bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary Localized Orbital Amyloidosis Composed of the Immunoglobulin γ Heavy Chain CH3 Domain
Authors: Tan S. Y. , Murdoch I. E. , Sullivan T. J. , Wright J. E. , Truong Oanh , Hsuan J. J. , Hawkins P. N. , Pepys M. B.
Published: August 2015

1. Primary orbital amyloidosis is a rare form of localized amyloidosis in which the precursor protein has not previously been identified. We report here the first extraction of amyloid fibrils from a tissue biopsy containing orbital amyloid, and characterization of the fibril protein.

2. The N-terminal nine residues were identical with residues 278–286 and 275–283 of the third constant (CH3) domains of IgG1 and IgG4 γ heavy chains, respectively. The mass of the fibril subunit protein was 6125 Da by time-of-flight mass spectrometry, compared with the expected masses of 6169.9 Da and 6214.9 Da for the CH3 domains of γ1 from residue 278 and γ4 from residue 275, respectively. The fibril protein thus appeared to consist exclusively of an immunoglobulin heavy chain constant domain.

3. Only two examples of immunoglobulin heavy chain derived amyloid have been reported previously and both of these, as well as all published cases of the usual immunoglobulin light chain derived amyloid, contained variable domain sequence. The present case therefore represents a form of local, presumably clonal, B-cell/plasma-cell disorder characterized uniquely by deposition of an amyloidogenic immunoglobulin heavy chain constant domain fragment.
Serum Vitamin A and E Concentrations in Acute Falciparum Malaria: Modulators or Markers of Severity?
Authors: Davis Timothy M. E. , Binh Tran Quang , Danh Phan Thi , Dyer John R. , St John Andrew , Garcia-Webb Peter , Anh Trinh Kim
Published: August 2015

1. To assess the association between vitamin A, vitamin E and the clinical course of severe malaria, serial morning blood samples were taken from 24 Vietnamese patients, aged 18–62 years, receiving intensive treatment for complicated Plasmodium falciparum infections. A single fasting blood sample was also taken from 10 control subjects aged 22–45 years. Serum retinol, carotene and vitamin E concentrations were measured by h.p.l.c.

2. Admission serum retinol concentration was depressed relative to that of the control subjects (0.69 ± 0.35 versus 1.86 ± 0.41μmol/l mean ± SD, P < 0.001) and correlated inversely with indices of hepatic function, but positively with the simultaneous serum creatinine concentration (P < 0.05). During the first week of treatment, serum retinol concentration increased in parallel with improving liver function, whereas serum creatinine concentration remained elevated in the majority of patients. Serum α- and β-carotene concentrations remained depressed throughout.

3. Serum vitamin E concentration, corrected for total serum cholesterol concentration in the form of a ratio, was also depressed at presentation (3.1 ± 1.8×103 versus 4.2 ± 0.8×103 in control subjects; P < 0.05), but tended to be higher than the control value at the time of discharge (0.1 > P > 0.05); there was a significant correlation between admission ratio and parasite clearance time (P = 0.04).

4. On the basis of this and previous studies, vitamin A replacement could be considered in selected severely ill patients without renal impairment. As found previously in animal models, depressed vitamin E levels may have a beneficial effect on the course of malarial infection.
Effects of Intravenous Calcitriol on Lipid Profiles and Glucose Tolerance in Uraemic Patients with Secondary Hyperparathyroidism
Authors: Lin Shih-Hua , Lin Yuh-Feng , Lu Kuo-Cheng , Diang Liang-Kuang , Chyr Shoou-Hwa , Liao Wen-Kuei , Shieh Shang-Der
Published: August 2015

1. Secondary hyperparathyroidism in chronic renal failure may contribute to abnormalities of lipid metabolism and glucose tolerance. Amelioration of secondary hyperparathyroidism has been reported to mitigate the hyperlipidaemia and improve glucose tolerance experimentally.

2. The effect of the partial suppression of hyperparathyroidism by intravenous calcitriol on lipid levels and glucose tolerance was studied in 15 haemodialysis patients with secondary hyperparathyroidism. All received intravenous calcitriol 1 μg at the end of haemodialysis thrice weekly for eight weeks. Oral glucose tolerance test and plasma lipid profiles including triglyceride, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoprotein A-I and apoprotein B were determined simultaneously before and after eight weeks of therapy.

3. Before calcitriol treatment, uraemic patients with secondary hyperparathyroidism displayed a significant higher triglyceride and a significant lower HDL-C and apoprotein A-I as well as marked glucose intolerance with an increment of the area below the glucose curve when compared with healthy control subjects.

4. After eight weeks of calcitriol treatment, there was a significant decrement in serum intact parathyroid hormone (476.45 ± 48.33 versus 191 37 ± 30.17 ng/l, P < 0.001) and plasma triglyceride (2.24 ± 0.34 versus 1.80 ± 0.29 mmol/l, P < 0.05) as well as a significant increment of plasma apoprotein A-I (38.13 ± 2.14 versus 44.19 ± 2.18 μmol/l, P < 0.05), whereas there was no significant change in serum total cholesterol, LDL-C, HDL-C, and apoprotein B. These patients also became more glucose tolerant with a significant decrease of the area below the glucose curve and a significant rise in the area under the insulin curve after glucose load. Furthermore, the insulinogenic index increased significantly.

