bluuebunny/crossref_metadata_2025 huggingface dataset:
Do Thiazides Reduce Intestinal Oxalate Absorption?: A Study In Vitro Using Rabbit Colon
Authors: Hatch M. , Vaziri N. D.
Published: August 2015

1. The purpose of the present study was to examine the effects of various diuretics on intestinal oxalate transport. Transmural oxalate fluxes were measured across isolated, short-circuited tissue segments removed from rabbits and placed in Ussing chambers.

2. The net absorptive flux of oxalate across the distal colon was significantly reduced in the presence of trichlormethiazide at 10−4 mol/l. In contrast, this diuretic had no effect on oxalate transport in the other intestinal segments examined. Several of the thiazide diuretics tested had some inhibitory effect on colonic oxalate absorption, but at higher concentrations of 10−3 mol/l or 10−2 mol/l.

3. We conclude that the previously reported hypooxaluric effects of hydrochlorothiazide and chlorthalidone are most likely not the result of an exclusive or primary effect on intestinal oxalate transport. It is suggested that the reduction in colonic oxalate absorption that was observed with the thiazides probably involves the transport system responsible for oxalate efflux across the basolateral membrane of the colonocyte.
Ambulatory Blood Pressure and Left Ventricular Hypertrophy in Subjects with Untreated Obstructive Sleep Apnoea and Snoring, Compared with Matched Control Subjects, and their Response to Treatment
Authors: Davies Robert J. O. , Crosby Joy , Prothero Anthony , Stradling John R.
Published: August 2015

1. Obstructive sleep apnoea and snoring are associated with daytime hypertension. It is uncertain whether this association is directly due to the disturbed sleeping respiration or the result of confounding variables, particularly obesity, smoking and alcohol intake.

2. Ambulatory blood pressure and echocardiographic left ventricular muscle mass were measured in 19 patients with obstructive sleep apnoea, 19 men who snore without apnoea and 38 control subjects matched for age, sex, body mass index, smoking and alcohol intake. Ambulatory blood pressure was also measured before and after treatment in 11 patients with obstructive sleep apnoea and their matched control subjects.

3. Compared with matched control subjects, untreated obstructive sleep apnoea and snoring were not associated with an increase in daytime blood pressure. A daytime elevation of either systolic or diastolic blood pressure of > 3.8 mmHg due to obstructive sleep apnoea or snoring was excluded with 95% confidence in each of the study groups. Daytime blood pressure was also unchanged when obstructive sleep apnoea was treated with nasal continuous positive airway pressure. Night-time blood pressure was not significantly different in the patients with obstructive sleep apnoea or the snorers when compared with their matched control subjects. However, a fall in night-time systolic blood pressure was seen in the patients with obstructive sleep apnoea after treatment [fall in systolic blood pressure −6.3 (SD 8.2) mmHg, P < 0.02].

4. Left ventricular diameter, wall thickness and calculated mass were similar in each of the study groups and their matched control groups.

5. Compared with well-matched control subjects, daytime ambulatory blood pressure is not increased in patients with obstructive sleep apnoea or snoring and these patients do not show left ventricular hypertrophy. Night-time ambulatory blood pressure may be raised by obstructive sleep apnoea since it falls with treatment.
Working Capacity and Expression of Myosin Heavy Chain Isoforms in Skeletal Muscle of Chronic Alcoholic Men without Liver Disease after I Day and 4 Weeks of Alcohol Abstinence
Authors: Sestoft L. , Iversen P. , Nordgaard I. , Amris S. , Joen T. , Overgaard O. , Klitgaard H.
Published: August 2015

1. The aim of this study was to examine the effect of chronic alcohol ingestion on working capacity and on the expression of myosin heavy chain isoforms in fibre types of human skeletal muscle.

2. Six alcoholic men having drunk more than 240 g of alcohol/day for more than 10 years underwent a test for working capacity and a muscle biopsy on the first day of alcohol abstinence (test 1) and again after 4 weeks of abstinence (test 2). The biopsies were analysed using histochemical, immunochemical and gel-electrophoretic techniques, and the results were compared with those from eight age-matched nonalcoholic control subjects.

3. The area of type IIB muscle fibres was decreased by 33% in the alcoholic patients compared with normal control subjects at both test 1 and test 2. The area of type IIA fibres was lower (13%) in alcoholic patients at test 1 than in the control group, and increased to the normal level at test 2.

4. The relative proportion of fibres expressing only myosin heavy chain type IIB isoforms was one-third of normal in the alcoholic patients at both tests 1 and 2. The relative proportion of fibres expressing only myosin heavy chain type IIA isoforms was the same in alcoholic patients at test 1 and in normal control subjects, but increased by 25% between test 1 and 2 in the alcoholic group.

5. The relative proportion of fibres showing co-expression of myosin heavy chain type IIA/IIB isoforms was about two-thirds of normal in alcoholic patients at both test 1 and test 2, whereas fibres with co-expression of myosin heavy chain type I/IIA were not seen in the control group, but were found in the alcoholic group, where they doubled from test 1 to test 2.

6. Thus, chronic heavy alcohol consumption modulates the expression of myosin heavy chain isoforms-in human skeletal muscle by decreasing the expression of myosin heavy chain type IIB and increasing the expression of myosin heavy chain type I. After 4 weeks of alcohol abstinence a shift in the expression of myosin heavy chain type I towards myosin heavy chain type IIA is evident, indicating that the effect of alcohol on myosin heavy chain expression is a reversible process. However, to obtain complete recovery with a normal level of myosin heavy chain type IIB expression, more than 4 weeks of abstinence is necessary.

