also demonstrate that potent inhibition of cytokine production can be achieved by incubating macrophages or monocytes in the presence of the glutaminase inhibitor 6-diazo-5-oxo-norleucine. On co-culture of BCG-activated macrophages and the clonal pancreatic β-cell line BRIN-BD11, macrophage-specific β-cell death was significantly reduced on prior exposure of macrophages to 6-diazo-5-oxo-norleucine. Thus glutamine metabolism may be essential for generation of cytotoxic products from macrophages, including tumour necrosis factor-α.
Chronic fatigue syndrome: a hypothesis focusing on the autonomic nervous system
Authors: PAGANI Massimo , LUCINI Daniela
Published: August 2015

Chronic fatigue syndrome is a debilitating illness of unknown aetiology, with estimated levels of prevalence of up to about 8.7/100 000 in the U.S.A. Like pain fatigue it is a personal, emotionally rich experience, which may originate from peripheral or central sites (or both). The nature of the symptoms is complex and reflects the interaction of the patient with the environment and cultural milieu. Accordingly the common use of the same terminology for different types of fatigue may be misleading. Autonomic activation is a key component of both real and simulated physical exercise. Alterations in autonomic nervous system activity are a key component of several physiopathological conditions. In chronic fatigue syndrome disturbances in autonomic activity, and in other homoeostatic mechanisms, such as the hormonal and immune systems, have been reported recently. In this review we followed the hypothesis that in chronic fatigue syndrome the paradoxical condition of disturbing somatic symptoms in the absence of organic evidence of disease might be addressed by focusing on attending functional correlates. In particular we addressed possible alterations in cardiovascular autonomic control, as can be assessed by spectral analysis of R–R interval and systolic arterial pressure variability. With this approach, in subjects complaining of unexplained fatigue, we obtained data suggesting a condition of prevailing sympathetic modulation of the sino-atrial node at rest, and reduced responsiveness to excitatory stimuli. Far from considering the issue resolved, we propose that in the context of the multiple physiological and psychological interactions involved in the perception and self-reporting of symptoms, attendant changes in physiological equivalents might furnish a convenient assessment independent from subjective components. Indices of sympathetic modulation could, accordingly, provide quantifiable signs of the interaction between subject's efforts and environmental demands, independently of self descriptions, which could provide convenient measurable outcomes, both for diagnosis and treatment titration in chronic fatigue syndrome.
Survival of human carrier erythrocytes in vivo
Authors: BAX Bridget E. , BAIN Murray D. , TALBOT Peter J. , John PARKER-WILLIAMS E. , CHALMERS Ronald A.
Published: August 2015

Erythrocytes offer the exciting opportunity of being used as carriers of therapeutic agents. Encapsulation within erythrocytes will give the therapeutic agent a clearance equivalent to the normal life of the erythrocyte therefore maintaining therapeutic blood levels over prolonged periods and also giving a sustained delivery to the monocyte–macrophage system (reticulo-endothelial system). Both the dose and frequency of therapeutic interventions could thus be reduced. Ensuring a near-physiological survival time of carrier erythrocytes is essential to their successful use as a sustained drug delivery system, and this has not been demonstrated in man. In this study we assessed the survival in vivo of autologous unloaded energy-replete carrier erythrocytes in nine volunteers, using a standard 51Cr erythrocyte-labelling technique. Within 144 h after infusion there was a 3 to 49% fall in circulating labelled cells, followed thereafter by an almost complete return to initial circulating levels; surface counting demonstrated an initial sequestration of erythrocytes by the spleen and subsequent release. Mean cell life and cell half-life of the carrier erythrocytes were within the normal range of 89 to 131 days and 19 to 29 days respectively. These results demonstrate the viability of carrier erythrocytes as a sustained drug delivery system.
Isoaspartyl bond formation within N-terminal sequences of collagen type I: implications for their use as markers of collagen degradation
Authors: BRADY Jeffrey D. , JU Julia , ROBINS Simon P.
Published: August 2015

An ELISA was developed for the measurement of N-telopeptides of the α2(I) collagen chain containing an isomerized Asp-Gly bond (β-peptide) using polyclonal antibodies raised against the synthetic peptide. The presence of this isomerized form in bone was confirmed by positive immunostaining of sections from human femoral head. The ELISA was used to measure isomerized peptide in both human bone digests and urine samples, showing that an isoaspartyl rearrangement occurs in the Asp-Gly sequence at the N-terminus of the α2(I) chain in an analogous fashion to that found in the C-terminal telopeptide of the α1(I) chain of collagen. Using this assay in conjunction with a monoclonal antibody ELISA to the non-isomerized α2(I) N-telopeptide (α-peptide), ratios of isomerized to normal peptides were estimated in the bone and urine samples. Urinary α2(I) N-telopeptides showed a higher degree of isomerization than the peptides derived from a human bone digest. This is possibly due to relative enrichment of the isoaspartyl-bonded peptide during metabolic processing due to the proximity of the isoaspartyl bond to a cross-link site. Urinary concentrations of isomerized and normal peptides were determined in normal adults, children, post-menopausal control subjects and subjects with osteoporosis. A lower ratio of β-peptide to α-peptide was observed in children's urine, indicative of a higher rate of bone metabolism allowing less time for the isomerization to occur. No significant differences were found between the post-menopausal control and osteoporotic populations although the trends observed supported the hypothesis that a lower degree of isomerization may be associated with faster bone turnover.