5. It was concluded that in addition to 1,25-dihydroxyvitamin D3 deficiency, secondary hyperparathyroidism may participate in the abnormal lipid metabolism, glucose tolerance and insulin secretion seen in dialysis patients and these abnormalities could be, at least in part, improved by intravenous calcitriol treatment.
Regional Fat Distribution by Dual-Energy X-Ray Absorptiometry: Comparison with Anthropometry and Application in a Clinical Trial of Growth Hormone and Exercise
Authors: Taaffe Dennis R. , Lewis Barbara , Marcus Robert
Published: August 2015

1. The purpose of this study was to determine the suitability of ratios derived from dual-energy X-ray absorptiometry (DXA) whole body scans to assess regional fat distribution in older men and women by comparing them with the waist-to-hip ratio (WHR) and to evaluate their clinical utility by applying them in a clinical trial involving resistance exercise and recombinant human growth hormone.

2. Sixty-four healthy older adults (39 women and 25 men), aged 65–82 years, served as subjects. The ratios of trunk fat-to-total fat, trunk fat-to-body weight, trunk fat-to-limb fat and trunk fat % were determined by DXA. WHR was assessed on the same day, as was the ratio of subscapular/triceps skinfolds in men. Cardiovascular disease risk factors, functional capacity and serum lipids were also assessed.

3. A moderate relationship (r = 0.36-0.54) between the WHR- and DXA-derived ratios were observed for both men and women. Both DXA and WHR showed similar associations with cardiovascular disease risk factors. However, in men, all DXA ratios were able to detect subtle changes in regional fat distribution resulting from daily administration of recombinant human growth hormone in conjunction with resistance exercise for 10 weeks, whereas the WHR or subscapular/triceps ratios did not.

4. This suggests that DXA-derived ratios may be more sensitive than conventional anthropometric methods in the assessment and categorization of body fat distribution.
Sulphonamides as Anti-Inflammatory Agents: Old Drugs for New Therapeutic Strategies in Neutrophilic Inflammation?
Authors: Ottonello Luciano , Dapino Patrizia , Scirocco Maria C. , Balbi Alessandro , Bevilacqua Maurizio , Dallegri Franco
Published: August 2015

1. It is well known that neutrophils act as mediators of tissue injury in a variety of inflammatory diseases. Their histotoxic activity is presently thought to involve proteinases and oxidants, primarily hypochlorous acid (HOCl). This oxidant is also capable of inactivating the specific inhibitor of neutrophil elastase (α1-antitrypsin), thereby favouring digestion of the connective matrix.

2. In the present work, we found that sulphanilamide and some sulphanilamide-related anti-inflammatory drugs such as dapsone, nimesulide and sulphapyridine reduce the availability of HOCl in the extracellular microenvironment of activated neutrophils and prevent the inactivation of α1-antitrypsin by these cells in a dose-dependent manner. The ability of each drug to prevent α1-antitrypsin from inactivation by neutrophils correlates significantly with its capacity to reduce the recovery of HOCl from neutrophils. Five other non-steroidal anti-inflammatory drugs were completely ineffective.

3. Therefore, sulphanilamide-related drugs, i.e. dapsone, nimesulide and sulphapyridine, have the potential to reduce the bioavailability of neutrophil-derived HOCl and, in turn, to favour the α1-antitrypsin-dependent control of neutrophil elastolytic activity. These drugs appear as a well-defined group of agents which are particularly prone to attenuate neutrophil histotoxicity. They can also be viewed as a previously unrecognized starting point for the development of new compounds in order to plan rational therapeutic strategies for controlling tissue injury during neutrophilic inflammation.
Cigarette Smoking Influences Cytokine Production and Antioxidant Defences
Authors: Tappia Paramjit S. , Troughton Kerry L. , Langley-Evans Simon C. , Grimble Robert F.
Published: August 2015

1. Smoking exerts an inflammatory stimulus on lung macrophages, and smokers generally have low intakes of antioxidant micronutrients. This study was performed to investigate the relationship between whole-blood tumour necrosis factor production, plasma interleukin-6 and acute-phase protein concentration and antioxidant vitamins in smokers and non-smokers.

2. Measurement of tumour necrosis factor was conducted in whole blood stimulated with endotoxin (lipopolysaccharide), and interleukin-6 concentrations were measured in the plasma of smokers and non-smokers. Enzyme and dietary antioxidant concentrations and acute-phase proteins were determined in the two groups.

3. Tumour necrosis factor production and plasma interleukin-6 concentrations were 38% (P = 0.01) and 16% (P = 0.07) greater, respectively, in smokers than in non-smokers. Plasma vitamin A and E concentrations were unaffected by smoking; however, a 21% lower plasma vitamin C (P = 0.04) concentration was observed in smokers, than in non-smokers despite a similar intake of this vitamin by the two groups.

4. Concentrations of the acute-phase proteins α1-acid glycoprotein, caeruloplasmin and α2-macroglobulin were increased in the plasma of smokers compared with non-smokers by 39%, 28% and 12% respectively (P < 0.01). Our studies indicate that smokers have a compromised antioxidant status and elevated concentrations of tumour necrosis factor and interleukin-6 as a consequence of smoking.

5. These observations may provide some insight into the biological mechanisms underlying the pathology associated with smoking.
Plasma Metadrenalines: Do they Provide Useful Information about Sympatho-Adrenal Function and Catecholamine Metabolism?
Authors: Eisenhofer Graeme , Friberg Peter , Pacak Karel , Goldstein David S. , Murphy Dennis L. , Tsigos Constantine , Quyyumi Arshed A. , Brunner Han G. , Lenders Jacques W. M.
Published: August 2015

1. The clinical utility of plasma metadrenalines for examination of sympatho-adrenal function and catecholamine metabolism was assessed from plasma measurements of these metabolites in a number of clinical conditions (hypertension, cardiac failure, bilateral adrenalectomy and X-chromosomal deletions of the gene for monoamine oxidase), and before and during activation of sympathetic outflow or infusions of noradrenaline and adrenaline.