7. Working capacity was low and unchanged by 4 weeks of alcohol abstinence. The low proportion of type IIB (fast twitch glycolytic) fibres at both test 1 and 2 coincided with a low lactate production during maximal exercise. The increased proportion of type I (slow twitch oxidative) fibres at test 1 coincided with an preferential lipid oxidation during the working period.
Inositol-Specific Phospholipase D Activity in Health and Disease
Authors: Raymond F. D. , Fortunato G. , Moss D. W. , Castaldo G. , Salvatore F. , Impallomeni M.
Published: August 2015

1. We report the first demonstration of the pathophysiological importance and clinical applications of the relatively recently discovered circulating enzyme, phosphoinositol-specific phospholipase D. This enzyme is known to cleave the large variety of important cell-surface molecules linked to the cell membrane by glycan-phosphatidylinositol linkages (glycan-phosphatidylinositol anchors).

2. When measured in the sera of healthy individuals, phosphoinositol-specific phospholipase D activity was found to show a strong negative correlation with age, the degree of depreciation being greater than that measured for most other analytes.

3. Serum phosphoinositol-specific phospholipase D activity was considerably depressed in patients presenting with conditions leading to reduced liver synthetic reserve, such as hepatocellular carcinoma or liver cirrhosis caused by chronic viral hepatitis, and correlated with reduced albumin levels in these conditions, indicating that the liver is the site of phosphoinositol-specific phospholipase D synthesis and that phosphoinositol-specific phospholipase D may be used as an additional marker of liver synthetic reserve.

4. When measured in patients with acute liver disease, such as acute viral hepatitis, or in patients with bronchopneumonia, phosphoinositol-specific phospholipase D activity was found to be significantly raised, demonstrating features characteristic of an acute-phase reactant.

5. These findings indicate that, besides its pathophysiological importance, phosphoinositol-specific phospholipase D and the measurement of its activity in serum may have a useful place in the investigation of a range of clinical conditions, including tissue injury and inflammation.
Loop—Sheet Polymerization: The Structural Basis of Z α1-Anti Trypsin Accumulation in the Liver
Authors: Lomas David A.
Published: August 2015

1. The Z deficiency variant of α1-antitrypsin predisposes the homozygote to early-onset panlobular emphysema and results in the accumulation of antitrypsin within the hepatocyte, which leads to hepatocellular damage and cirrhosis. The mechanism of this accumulation has been shown to be due to the Z mutation (Glu-342→Lys) perturbing the structure of the protein, allowing a unique interaction between the reactive-centre loop of one molecule and the A sheet of a second. This loop—sheet polymerization occurs spontaneously at 37°C in purified plasma Z but not M antitrypsin. The rate of polymerization is greatly accelerated at 41 C and is blocked by the insertion of a specific peptide into the A sheet of the antitrypsin molecule. Electron microscopy and circular dichroic spectral analysis confirm that the Z antitrypsin polymers formed in vitro have structural identity with those isolated from the liver of a Z homozygote.

2. That loop—sheet polymerization is a more general phenomenon was shown by the examination of a second deficiency variant, antitrypsin Siiyama (Ser-53→Phe), which is also associated with liver inclusions. Electron microscopy confirmed that isolated antitrypsin Siiyama from the plasma of a homozygote was present as long chains of polymers identical with those of Z antitrypsin.
Improvement of Ketoacidosis in the Diabetic Rat after the Administration of the Oral Antilipolytic Agent Gr 79236
Authors: Thompson Cecil S. , Strong Peter , Mikhailidis Dimitri P.
Published: August 2015

1. We assessed the effect of a novel oral antilipolytic agent, N-[(1S, trans) − 2 – hydroxycyclopentyl] adenosine (GR 79236), in experimental diabetic ketoacidosis. Ketotic rats were gavaged with GR 79236 (1 mg/kg) or water (vehicle) and their blood/plasma/serum biochemistry and haematological profile was determined.

2. We found that GR 79236 reduced the plasma non-esterified fatty acid concentration. This effect was associated with the correction of blood/plasma/serum biochemical variables (β-hydroxybutyrate, acetoacetate, triacylglycerol) directly related to diabetic ketoacidosis, and of others (cholesterol, creatinine, creatine kinase and aspartate transaminase) which are not directly related to this metabolic abnormality.

3. There was, however, no evidence of GR 79236 lowering blood glucose in this model. One possible explanation for this observation is that GR 79236 stimulated gastric emptying leading to enhanced absorption of stomach contents when compared with untreated animals.
Sepsis Modifies the Contribution of Different Organs to Whole-Body Protein Synthesis in Rats
Authors: Breuille D. , Rose F. , Arnal M. , Melin C. , Obled C.
Published: August 2015

1. Protein synthesis rate was measured in the liver, muscle, intestine and whole body of septic rats and pair-fed controls by administration of a large dose of l-[U14C]valine. Sepsis was induced by intravenous injection of live bacteria, and protein synthesis measurements were carried out 48 h later.

2. Septic rats exhibited a reduction in food intake to between 10 and 50% of the normal level on the 2 days after infection. Animals lost body weight and the relative organ weight was increased in liver, unchanged in intestine and decreased in skeletal muscle.

3. The fractional protein synthesis rate of the whole body excluding liver was increased by 19% in septic rats in comparison with pair-fed controls, but the absolute protein synthesis rate was similar in the two groups because of the low protein content of the infected group.

4. The fractional protein synthesis was increased in whole intestine and liver but was decreased in skeletal muscle. In muscle and liver, the difference between infected and pair-fed animals was more pronounced for the absolute than for the fractional protein synthesis rate. In intestine, the fractional protein synthesis rate was similarly increased in whole intestine and the muscular layer of ileum. This suggests different regulation of protein synthesis in skeletal and smooth muscles.