2. Plasma concentrations of normetadrenaline were less than 25% of those of noradrenaline, concentrations of metadrenaline and adrenaline were similar and those of sulphate-conjugated metadrenalines were 20- to 30-fold higher than free metadrenalines. Hypertensive patients had elevated plasma concentrations of adrenaline, noradrenaline and conjugated but not free metadrenalines. Cardiac failure patients had 2- to 4-fold increases in plasma noradrenaline and free and conjugated normetadrenaline. Adrenalectomy resulted in undetectable plasma concentrations of adrenaline, 91–97% decreases in free and conjugated metadrenaline and a 40% decrease in normetadrenaline relative to noradrenaline. Patients with X-chromosomal deletions of the gene for monoamine oxidase had 6- and 16-fold increases in plasma free and conjugated normetadrenaline and 2- and 4-fold increases in free and conjugated metadrenaline.

3. Infusion of catecholamines increased plasma concentrations of free metadrenalines by less than 6% of increases in precursor amines, indicating that most plasma normetadrenaline (84%) and metadrenaline (90%) is derived from metabolism of catecholamines before their entry into the circulation. Considerable O-methylation of catecholamines within the adrenals explains why sympatho-adrenal activation resulted in smaller proportional increases in plasma metadrenalines than catecholamines.

4. Plasma metadrenalines provide supplementary information about sympatho-adrenal activity to that provided by catecholamines, but are more useful for examination of the extraneuronal inactivation of catecholamines, particularly detection of neurochemical phenotypes in genetic disorders of catecholamine metabolism. Significant formation of metadrenalines within chromaffin tissue explains why measurements of plasma metadrenalines provide an extraordinarily sensitive method for diagnosis of phaeochromocytoma.
Glucocorticoid-Suppressible Hyperaldosteronism: Effects of Crossover Site and Parental Origin of Chimaeric Gene on Phenotypic Expression
Authors: Jamieson Andrew , Slutsker Liliya , Inglis Gordon C. , Fraser Robert , White Perrin C. , Connell John M. C.
Published: August 2015

1. Genetic analysis of five kindreds with glucocorticoid-suppressible hyperaldosteronism, four of whom had not been subjected to any previous genetic analysis, revealed three different crossover breakpoints within the five kindreds clustered in the exon 3-intron 4 region of the chimaeric gene. The site of the crossover point had no effect on blood pressure within the kindreds studied.

2. The gene causing glucocorticoid-suppressible hyperaldosteronism was in strong linkage disequilibrium with an allele of a newly described restriction enzyme polymorphism of the aldosterone synthase gene promoter region, suggesting a possible role for this allele in the development of the chimaeric gene.

3. A novel observation on subjects inheriting glucocorticoid-suppressible hyperaldosteronism from their mothers showed that they had significantly higher plasma aldosterone concentrations and mean arterial blood pressures than those inheriting glucocorticoid-suppressible hyperaldosteronism from their fathers.

4. These results raise the possibility that chronic exposure in utero to elevated plasma aldosterone concentrations may result in the permanent programming of mineralocorticoid-dependent blood pressure regulatory mechanisms, which is amplified in later life by the elevated plasma aldosterone concentrations found in glucocorticoid-suppressible hyperaldosteronism.
Differential Nitric Oxide Synthase Activity in Human Platelets during Normal Pregnancy and Pre-Eclampsia
Authors: Delacrétaz Etienne , de Quay Nicolas , Waeber Bernard , Vial Yvan , Schulz Pierre-E. , Burnier Michel , Brunner Hans R. , Bossart Hans , Schaad Nicolas C.
Published: August 2015

1. Nitric oxide released from endothelial cells is a potent vasodilator that might play an important role in cardiovascular regulation during pregnancy. Platelets, like endothelial cells, contain a constitutive form of nitric oxide synthase.

2. The present study aimed to measure the activity of this nitric oxide-forming enzyme in normotensive pregnant and non-pregnant women, as well as in women who had developed pre-eclampsia. Nitric oxide synthase activity was measured in the platelets of 21 normotensive pregnant women, 16 non-pregnant women and seven pregnant women who had developed pre-eclampsia.

3. The nitric oxide synthase activity was significantly higher in normotensive pregnant women [36.8 ± 2.7 pmol h−1 mg−1 of protein (mean ± SEM), P < 0.001] than in non-pregnant control subjects (16.8 ± 1.4 pmol h−1 mg−1 of protein) and in women with pre-eclampsia (24.5 ± 2.1 pmol h−1 mg−1 of protein, P < 0.01).

4. These data suggest that nitric oxide synthesis is increased during normal pregnancy, possibly contributing to the vasodilatation associated with this condition. Nitric oxide generation, however, may be inappropriately low in pregnant women developing pre-eclampsia, thus leading to an enhanced vasoconstriction.
Tricarboxylic Acid Cycle Intermediates during Incremental Exercise in Healthy Subjects and in Patients with McArdle's Disease
Authors: Sahlin K. , Jorfeldt L. , Henriksson K.-G. , Lewis S. F. , Haller R. G.
Published: August 2015

1. The importance of the level of tricarboxylic acid cycle intermediates (malate, citrate and fumarate) for energy transduction during exercise has been investigated in six healthy subjects and in two patients with muscle phosphorylase deficiency (McArdle's disease).

2. Healthy subjects cycled for 10 min at low (50 W), moderate [130 ± 6 W (mean ± SEM)] and high (226 ± 12 W) work rates, corresponding to 26, 50 and 80% of their maximal O2 uptake, respectively. Patients with McArdle's disease cycled for 11–13 min at submaximal (40 W) rates, and to fatigue at maximal work rates of 60–90 W.

3. In healthy subjects, phosphocreatine was unchanged during low work rates, but decreased to 79 and 32% of the initial level during moderate and high work rates. In patients with McArdle's disease, phosphocreatine decreased to 82 and 34% of the initial level during submaximal and peak exercise. Muscle lactate increased in healthy subjects during exercise at moderate and high work rates, but remained low in patients with McArdle's disease.

4. In healthy subjects, tricarboxylic acid cycle intermediates were similar at rest and at low work rates (0.48 ± 0.04 mmol/kg dry weight), but increased to 1.6 ± 0.2 mmol/kg dry weight and 4.0 ± 0.3 mmol/kg dry weight at moderate and high work rates. The tricarboxylic acid cycle intermediate level in patients with McArdle's disease was similar to that in healthy subjects at rest, but was markedly reduced during exercise when compared at the same relative intensity. The peak level of tricarboxylic acid cycle intermediates in patients with McArdle's disease was 22% of that in healthy subjects. However, when compared at the same absolute workload, tricarboxylic acid cycle intermediates were similar in patients with McArdle's disease and in healthy subjects.

5. The decrease in glutamate and increase in alanine suggest that the alanine aminotransaminase reaction was the major anaplerotic process in healthy subjects. However, in patients with McArdle's disease (n = 1), muscle alanine remained unchanged and the purine nucleotide cycle may instead be the route of a limited anaplerosis during maximal exercise. The muscle content of glutamate and glutamine (n = 1) was markedly reduced in patients with McArdle's disease.

6. It is concluded that the tricarboxylic acid cycle intermediate level is related to the work rate in healthy subjects, and that the attenuated peak level in patients with McArdle's disease may be a limitation for aerobic energy transduction.
Ventricular Expression and Circulating Levels of Insulin-Like Growth Factor 1 in Heart Transplant Recipients
Authors: Ationu ART , Burch Michael , Singer Donald , De Leval Marc , Whitehead Bruce , Carter Nicholas
Published: August 2015

1. Insulin-like growth factor I is a major mediator of growth-promoting activities. We studied the ventricular insulin-like growth factor I gene expression at mRNA and peptide levels in 24 heart transplant recipients (14 children and 10 adults), using ‘slot blot' hybridization with insulin-like growth factor I cDNA probe and a specific radioimmunoassay.

2. Ventricular insulin-like growth factor I mRNA was detected in all the cardiac transplant children but was below the limit of detection in the cardiac transplant adults. Ventricular insulin-like growth factor I levels were significantly higher in the transplant children [174 ± 15 (SEM; range 39–950) pg/mg soluble protein] than in transplant adults [39 ± 2 (range 14–85) pg/mg soluble protein, P < 0.01, n = 14]. Circulating levels of insulin-like growth factor I in the cardiac transplant children [164 ± 10 (range 105–192) ng/ml] and adults [176 ± 15 (range 126–244) ng/ml] were within normal ranges for children and adults.

3. These results suggest that the human heart is a site for insulin-like growth factor I production and provide support for an autocrine role for insulin-like growth factor I in the ventricle, despite cardiac denervation.
Contribution of Vascular Nitric Oxide to Basal Blood Pressure in Conscious Spontaneously Hypertensive Rats and Normotensive Wistar Kyoto Rats
Authors: Minami Naoyoshi , Imai Yutaka , Hashimoto Jun-Ichiro , Abe Keishi
Published: August 2015

1. The aim of this study was to clarify the extent to which vascular nitric oxide contributes to basal blood pressure in conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats.

2. The contribution of vascular nitric oxide to maintenance of blood pressure was estimated by measuring the pressor response to an intravenous injection of nitric oxide synthase inhibitor, Nω-l-arginine methyl ester, given after serial injections of captopril, vasopressin V1-receptor antagonist (V1-antagonist) and ganglion blocker (pentolinium) in conscious spontaneously hypertensive and Wistar Kyoto rats aged 20–28 weeks. To estimate the ‘amplifier property’ of hypertrophied vasculature in spontaneously hypertensive rats, which is known to modulate pressor responses, the lower blood pressure plateau after serial injections of captopril, V1-antagonist and pentolinium and the maximum blood pressure elicited by subsequent injection of increasing doses of phenylephrine were also measured.

3. The serial injections of captopril, V1-antagonist and pentolinium decreased mean arterial pressure from 164 ± 9 mmHg to 67 ± 2 mmHg and from 117 ± 2 mmHg to 49 ± 1 mmHg in spontaneously hypertensive and Wistar Kyoto rats respectively. The subsequent injection of Nω-l-arginine methyl ester restored mean arterial pressure almost to its control levels in both spontaneously hypertensive and Wistar Kyoto rats. The absolute changes in mean arterial pressure elicited by Nω-l-arginine methyl ester were significantly greater in spontaneously hypertensive than in Wistar Kyoto rats (P < 0.01), but there was no significant difference in the responses to Nω-l-arginine methyl ester when they were expressed as percentages of either the lower blood pressure plateau or maximum blood pressure.