5. The present investigation shows a complete redistribution of protein synthesis in sepsis. Liver represents about a third of the whole-body protein synthesis instead of 15% and becomes predominant over synthesis of muscle.
Impaired Contraction and Endothelium-Dependent Relaxation in Isolated Resistance Vessels from Patients with Insulin-Dependent Diabetes Mellitus
Authors: McNally Paul G. , Watt Pamela A. C. , Rimmer Timothy , Burden Andrew C. , Hearnshaw John R. , Thurston Herbert
Published: August 2015

1. An increase in capillary blood flow and pressure has been implicated in the pathogenesis of diabetic microangiopathy. Abnormal vascular reactivity of the resistance vasculature may play a contributory role by permitting alterations in regional haemodynamics.

2. We have studied the contractile behavior of isolated resistance arteries from normotensive patients with insulin-dependent diabetes mellitus and non-diabetic matched control subjects. Contractile responses to potassium (123 mmol/l), noradrenaline (10−8 to 3 × 10−5 mol/l) and angiotensin II (10−11 to 3 × 10−8 mol/l) were recorded. Relaxation studies were performed in maximally contracted vessels using acetylcholine (10−8 to 10−5 mol/l) and bradykinin (10−9 to 10−6 mol/l) (endothelium-dependent) and sodium nitroprusside (10−9 to 10−5 mol/l) (endothelium-independent).

3. The maximal contractile responses to potassium (P < 0.05), noradrenaline (P < 0.01) and angiotensin II (P < 0.01) were depressed in diabetic patients. Relaxation to acetylcholine was impaired (P < 0.05), but was normal with bradykinin and sodium nitroprusside.

4. These results suggest that there may be a defect in the endothelial cell acetylcholine receptor excitation-coupling in diabetes mellitus rather than a decreased ability to synthesize and release endothelium-derived relaxing factor. Impaired contraction and endothelium-dependent relaxation of resistance arteries in diabetic patients may contribute to the development of diabetic microangiopathy by causing an increase in tissue blood flow, a rise in capillary pressure and, as a result, an increase in vascular permeability.
Functional Relationship between Mast Cells and C-Sensitive Nerve Fibres Evidenced by Histamine H3-Receptor Modulation in Rat Lung and Spleen
Authors: Dimitriadou V. , Rouleau A. , Tuong M. Dam Trung , Newlands G. J. F. , Miller H. R. P. , Luffau G. , Schwartz J.-C. , Garbarg M.
Published: August 2015

1. Mast cell populations in rat lung and spleen were characterized by the presence of two specific protease markers, rat mast cell protease I and II, using both histochemical and radioimmunoassay techniques. Three mast cell populations with different size, morphology and localization were found in lung and spleen and were identified according to the expression of rat mast cell protease I (RMCPI+) or rat mast cell protease II (RMCPII+) or of both proteases (RMCPI/II+).

2. All three mast cell types were in the vicinity of calcitonin-gene-related-peptide-immunoreactive (CGRP+) nerve fibres in controls as well as in rats infected by Nippostrongylus brasiliensis in which a large increase in the number of both RMCPII+ and RMCPI/II+ mast cells was found. Ablation of the CGRP+ fibres by neonatal treatment with capsaicin resulted in a marked increase in the number of RMCPII+ and RMCPI/II+ cells in lung and, even more, in spleen of adult rats.

3. The interaction of mast cells with CGRP+ C-fibres was assessed pharmacologically by evaluation of the effects of histamine H3-receptor ligands known to act on various types of nerve endings, including those of C-fibres. The effects of H3-receptor ligands were assessed in controls, nematode-infected rats and neonatally capsaicinized rats. Mast cell activity was evaluated by measurement of [3H]histamine synthesis from [3H]histidine. In control rats, administration of the H3-receptor agonist (R)-α-methylhistamine and antagonist thioperamide, decreased and enhanced respectively [3H]histamine synthesis in lung and spleen, indicating a tonic control of mast cell activity by histamine via H3-receptors. Such effects were not found in the jejunum, although RMCPII+ mast cells are in close apposition with neuropeptide-containing fibres. The effects of the H3-receptor agents were maintained in lung and spleen of nematode-infected rats, but were almost suppressed in capsaicinized rats. 4. It is concluded that the control of mast cells by histamine acting at H3-receptors involves neuropeptide-containing nerves and presumably reflects the operation of a local neuron-mast cell feedback loop controlling processes such as ‘neurogenic inflammation’. This loop still functions when mast cells proliferate in an inflammatory condition. These observations suggest that the use of histamine H3-receptor agonists may constitute a novel therapeutic approach to limit excessive inflammatory responses resulting from dysregulation of this feedback loop.
Effect of the Serine Protease Inhibitor, Aprotinin, on Systemic Haemodynamics and Renal Function in Patients with Hepatic Cirrhosis and Ascites
Authors: MacGilchrist Alastair , Craig Kathrine J. , Hayes Peter C. , Cumming Allan D.
Published: August 2015

1. Previous studies have documented activation of protease enzymes, such as the plasma kallikrein-kinin system, in hepatic cirrhosis. Increased plasma kinin generation could contribute to pathological systemic vasodilatation in cirrhosis, and reduced systemic vascular resistance has been suggested as a trigger to renal sodium retention in this disease. We investigated the effect of aprotinin, a protease inhibitor which binds to plasma kallikrein, on systemic haemodynamics and renal function in patients with hepatic cirrhosis and ascites.