4. These results indicate that basal blood pressure in both spontaneous hypertensive and Wistar Kyoto rats is maintained by a balance between vascular nitric oxide and major pressor systems. They also suggest that the vasodilatory effect of vascular nitric oxide does not differ between spontaneously hypertensive and Wistar Kyoto rats, and that the increased pressor effect of Nω-l-arginine methyl ester in spontaneously hypertensive rats is due to a vascular amplifier mechanism.
Effect of Dietary Restriction on Protein Synthesis and Wound Healing after Surgery in the Rat
Authors: Emery Peter W. , Sanderson Peter
Published: August 2015

1. The healing of an abdominal muscle wound after surgery is associated with a considerable increase in the rate of protein synthesis. We have investigated whether this increase in protein synthesis is affected by chronic undernutrition, and whether this causes a delay in wound healing.

2. A group of rats was fed 58% of the voluntary food intake of a matched control group. After 7 days half the rats in each group underwent abdominal surgery. Forty-eight hours later all the rats were killed and muscle protein synthesis rate was measured by the flooding dose technique.

3. In a second experiment using the same dietary regimen rats were placed in metabolic cages after surgery and killed 7 days later. In addition to measurements of muscle protein synthesis, wound breaking strength was measured with a tensiometer and collagen content was also measured at the wound site.

4. Dietary restriction caused a loss of body weight, a decrease in nitrogen balance and a deficit in muscle protein mass. It also caused a decrease in protein synthesis rate in gastrocnemius muscle and in parts of the abdominal muscle distant from the site of the wound. However, it had no effect on the rate of muscle protein synthesis at the site of the wound either 2 or 7 days after surgery. The tensile strength and the collagen content of the wound were also unaffected by food restriction.

5. It is concluded that the wound healing process is uniquely protected from the effects of moderate undernutrition such as might be experienced by a chronically ill patient.
Expression and Regulation of Glycosyltransferases for N-Glycosyl Oligosaccharides in Fresh Human Surgical and Murine Tissues and Cultured Cell Lines
Authors: Li M. , Andersen V. , Lance P.
Published: August 2015

1. Mammalian membrane and serum proteins are glycosylated by the addition of heterogeneous N-linked oligosaccharides. It has been widely speculated that oligosaccharide diversity is achieved by corresponding heterogeneity of expression of the glycosyltransferases that are responsible for oligosaccharide synthesis.

2. We surveyed mRNA levels of three sequentially acting glycosyltransferases, N-acetylglucosaminyltransferase I, β1,4-galactosyltransferase and α2,6-sialyltransferase, in 11 human tissues and confirmed the expected variations.

3. The size heterogeneity of α2,6-sialyltransferase transcripts reported in rat tissues was evident neither in the human tissue survey nor in a panel of murine RNAs. Tissue distributions of alternative terminal sialyltransferases, α2,6-sialyltransferase and α2,3-sialyltransferase, were distinct.

4. Relative glycosyltransferase mRNA levels in four transformed human cell lines cultured in vitro did not fully reflect levels in the corresponding human tissues.

5. Expression of α2,6-sialyltransferase mRNA was approximately 2.6-fold greater in adenocarcinomatous than in normal human colon, and β1,4-galactosyltransferase expression was approximately 1.8-fold greater in normal than in adenocarcinomatous colon.

6. n-Butyrate (0.003–0.005 mol/l), a short-chain fatty acid that is produced by colonic bacterial fermentation, caused approximately 80% inhibition of α2,6-sialyltransferase, approximately 2.5-fold induction of β1,4-galactosyltransferase and approximately 6-fold induction of N-acetylglucosaminyltransferase mRNAs in T84 (colonic) cells. The effects on α2,6-sialyltransferase and β1,4-galactosyltransferase were near maximal by 6 h, but induction of N-acetylglucosaminyltransferase was fully apparent only after exposure for 24 h.
Interleukin-6 Induces Proteolysis by Activating Intracellular Proteases (Cathepsins B and L, Proteasome) in C2C12 Myotubes
Authors: Ebisui Chikara , Tsujinaka Toshimasa , Morimoto Takashi , Kan Kazuomi , Iijima Shouhei , Yano Masahiko , Kominami Eiki , Tanaka Keiji , Monden Morito
Published: August 2015

1. A cell culture system of C2C12 myotubes was established as a model of the muscle. With the aid of this model, the half-lives of intracellular proteins as well as the activities and mRNA levels of proteasomes (26S and 20S) and cathepsins (B, L, and H) were examined in the presence of various amounts of cytokines.

2. It was found that 100 units/ml recombinant human interleukin-6 somewhat shortened the half-life of long-lived proteins to 23.79 ± 1.55 h (control: 25.60 ± 1.87 h). When 1% fetal bovine serum contained in the culture medium was replaced by 0.5 mg/ml bovine serum albumin, interleukin-6 was more effective since 10 units/ml of interleukin-6 shortened the half-life to 19.09 ± 2.87 h (control: 22.26 ± 321 h). Interleukin-6 (100 units/ml) increased the activity of 26S proteasome by 31.5%, of cathepsin B by 53.5% and of cathepsin B + L by 21.3%. These increases occurred in association with an increase in their transcription.

3. On the other hand, 1000 units/ml of recombinant human tumour necrosis factor α prolonged the half-life of long-lived proteins while reducing the protease activities of 20S proteasome (−27.1%), cathepsins B (−64.6%) and B + L (−54.9%).

4. These results suggest that interleukin-6 induces degradation of long-lived intracellular proteins by activating both the non-lysosomal (proteasomes) and lysosomal (cathepsins) proteolytic pathways. It is therefore concluded that interleukin-6 is a candidate for a proteolysis-inducing factor in myotubes and may play an important role in the progression of muscle degradation in systemic inflammatory responses induced by sepsis or severe injury.
Effects of Different Lipoproteins on the Proliferative Response of Interleukin-2-Activated T Lymphocytes and Large Granular Lymphocytes
Authors: De Sanctis Juan B. , Blanca Isaac , Bianco Nicholas E.
Published: August 2015

1. T lymphocytes and large granular lymphocytes internalized chylomicrons, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and acetyl modified low-density lipoprotein through different receptors as assessed by flow cytometry. The observed internalization ranged from 8% to 20%.