2. Aprotinin was infused intravenously in high dosage (2 × 106 kallikrein inhibitory units loading, 1 × 106 kallikrein inhibitory units/h).

3. Of 13 patients, 10 had a low systemic vascular resistance (< 1200 dyn s cm−5) at baseline. In this group, eight showed an increase in systemic vascular resistance during aprotinin infusion. Overall, the increase in systemic vascular resistance was significant, and there was a small but significant increase in mean arterial pressure. In all patients, there were increases in renal plasma flow, glomerular filtration rate, and absolute and fractional urinary sodium excretion during aprotinin infusion.

4. Plasma renin activity, plasma angiotensin II and plasma aldosterone fell significantly during aprotinin infusion. Plasma prekallikrein, plasma noradrenaline and plasma atrial natriuretic peptide did not change. Plasma aprotinin concentration was 209 ± 11 kallikrein inhibitory units/ml at the end of the infusion.

5. Before and during the infusion, there was a significant negative correlation between systemic vascular resistance and plasma renin activity. There was a positive correlation between the change in systemic vascular resistance and the change in renal plasma flow during aprotinin infusion.

6. In patients with hepatic cirrhosis and ascites, treatment with aprotinin appears beneficial in relation to systemic and renal haemodynamics, sodium excretion and hormonal stimulation, with no evidence of adverse effects. The results are compatible with an association between plasma kallikrein-kinin activation, systemic vasodilatation, renin-angiotensin activation, and renal vasoconstriction and sodium retention in this condition.
Anti-Tumour Necrosis Factor-α Treatment Interferes with Changes in Lipid Metabolism in a Tumour Cachexia Model
Authors: Carbó Neus , Costelli Paola , Tessitore Luciana , Bagby Gregory J. , López-Soriano Francisco J. , Baccino Francesco M. , Argilés Josep M.
Published: August 2015

1. Rats bearing the Yoshida ascites hepatoma AH-130 showed an important decrease in white adipose tissue lipoprotein lipase activity as compared with non-tumour bearing rats. This was associated with a lower adipose tissue mass, as estimated from the weight of the lumbar fat-pads. Conversely, lipoprotein lipase activity was markedly increased in brown adipose tissue and heart.

2. These changes were associated with a distinct hyperlipaemia, essentially manifested as an increase in circulating triacylglycerol levels, whereas no changes were observed in glycaemia.

3. Tumour-bearing rats were treated with a polyclonal anti-murine tumour necrosis factor-α antibody or with a non-immune IgG preparation. Control animals were either untreated or received a nonimmune IgG preparation. Anti-tumour necrosis factor-α treatment resulted in a significant increase in lipoprotein lipase activity in white adipose tissue in animals bearing a tumour growing exponentially (day 4 after inoculation) as compared with the animals receiving a non-immune goat IgG preparation. In addition, animals bearing an stationary tumour (day 7 after inoculation) and submitted to anti-tumour necrosis factor-α treatment had a higher adipose tissue lipoprotein lipase activity as compared with the IgG- or the non-treated groups. Correspondingly, circulating triacylglycerol levels were markedly decreased, with a lower hyperlipaemia than in control tumour-bearing rats.

4. These observations suggest that tumour necrosis factor-α is involved in activating the lipid metabolic changes that develop in rats after transplantation of a fast-growing tumour.
Sympathetic Overactivity in Subjects Complaining of Unexplained Fatigue
Authors: Pagani Massimo , Lucini Daniela , Mela Giuseppe Sandro , Langewitz Wolf , Malliani Alberto
Published: August 2015

1. Theoretical and practical considerations suggest that in subjects complaining of fatigue, in the absence of evident organ dysfunction, an alteration in the autonomic nervous system might be present as a functional correlate.

2. Autoregressive spectral analysis of R-R interval variability from a surface ECG, was used in healthy control subjects (n = 24, age 45 ± 4 years) and in subjects complaining of unexplained fatigue (n = 53, age 46 ± 9 years) to obtain quantitative indices of the state of the sympathovagal balance, both at rest and during a mental stimulus (mental arithmetic), capable of enhancing sympathetic drive. Sympathetic and vagal modulations were inferred from the normalized powers of the low frequency and high frequency spectral components respectively.

3. We observed in patients, at rest, a prevailing low frequency component of R-R variability (patients low frequency = 73 ± 11, control subjects 51 ± 10 normalized units, P < 0.05). The responsiveness to mental arithmetic was reduced in patients as compared with controls. Systolic blood pressure variability did not differ. This suggested a selective imbalance in autonomic control of the sinoatrial node, characterized by sympathetic predominance as well as by vagal withdrawal, at rest.

4. The possibility of discriminating patients from control subjects on the basis of simple non-invasive functional markers might provide a better understanding of the mechanisms, clinical evolution and outcome of conditions such as the chronic fatigue syndrome, which lack ordinary evidence of disease, but comprise, as physiopathological correlate, a quantitative alteration of autonomic control.
Effect of Oral Creatine Supplementation on Respiratory Gas Exchange and Blood Lactate Accumulation during Steady-State Incremental Treadmill Exercise and Recovery in Man
Authors: Stroud Michael A. , Holliman Dawn , Bell Doug , Green Allison L. , Macdonald Ian A. , Greenhaff Paul L.
Published: August 2015

1. Oral creatine supplementation has been shown to increase muscle creatine and phosphocreatine concentrations with consequent benefits on performance during short-term maximal exercise. However, recently there have been anecdotal reports that creatine supplementation can also influence the pattern of substrate utilization and improve performance during more prolonged, submaximal exercise, which, based on recent experimental evidence, may have some scientific justification.