2. All lipoproteins induced proliferative responses in T lymphocytes and large granular lymphocytes at optimum concentrations (40 μg of protein/ml for all lipoproteins except high-density lipoprotein). Chylomicrons, very low-density lipoprotein and low-density lipoprotein increased T-lymphocyte proliferative response by fourfold while inducing respectively a seven-, nine- and sevenfold increment in large granular lymphocytes. Similarly, high-density lipoprotein and acetyl modified low-density lipoprotein respectively induced a nine- and sevenfold increment in T cells and a 17- and eightfold increment in large granular lymphocyte proliferative response.

3. Both cell types internalized more lipoprotein when they were stimulated with interleukin 2. Chylomicrons and low-density lipoprotein internalization was increased threefold and very low-density lipoprotein internalization twofold, while high-density lipoprotein internalization was unchanged in both cell types. Acetyl modified low-density lipoprotein internalization was fourfold higher in large granular lymphocytes only.

4. The proliferative response of interleukin-2 stimulated cells was different from that of unstimulated cells. Chylomicrons and very low-density lipoprotein induced a sixfold increment in T-cell proliferative response but only a fourfold increment in large granular lymphocytes. Low-density lipoprotein and acetyl modified low-density lipoprotein induced respectively a sevenfold and eightfold increment in T cells and a eightfold and threefold increment in large granular lymphocyte proliferative response. Highdensity lipoprotein did not affect T-lymphocyte proliferative response while inducing a twofold increase in large granular lymphocytes.

5. Lipoproteins are important in the proliferative response of unstimulated and interleukin-2-stimulated cells.
On the Quantification of Heart Rate Changes in Autonomic Function Tests: Relations between Measures in Beats per Minute, Seconds and Dimensionless Ratios
Authors: Faes Theo J. C. , De Neeling Nico N. D. , Kingma Rene , TenVoorde Ben J. , Karemaker John M.
Published: August 2015

1. Disorders of the autonomic nervous system are frequently diagnosed by measuring heart rate changes in response to deep-breathing and lying-to-standing manoeuvres. The heart rate changes in these manoeuvres are quantified in measures using various units, like beats per minute, seconds and dimensionless ratios.

2. In the present study we mathematically derived relationships between the measures which quantify heart rate changes in beats per minute, seconds and dimensionless ratios. The theoretical outcomes were experimentally confirmed by the results of the deep-breathing and the lying-to-standing test in 525 healthy and diabetic subjects. The measures were found to be non-equivalent, because the mean RR interval duration influenced the measures in different ways.

3. It is argued that measures in seconds are preferable to measures in beats per minute or ratios, because the physiological interpretation of this measure is easier, and the sensitivity of measures in seconds is expected to be greater.

4. Finally, we recommend that measures of heart rate variation in the deep-breathing and lying-to-standing manoeuvre are accompanied by information on the mean RR interval duration or mean heart rate to allow correct interpretation of the measures.
Calf Muscle Mitochondrial and Glycogenolytic Atp Synthesis in Patients with Claudication Due to Peripheral Vascular Disease Analysed Using 31P Magnetic Resonance Spectroscopy
Authors: Kemp G. J. , Hands L. J. , Ramaswami G. , Taylor D. J. , Nicolaides A. , Amato A. , Radda G. K.
Published: August 2015

1. We set out to define abnormalities of oxidative ATP synthesis, cellular proton efflux and the efficiency of ATP usage in gastrocnemius muscle of patients with claudication due to peripheral vascular disease, using data obtained by 31P magnetic resonance spectroscopy during aerobic exercise and recovery.

2. Eleven patients with moderate claudication were studied and results were compared with 25 age-matched control subjects. Changes in pH and phosphocreatine concentration during recovery were used to calculate the maximum rate of oxidative ATP synthesis (Qmax.) and the capacity of net proton efflux. Changes in pH and phosphocreatine concentration were used to estimate rates of non-oxidative and (indirectly) oxidative ATP synthesis throughout exercise, taking account of abnormalities in proton efflux during exercise.

3. In patients with claudication, slow post-exercise phosphocreatine recovery showed a 42 ± 9% decrease in Qmax., and the slow ADP recovery was consistent with this. pH recovery was slow, showing a 77 ± 9% decrease in the capacity for proton efflux. Both abnormalities are compatible with a substantial reduction in muscle blood flow.

4. During exercise, increased phosphocreatine depletion and intracellular acidification were a consequence of impaired oxidative ATP synthesis and the consequent increase in non-oxidative ATP synthesis, compounded by reduced proton efflux. The acidification prevented an increase in ADP concentration which could otherwise partially compensate for the oxidative defect. All these abnormalities are compatible with a reduced muscle blood flow.

5. In addition, initial-exercise changes in pH and phosphocreatine concentration implied a 44 ± 5% reduction in ‘effective muscle mass’, necessitating an ATP turnover (per litre of muscle water) twice as high for given power output as in control muscle. Some of this is probably due to a localized loss of muscle fibres, but the rest appears to reflect reduced metabolic efficiency of the muscle. This is not a direct consequence of reduced blood flow, and may be related to change in muscle fibre type.
Effect of Ozone Exposure on Maximal Airway Narrowing in Non-Asthmatic and Asthmatic Subjects
Authors: Hiltermann T. J. N. , Stolk J. , Hiemstra P. S. , Fokkens P. H. B. , Rombout P. J. A. , Sont J. K. , Sterk P. J. , Dijkman J. H.
Published: August 2015

1. Ozone is a major constituent of air pollution in the summer. Epidemiological studies have demonstrated that there is an increase in hospital admissions for respiratory diseases 1 day after peak levels of ambient ozone. This may be due to an increase in the responsiveness of the airways to bronchoconstrictor stimuli.

2. In the present study we therefore studied the effect of a controlled exposure to ozone on the maximal degree of airway narrowing to a non-specific bronchoconstrictor, methacholine, 12 h after exposure. Both non-asthmatic and mild-asthmatic volunteers were exposed to ozone.

3. The study had a single blind design. Experimental exposures were to filtered air, 0.40 ppm ozone and filtered air respectively, at 1-week intervals. The duration of each exposure was 2 h with alternating periods of 15 min rest and exercise. At 12 h after exposure, methacholine inhalation challenge tests and sputum induction were performed.

4. Twelve hours after exposure to ozone there was a significant increase in the maximal degree of airway narrowing to methacholine (P < 0.02) compared with exposure to air, in non-asthmatic as well as asthmatic subjects. These physiological changes were accompanied by a significant rise in the percentage of neutrophils in induced sputum (P < 0.02). All changes had returned to baseline values 1 week after exposure to ozone.

5. Exposure to ozone causes a transient increase in the maximal degree of airway narrowing to methacholine in both non-asthmatic and asthmatic subjects. These laboratory results, obtained using relatively high ozone exposure in carefully selected subjects, might provide an explanation for the temporal relationship between ambient ozone levels and hospital admissions for asthma.
Metabolic Acidosis Does Not Contribute to Chronic Renal Injury in the Rat
Authors: Throssell D. , Brown J. , Harris K. P. G. , Walls J.
Published: August 2015

1. Metabolic acidosis invariably accompanies chronic renal failure, and short periods of metabolic acidosis cause renal growth and proteinuria in normal rats. Rates of ammoniagenesis are increased in chronic renal failure, and it has been suggested that this contributes to disease progression. This study assessed (i) whether prolonged acidosis causes chronic renal injury in the normal kidney and (ii) whether abrogation of acidosis slows disease progression in the remnant kidney.

2. Metabolic acidosis was induced in normal rats by dietary hydrochloric acid. Urinary excretion of total protein, lysozyme and albumin increased, peaking at week 8 but returning to baseline by week 14. At killing after 14 weeks, kidney weights, glomerular filtration rates and serum creatinine were the same in both groups, but kidney/body weight and kidney/heart weight ratios were greater in the acidotic group. All kidneys were normal by light microscopy.

3. Rats subjected to five-sixths nephrectomy were given sufficient dietary bicarbonate to abolish uraemic acidosis, and their outcome was compared with that of non-alkalinized remnants (controls). Proteinuria, glomerular filtration rates, blood pressure, histological injury and time to the development of terminal uraemia were no better in bicarbonate-supplemented animals than in controls.

4. These data demonstrate that metabolic acidosis neither causes nor exacerbates chronic renal injury. We conclude that the treatment of uraemic acidosis is unlikely to influence disease progression in patients with chronic renal failure.
Seasonal Variation in Blood Pressure in Normotensive Women Studied by Home Measurements
Authors: Imai Yutaka , Munakata Masanori , Tsuji Ichiro , Ohkubo Takayoshi , Satoh Hiroshi , Yoshino Hiroshi , Watanabe Noriko , Nishiyama Akimitsu , Onodera Noriko , Kato Junko , Sekino Makoto , Aihara Akiko , Kasai Yutaka , Abe Keishi
Published: August 2015

1. The factors influencing the seasonal variation in blood pressure measured at home in normotensive women were examined.

2. Sixteen female subjects (56.3 ± 7.9 years old, mean ± SD) measured their blood pressure and pulse rate at home each morning for more than 20 times per month for at least 1.5 years. Blood pressure and body weight were also determined in the office once or twice a month in that period. Monthly means of outdoor and indoor temperatures and daytime length were obtained from the Meteorological Observatory. The single cosinor method was used to evaluate circannual rhythm.

3. We observed a biphasic seasonal variation in self-recorded blood pressure measured at home, environmental temperature and daytime length but found no apparent seasonal variation in body weight and blood pressure measured in the office. The lowest levels of systolic and diastolic blood pressure measured at home were observed in July. The longest daytime length was recorded in June, while the highest outdoor temperature and indoor temperature were recorded in August, indicating that the longest daytime length preceded and the highest environmental temperature lagged behind the lowest level of blood pressure. The shortest daytime length is in December. The lowest outdoor and indoor temperature were observed in January, while the highest levels of self-recorded systolic blood pressure and diastolic blood pressure were in January and December, respectively. Half-amplitudes of self-recorded systolic and diastolic blood pressure were 2.6 ± 1.0 mmHg and 2.0 ± 0.8 mmHg, respectively.

4. These findings indicate the importance of a seasonal effect, i.e. daytime length and the environmental temperature, on the blood pressure of individuals.
Renal Effects of Angiotensin I-Receptor Blockade and Angiotensin Convertase Inhibition in Man
Authors: Schmitt Francois , Natov Svetlozar , Martinez Frank , Lacour Bernard , Hannedouche Thierry P.
Published: August 2015

1. The objective was to compare two means of inhibition of the renin—angiotensin system [angiotensin-converting enzyme inhibition and selective antagonism of angiotensin II subtype 1 (AT1) receptor] on renal function in 10 healthy normotensive volunteers on a normal sodium diet. Since mechanisms of action may differ between both drugs, a synergistic action was further studied by combining the two drugs.