2. Eight men performed a continuous incremental exercise test running at 10 km/h on a motorized treadmill at predetermined workloads from 50% to 90% of maximal oxygen uptake, before and after 5 days of creatine supplementation (4 × 5 g daily). Exercise was performed for 6 min at each workload to achieve a steady state, and respiratory gas exchange and blood lactate concentrations were measured during the last 30s at each workload. Measurements were also made at 5-min intervals for the first 15 min of recovery.

3. The results showed no measurable effect of creatine supplementation on respiratory gas exchange and blood lactate concentrations during either incremental submaximal exercise or recovery. This suggests that creatine supplementation does not influence substrate utilization during and after this type of exercise.
Comparison of the Modulatory Influence of Maize and Olive Oils and Butter on Metabolic Responses to Endotoxin in Rats
Authors: Besler H. T. , Grimble R. F.
Published: August 2015

1. n-3 polyunsaturated fatty acids decrease responses to cytokines and inflammatory agents. The present study examines how different intakes of n-6 and n-9 fatty acids influence the metabolic response to endotoxin in Wistar rats.

2. Weanling male rats were, for 4 weeks, fed diets containing 50, 100 or 200 g/kg fat in the form of maize oil (rich in linoleic acid), butter (poor in linoleic acid, rich in oleic acid) or olive oil (adequate in linoleic acid, rich in oleic acid) or standard laboratory chow. All butter and olive oil diets included 10 g/kg maize oil, in total fat, to avoid essential fatty acid deficiency.

3. Rats subsequently received 800 μg/kg Escherichia coli endotoxin or sterile saline subcutaneously. Twenty-four hours after injection, the rate of tissue protein synthesis was measured in liver, lung, kidney, tibialis muscle and spleen by the ‘flooding dose’ method. Protein and zinc concentrations were assayed in all tissues and serum albumin and caeruloplasmin measured.

4. In animals fed chow, protein synthetic rate increased by 18%, 29% and 27% in liver, lung and kidney respectively. Tissue zinc concentrations increased by 33% in kidney, and tissue protein increased by 17%, 23% and 17% in liver, lung and kidney respectively. Serum caeruloplasmin increased by 60% and albumin concentration fell by 14%.

5. In animals consuming the 50 g/kg maize oil diet, protein synthetic rate increased by 56%, 36% and 34% in liver, lung and kidney respectively. Tissue zinc concentration increased by 14%, 15% and 17% in the three tissues respectively, and tissue protein concentration increased by 7%, 9% and 51% respectively. Serum caeruloplasmin increased by 172% and albumin concentrations fell by 22%.

6. No change in any parameter occurred in response to endotoxin in rats given diets containing fat predominantly as butter (50 and 100 g/kg), or olive oil (50, 100 and 200 g/kg).

7. In animals fed maize oil diets, responses increased in magnitude in parallel with dietary intake.

8. Responses in rats fed fat (200 g/kg) predominantly as butter were similar to those seen when diets contained 50 g/kg fat as maize oil.

9. The data suggest that the metabolic response to endotoxin is enhanced by n-6 and suppressed by n-9 unsaturated fatty acids. The modulatory influence of fats on responses to inflammatory agents may depend on the relative proportions of these substances.
Effect of Head-Down Tilt on Cardiovascular Control in Healthy Subjects: A Spectral Analytic Approach
Authors: Weise F. , London G. M. , Guerin A. P. , Pannier B. M. , Elghozi J.-L.
Published: August 2015

1. The purpose of this investigation was to determine non-invasively the changes in autonomic cardiovascular control observed in normal subjects submitted to acute cardiopulmonary blood volume expansion by 100° head-down tilt. The effect of head-down tilt on finger blood pressure and heart rate fluctuations was studied by means of power spectral analysis in 12 healthy men.

2. Amplitude spectra of heart rate and blood pressure rhythmicity were estimated at the low-frequency (60–140 mHz, 10-s rhythm) and high-frequency (area under the curve at mean respiration rate ± 50 mHz) component. Transfer gain and phase were calculated between systolic blood pressure and heart rate. Forearm vascular resistance was estimated to validate the head-down procedure.

3. Forearm vascular resistance decreased significantly from 19.82 (16.34–26.46) mmHg ml−1 min 100 ml to 18.05 (13.69–22.88) mmHg ml−1 min 100 ml (P < 0.01) during head-down tilt (values are medians and 25 and 75 percentiles). The overall variability (total area under the curve of the spectrum from 20 to 500 mHz) of blood pressure and heart rate time series was consistently reduced with head-down tilt.

4. The spectral pattern of systolic blood pressure showed a diminution of the absolute and relative low-frequency component during head-down tilt: absolute log-transformed values, 2.86 (2.80–2.94) mmHg/Hz1/2 versus 2.77 (2.72–2.82) mmHg/Hz1/2 (P < 0.05); relative values, 35% (32–37%) versus 32% (29–32%) (P < 0.05). In heart rate spectra only the absolute low-frequency component decreased. There was no change in the high-frequency component in all time series or in the transfer gain and phase during head-down tilt.

5. It is concluded that head-down tilt is a simple manoeuvre to diminish the 10-s rhythm in systolic blood pressure, which may reflect the reduced sympathetic vasomotor control after cardiopulmonary baroreceptor loading.
Acute Effect of Parathyroid Hormone on Urine Concentration in the Rat
Authors: Carney S. L. , Gillies A. H. B.
Published: August 2015

1. It has been demonstrated that parathyroid hormone can increase adenylate cyclase activity in the rat papilla, produce a small antidiuretic effect and in vitro can interfere with the action of arginine vasopressin on water transport. Clearance studies were performed in the anaesthetized water diuretic thyroparathyroidectomized rat to evaluate further the effect of parathyroid hormone on urine concentration in the presence and absence of arginine vasopressin.

2. A maximal phosphaturic concentration of rat parathyroid hormone (2 μg/kg) reduced urine flow from 125 ± 7 to 81 ± 9 μl/min within 10 min (P < 0.01). Addition of a maximal antidiuretic concentration of arginine vasopressin (100 ng/kg) produced a delayed and diminished antidiuretic response when compared with a group of rats not pretreated with parathyroid hormone (47 ± 5 compared with 27 ± 5 μl/min; P < 0.01). However, a supramaximal arginine vasopressin concentration (1000 ng/kg) produced a maximal antidiuretic effect in the presence of parathyroid hormone.

3. To evaluate further the inhibitory effect of parathyroid hormone on arginine vasopressin-induced anti-diuresis, parathyroid hormone (2 μg/kg) was administered to one group of rats and a minimally effective arginine vasopressin concentration (7.5 ng/kg) to another group, which produced a similar antidiuretic effect. However, the subsequent effect of a maximal antidiuretic arginine vasopressin concentration (100 ng/kg) was again significantly blunted in the group pretreated with parathyroid hormone.

4. Parathyroid hormone produced only a small increase in mean plasma calcium concentration, and glomerular filtration rate was not altered by either hormone.

5. These results demonstrate that high physiological concentrations of parathyroid hormone do have a significant antidiuretic effect and can interfere with the action of arginine vasopressin. This suggests that parathyroid hormone may act as a partial agonist to arginine vasopressin in the collecting system.
Effects of Dietary Polyunsaturated Fatty Acids on Small Intestinal Secretory and Absorptive Function: Studies in Rat Jejunum In Vitro
Authors: Lindley K. J. , Muller D. P. R. , Milla P. J.
Published: August 2015

1. Recent initiatives which advocate an increase in dietary polyunsaturated fat intake have led to the study of the effects of this upon gastrointestinal function.

2. Weanling rats were for 21 weeks fed diets containing 10% fat that were either high or low in polyunsaturated fats. Jejunal function was studied in vitro in an Ussing chamber.

3. Basal intestinal short-circuit was similar in both groups.

4. A decreased EC50 for the non-neural electrogenic secretory responses to acetylcholine, bethanecol and isobutylmethylxanthine was apparent in the jejuna of rats fed a diet high in polyunsaturated fatty acids.

5. Submaximal electrogenic galactose absorption was increased in the rats fed a diet high in polyunsaturated fatty acids.

6. Changing the composition of dietary lipid resulted in a change in the fatty composition of the apical enterocyte membrane.

7. Diets high in polyunsaturated fatty acids may be both prosecretory and proabsorptive in the small intestine.
A Map of the Heart: Gap Junctions, Connexin Diversity and Retroviral Studies of Conduction Myocyte Lineage
Authors: Gourdie Robert G.
Published: August 2015

1. The heartbeat is co-ordinated by organized propagation of electrical excitation through cardiac muscle. Intercellular conduction and propagation of the cardiac action potential is dependent on electrical connections between myocytes, termed gap junctions.

2. In the last few years, our conception of the structure and function of cardiac gap junctions has been revised substantially. It seems that these structures show unexpected levels of specialization within the myocardium and they can no longer be viewed simply as passive conduits for the regulated movement of electrical current between heart muscle cells.

3. In this article, some of the contributions to this field by the author and his collaborators are summarized. Studies using confocal microscopy and digital imaging techniques to characterize the three-dimensional organization of electrical contacts between myocytes in the mature and developing heart are described, data on the unique expression and spatial distribution patterns of gap-junctional subunit proteins (connexins) are given, and finally the author's current work on the differentiation of cardiac conduction tissues, and how this work arose from studies of gap junctions in the heart, is introduced.
Circulating Antibodies to Cardiac Protein—Acetaldehyde Adducts in Alcoholic Heart Muscle Disease
Authors: Harcombe A. A. , Ramsay L. , Kenna J. G. , Koskinas J. , Why H. J. F. , Richardson P. J. , Weissberg P. L. , Alexander G. J. M.
Published: August 2015

1. Serum samples from patients with alcoholic heart muscle disease and from control subjects with and without heart disease who did not drink to excess were screened by Western immunoblotting for antibodies to acetaldehyde-modified cardiac cytosolic proteins.

2. Two of the 64 control samples (from subjects with and without heart disease who were not drinking and from subjects with alcoholic liver disease) had detectable (IgG) antibody to acetaldehyde-modified cardiac proteins.

3. By contrast, 7 of 21 (33%) patients with alcoholic heart muscle disease had antibodies against cyanoborohydride-stabilized, acetaldehyde-modified human cardiac cytosolic protein antigens (P < 0.001).

4. Antibodies were of IgG class in six patients and IgA class in five. The molecular sizes of the protein antigens observed ranged from 58 to 120 kDa.

5. These results suggest that a proportion of patients with alcoholic heart muscle disease develop immunogenic cardiac protein—acetaldehyde adducts. The presence of antibodies to these adducts may be a marker for the diagnosis of this heart disease, or possibly for its pathogenesis.
Impaired Platelet Aggregation after Cardiopulmonary Bypass in Man: Enhancement of Collagen-Induced Aggregation in whole Blood and Plasma by Adrenaline Ex Vivo
Authors: Menys Valentine C. , Belcher Philip R. , Noble Mark I. M. , Drossos George E. , Pillai Ravi , Westaby Steve
Published: August 2015

1. We tested the effect of intravenous adrenaline at 0.55–1.10 nmol min−1 kg−1 (for 3–8 min, at 7–10 min post bypass; n = 7) on both microaggregation in hirudinized whole blood, using platelet counting, and macroaggregation in platelet-rich plasma, using optical aggregometry. Control (n = 12) blood samples were taken before and at 10 and 20 min after bypass.