2. The design was a double-blind randomized acute administration of either placebo or a single oral dose of enalapril, 20 mg, followed in each case by administration of the AT1 selective antagonist losartan potassium, 50 mg orally.

3. The methods included measurements of hormones (plasma renin activity, plasma aldosterone), blood pressure and renal function from 45 to 135 min after administration of placebo or enalapril, and from 45 to 135 min after losartan and placebo or losartan and enalapril. Renal function was studied using clearance of sodium, lithium, uric acid, inulin and para-aminohippuric acid. To examine further the determinants of glomerular filtration at the microcirculation level, fractional clearance of neutral dextran was determined and sieving curves were applied on a hydrodynamic model of ultrafiltration.

4. Losartan did not change plasma renin activity, blood pressure or glomerular filtration rate, but increased significantly renal plasma flow and urinary excretion of sodium and uric acid. Enalapril increased plasma renin activity and renal plasma flow, and decreased blood pressure without natriuretic, lithiuretic or uricosuric effects. The renal vasodilatation was potentiated when losartan and enalapril were combined, despite a further rise in plasma renin. In contrast to enalapril, losartan either alone or in combination with enalapril significantly depressed fractional clearances of dextran of small radii (34–42 Å). These changes in fractional clearances of dextran were presumably related to the rise in glomerular plasma flow since the other major determinants of filtration, i.e. transcapillary glomerular pressure gradient, ultrafiltration coefficient and membrane property, were computed as unchanged by either losartan, enalapril or a combination of both.

5. In conclusion, these findings suggest that in normal sodium-repleted man the renal, hormonal and blood pressure effects of AT1 antagonism and angiotensin-converting enzyme inhibition are not strictly similar and could be synergistic.
Salvage of Exogenous Urea Nitrogen Enhances Nitrogen Balance in Normal Men Consuming Marginally Inadequate Protein Diets
Authors: Meakins Tracey S. , Jackson Alan A.
Published: August 2015

1. Urea kinetics were measured in six healthy men using prime/intermittent oral doses of [15N15N] urea, after five days consuming one of four diets which varied in their nitrogen content: a reference diet (REF, 70 g of protein and 11.2 g of N); a low-protein diet (LP, 30 g of protein and 4.8 g of N); a low-protein diet with 6.9 g of urea added (LP-U1, 30 g of protein and 8 g of N); a low-protein diet with 13.7 g of urea added (LP-U2, 30 g of protein and 11.2 g of N).

2. Apparent nitrogen balance on the REF diet was significantly better than on the LP or the LP-U1 diets. The addition of the higher level of urea in the LP-U2 diet enhanced apparent nitrogen balance compared with the LP or LP-U1 diets, and was not different to apparent nitrogen balance on the REF diet.

3. On the LP, LP-U1 and LP-U2 diets, the rate of endogenous urea production was not different, and was about 60% of that on the REF diet, a statistically significant difference. The addition of a dietary supplement of urea increased the rate of urea appearance in the urea pool in direct relation to the dose of urea taken. There was no difference in the rate of appearance between the REF and LP-U2 diets, for both of which the rate of appearance was significantly greater than on the LP diet.

4. The excretion of urea in urine on the LP diet was 62% of that on the REF diet, a significant difference. There was no significant difference in the rate of urea excretion between the REF, LP-U1 and LP-U2 diets.

5. The rate of urea hydrolysis by the colonic microflora on the REF diet was more than twice that on the LP or LP-U1 diets. Supplementation with urea at the higher level, LP-U2, significantly increased hydrolysis to the same level as on the REF diet. Most of the nitrogen derived from urea hydrolysis was retained in the metabolic pool (>80%), with no difference in the rate of retention between the REF and LP-U2 diets, both greater than the LP or LP-U1 diets.

6. The dietary supplements of urea increased the size of the body urea pool significantly. Renal clearance of urea was highest on the REF diet and decreased 13–29% on the low-protein diets. Bowel clearance was highest on the REF diet and decreased 46–55% on the low-protein diets. Neither urinary excretion of urea nor urea hydrolysis in the bowel were related simply to the concentration of urea in blood. Urea hydrolysis related most closely to the rate of appearance of urea in the urea pool.

7. The salvage of urea nitrogen was increased on the highest level of supplementation, but the overall sensitivity of the system was low, suggesting that other factors might be limiting for effective urea hydrolysis and the salvage of urea nitrogen.
Antioxidant Status and Lipid Peroxidation in Type II Diabetes Mellitus with and without Complications
Authors: Sundaram Ranjini K. , Bhaskar Anusha , Vijayalingam Selvamani , Viswanathan Moopil , Mohan Rema , Shanmugasundaram Kalathinkal R.
Published: August 2015

1. This study was conducted on 467 cases of non-insulin-dependent diabetes mellitus and 180 healthy controls. Lipid peroxidation products in plasma and erythrocytes were assayed as thiobarbituric acid reactive substances, along with the erythrocyte antioxidant enzymes, namely superoxide dismutase, catalase and glutathione peroxidase. In addition, scavenger vitamins A, C and E and reduced glutathione levels in blood were also measured.

2. Lipid peroxidation was significantly raised within the first 2 years of diagnosis, and superoxide dismutase, catalase, reduced glutathione and vitamins C and E were significantly lowered.

3. These changes were correlated with the duration of the disease and were of a higher magnitude with the development of complications.

4. The results suggest that the antioxidant deficiency and excessive peroxide-mediated damage may appear early on in non-insulin-dependent diabetes mellitus, before the development of secondary complications.