2. Post-bypass plasma adrenaline levels (nmol/l) increased slightly in controls (1.0 versus 0.7 at 10 min, medians; P = 0.05) and markedly with adrenaline infusion (36 versus 0.5 before infusion, P = 0.02). Microaggregation (percentage decrease in single platelets) in stirred blood, reflecting largely ADP-dependent ‘spontaneous’ aggregation, was not influenced by adrenaline infusion. In contrast, collagen (0.2 μg/ml)-induced microaggregation in blood was enhanced by adrenaline (92% versus 41%, P = 0.02), with no change in controls (60% versus 53%, P = 0.61).

3. In controls, collagen (0.6 μg/ml)-induced macroaggregation in platelet-rich plasma (extent of increase in light transmission, cm) was impaired at 10 min post bypass (5.3 versus 12.1 before bypass, P = 0.01), but was enhanced by adrenaline (7.0 versus 3.6 before infusion, P = 0.02). Platelet counts (×109/1) were decreased postbypass (155 versus 220, P = 0.02) and were not influenced by adrenaline infusion (167, P = 0.93).

4. In conclusion, following bypass and at normocalcaemia, adrenaline enhances collagen-induced aggregation in both plasma and whole blood ex vivo, independently of any change in platelet counts, but has no effect on stirring-induced ‘spontaneous’ aggregation in blood.
Human Erythrocyte Membrane Fluidity and Calcium Pump Activity in Primary Combined Hyperlipidaemia
Authors: Muzulu S. I. , Bing R. F. , Norman R. I.
Published: August 2015

1. Human erythrocyte membrane cholesterol, fluidity and basal and calmodulin-stimulated calcium pump (Ca2+-Mg2+-ATPase) activities were compared in 24 patients with primary combined hyperlipidaemia and 20 age-matched normolipidaemic control subjects.

2. There was no correlation between serum and membrane cholesterol. Despite the differences in serum cholesterol levels between the two groups, membrane cholesterol levels were similar.

3. 1,6-Diphenyl-1,3,5-hexatriene anisotropy was lower in the hyperlipidaemic group, suggesting increased fluidity in the hydrocarbon core of the phospholipid membrane bilayer.

4. Basal calcium pump activity was lower in the hyperlipidaemic group with increased membrane fluidity.

5. These results suggest that membrane adaptive mechanisms can maintain membrane cholesterol within a narrow range, that serum triacylglycerol is more important than serum cholesterol in determining membrane fluidity and that increased membrane fluidity reduces basal calcium pump activity.
Combined Intestinal Trefoil Factor and Epidermal Growth Factor is Prophylactic against Indomethacin-Induced Gastric Damage in the Rat
Authors: Chinery Rebecca , Playford Raymond J.
Published: August 2015

1. The availability of recombinant epidermal growth factor provides a potentially exciting development for the treatment of gastrointestinal ulceration. However, because of its potent mitogenic activity, there is a need for strategies which reduce the dose required. Intestinal trefoil factor stimulates mucosal healing without increasing proliferation. Studies were undertaken to examine the biological effects of rat intestinal trefoil factor and/or human epidermal growth factor upon gastrointestinal epithelial cell functions pertinent to mucosal protection, using two wounding models.

2. The study of epithelial restitution in vitro demonstrated a marked synergistic effect on the rate of migration of the wound edge when intestinal trefoil factor was used in combination with epidermal growth factor. There was no increased cellular proliferation due to the addition of intestinal trefoil factor to the cells when given alone, or to the stimulatory effect of cells treated with epidermal growth factor. In the rat model of gastric ulceration, the presence of both epidermal growth factor and intestinal trefoil factor protected against the development of indomethacin-induced gastric lesions.

3. We conclude that combination therapy of epidermal growth factor with intestinal trefoil factor could provide a more potent, safer approach to the treatment of human gastrointestinal ulceration.
Relationship between Plasma Volume, Carotid Baroreceptor Sensitivity and Orthostatic Tolerance
Authors: El-Sayed H. , Hainsworth R.
Published: August 2015

1. Studies were carried out on 43 otherwise healthy patients referred for investigation for attacks of syncope of unknown cause and on six healthy volunteers.

2. Plasma volume was determined by Evans Blue dye dilution and blood volume was estimated using haematocrit. Carotid baroreceptor sensitivity was determined from the changes in pulse interval in response to subatmospheric pressures applied to the neck overlying the carotid sinuses, and orthostatic tolerance was assessed as the time to presyncope in a test of head-up tilt, followed by the addition of graded lower body suction.

3. Eight patients and one volunteer fainted during head-up tilt alone, 23 patients and two volunteers fainted during tilt with lower body suction at −20 mmHg and 12 patients and three volunteers either fainted during suction at −40 mmHg or tolerated the entire procedure.

4. Although plasma and blood volumes were higher in males than females, the values normalized for either body weight or for calculated lean body mass were not different between male and female patients and asymptomatic volunteers. The subjects showing the greatest resistance to syncope were found to have significantly larger plasma and blood volumes (P < 0.0001) and significantly smaller baroreceptor sensitivities (P < 0.0002) than those who fainted earlier.

5. There was a highly significant positive correlation in all subjects between orthostatic tolerance (time to onset of syncope) and plasma and blood volumes (r = 0.60, P < 0.0001; r = 0.53, P < 0.0002), and highly significant negative correlations between time to syncope and baroreceptor sensitivity (r = −0.61, P < 0.0001) and between baroreceptor sensitivity and plasma and blood volumes (r = −0.54, P < 0.0001; r = −0.31, P < 0.03).

6. These results show that tolerance to orthostatic stress is favoured by large plasma and blood volumes and a low sensitivity of the carotid baroreceptor—heart rate reflex.
Demonstration of Hypomethylation of Proteins in the Brain of Pigs (but Not in Rats) Associated with Chronic Vitamin B12 Inactivation
Authors: McKeever M. , Molloy A. , Young P. , Kennedy S. , Kennedy D. G. , Scott J. M. , Weir D. G.
Published: August 2015

1. Pigs treated with nitrous oxide for periods of 1, 2 and 4 months demonstrated markedly reduced levels of methionine synthase and concomitant reduction in the ratio of S-adenosylmethionine to S-adenosylhomocysteine, the methylation ratio, at all time intervals.

2. Both ‘O’ and ‘N’ methylations were significantly reduced in pigs after 4 months in nitrous oxide but not after shorter periods.

3. Hypomethylation correlated with the development of clinical ataxia, but was absent when the pigs were clinically normal. It also only occurred when the S-adenosylmethionine level fell.

4. Rats maintained in nitrous oxide for 4 months showed a marked reduction of methionine synthase but no reduction in the methylation ratio or in brain hypomethylation. None of the rats became clinically ataxic.

5. Using an exogenous protein as a methyl group acceptor, it was demonstrated in an in vitro assay that the methyltransferase enzymes responsible for brain ‘O’ and ‘N’ methylation were not affected per se by nitrous oxide treatment.

6. It is concluded that reduction of the methylation ratio in the brain of pigs as a consequence of methionine synthase inhibition leads to brain hypomethylation. This hypomethylation could affect critical components of nerve tissue, inducing the vacuolar myelopathic changes seen in the spinal cord of these animals, which mimic those of subacute combined degeneration in man.
n-Butyrate Mediation of Ganglioside Expression of Human and Murine Cancer Cells Demonstrates Relative Cell Specificity
Authors: Berenson Charles S. , Patterson Melissa A. , Miqdadi Jehad A. , Lance Peter
Published: August 2015

1. n-Butyrate, a short chain fatty acid produced by colonic fermentation, induces differentiation in human neoplastic cell lines, and reduces expression in vitro of a sialyltransferase that glycosylates N-linked glycoproteins in hepatoblastoma cells. Gangliosides are amphipathic, sialylated glycosphingolipids that undergo profound changes in many transformed cells and may protect neoplastic cells from host immune surveillance. Colonic mucosal cells are exposed to luminal short-chain fatty acid concentrations of up to 80 mmol/l, and there is some evidence that short-chain fatty acids may alter ganglioside expression in colon cancer cells.

2. Because of the importance of gangliosides in cancer pathogenesis, we investigated the effects of n-butyrate on ganglioside expression of colonic (human and murine) and non-colonic cancer cells.

3. Three separate colon cancer cell lines (LS174T, T84 and MCA-38), when butyrate treated, demonstrated striking amplification of specific individual gangliosides. However, the total lipid-bound sialic acid content of gangliosides of butyrate-treated LS174T cells diminished. In contrast to earlier reports, n-butyrate did not mediate expression of all gangliosides and specifically did not mediate expression of GM3. This effect persisted even after removal of butyrate.

4. In contrast, exposure of extracolonic cells to butyrate, including cervical cancer (HeLa) and laryngeal cancer (HEp-2) cell lines in this study and hepatoblastoma cells (Hep G2) in our previous work, caused no detectable changes in ganglioside expression.

5. In conclusion, our results indicate a relative tissue specificity of butyrate-mediated alterations in ganglioside expression that is not universal but is limited to specific gangliosides.
A New Non-Invasive Statistical Method to Assess the Spontaneous Cardiac Baroreflex in Humans
Authors: Ducher Michel , Fauvel Jean Pierre , Gustin Marie Paule , Cerutti Catherine , Najem Robert , Cuisinaud Guy , Laville Maurice , Pozet Nicole , Paultre Christian Zacharie
Published: August 2015

1. A new method was developed to evaluate cardiac baroreflex sensitivity. The association of a high systolic blood pressure with a low heart rate or the converse is considered to be under the influence of cardiac baroreflex activity. This method is based on the determination of the statistical dependence between systolic blood pressure and heart rate values obtained non-invasively by a Finapres device. Our computerized analysis selects the associations with the highest statistical dependence. A ‘Z-coefficient’ quantifies the strength of the statistical dependence. The slope of the linear regression, computed on these selected associations, is used to estimate baroreflex sensitivity.

2. The present study was carried out in 11 healthy resting male subjects. The results obtained by the ‘Z-coefficient’ method were compared with those obtained by cross-spectrum analysis, which has already been validated in humans. Furthermore, the reproducibility of both methods was checked after 1 week.

3. The results obtained by the two methods were significantly correlated (r = 0.78 for the first and r = 0.76 for the second experiment, P < 0.01). When repeated after 1 week, the average results were not significantly different. Considering individual results, test—retest correlation coefficients were higher with the Z-analysis (r = 0.79, P < 0.01) than with the cross-spectrum analysis (r = 0.61, P < 0.05).

4. In conclusion, as the Z-method gives results similar to but more reproducible than the cross-spectrum method, it might be a powerful and reliable tool to assess baroreflex sensitivity in humans.