bluuebunny/crossref_metadata_2025 huggingface dataset:
High resolution proton nuclear magnetic resonance studies of human cerebrospinal fluid
Authors: Bell Jimmy D. , Brown Judith C. C. , Sadler Peter J. , MacLeod Andrew F. , Sönksen Peter H. , Hughes Robin D. , Williams Roger
Published: August 2015

1. One- and two-dimensional (correlated shift spectroscopy) high resolution proton n.m.r. spectra of human cerebrospinal fluid (CSF) are reported. The merits of water suppression by freeze drying or irradiation, and spectral simplification by spin-echo methods, are discussed.

2. Well-resolved resonances for a range of low molecular weight metabolites such as lactate, 3-d-hydroxybutyrate, alanine, acetate, citrate, glucose, valine and formate were observed. Resonances for glutamine were observed only from freeze dried samples. Concentrations determined by n.m.r. were in reasonable agreement with those from conventional methods.

3. The n.m.r. spectra of CSF were related to the clinical conditions of the subjects. No resonances for citrate were present in spectra of CSF from subjects (three infants) with bacterial meningitis; high lactate and lowered glucose levels were observed. Strong resonances for glucose and glycine were observed for mildly diabetic subjects. Both the aromatic and the aliphatic regions of the CSF spectra from subjects suffering from liver failure contained distinctive features characteristic for hepatic coma: intense resonances for lactate, alanine, valine, methionine, tyrosine, phenylalanine and histidine. In some cases guanine was also present, which does not appear to have been reported previously. The two-dimensional spectrum suggested the presence of abnormally high levels of a number of endogenous metabolites. Such assignments were not possible using one-dimensional spectra alone because of signal overlap.
Renal and cardiovascular effects of caffeine: A dose–response study
Authors: Passmore A. P. , Kondowe G. B. , Johnston G. D.
Published: August 2015

1. The effects of increasing oral doses of caffeine (45, 90, 180 and 360 mg) on effective renal plasma flow (ERPF), plasma renin activity (PRA), serum electrolytes, plasma noradrenaline, blood pressure and heart rate were studied in eight healthy male volunteers.

2. Urine volume was increased by 360 mg of caffeine only. At caffeine doses greater than 90 mg urinary sodium excretion was significantly increased. There were no changes in ERPF.

3. Serum potassium was significantly reduced by 360 mg of caffeine.

4. Caffeine increased systolic pressure in a dose related manner. Diastolic pressure was also increased, but not in relation to dose. A 360 mg dose of caffeine produced a late increase in heart rate. These changes were not associated with any alterations in PRA or in plasma noradrenaline.
Chlorpropamide alcohol flushing: A normal response?
Authors: Hoskins P. J. , Wiles P. G. , Volkmann H. P. , Pyke D. A.
Published: August 2015

1. The relationship between chlorpropamide alcohol flushing and non-insulin dependent diabetes remains uncertain. It is known, however, that the frequency of facial flushing with alcohol and the temperature response depend upon both the plasma level of chlorpropamide and the starting facial temperature [10].

2. We tested 23 young adult non-diabetic subjects with 8 g of ethanol after a dose of chlorpropamide 250 mg twice daily for 2 days or a placebo, in a double blind, cross-over manner. Previously, nine other subjects had participated in a pilot study to assess the safety of the chlorpropamide dose and to ensure that adequate plasma chlorpropamide levels were achieved.

3. No subject was negative for chlorpropamide alcohol flushing, as defined by the following criteria: (1) facial temperature rise of 35% or more of maximum possible rise, (2) observer assessment or (3) subject assessment. In 26 of the total 32 subjects, all three criteria were fulfilled.

4. Thus, among young, healthy non-diabetic adults chlorpropamide alcohol flushing would appear to be a normal phenomenon.
Water depletion, not oral sodium loading, increases levels of sodium, potassium-dependent adenosine triphosphatase inhibitors in rat plasma
Authors: Wellard R. Mark , Adam William R.
Published: August 2015

1. In order to define a physiological role for circulating inhibitors of sodium, potassium-dependent adenosine triphosphatase (Na+,K+-ATPase), plasma was obtained from control, water deplete, water repleted, sodium deplete and sodium loaded rats. The effect of this plasma on Na+,K+-ATPase activity, and its transport equivalent 86Rb uptake, was measured in separated guinea pig renal cortical tubules.

2. Plasma from water deplete rats had a raised plasma osmolality and sodium concentration and a significant inhibitory effect on Na+,K+-ATPase (14%) and 86Rb uptake (24%) compared with control or water repleted rats.

3. Inhibition of Na+,K+-ATPase and 86Rb transport was not seen with plasma from rats after dietary sodium loading (urine sodium 5.2 ± 0.9 mmol/day) compared with low sodium diet controls (urine sodium 0.41 ± 0.08 mmol/day).

4. Des-amino arginine vasopressin in vivo produced no inhibition of Na+,K+-ATPase or Rb transport.

5. These studies suggest, that in terms of common homoeostatic insults, circulating inhibitors of Na+,K+-ATPase are more responsive to water depletion than to oral sodium loading. The inhibitors may fulfil a physiological role in increasing sodium excretion to maintain osmolality after dehydration.
Comparison of the natriuretic response to atriopeptin III and loop diuretic in the isolated perfused rat kidney
Authors: Itabashi Akira , Chan Laurence , Shapiro Joseph I. , Cheung Cynthia , Schrier Robert W.
Published: August 2015

1. Isolated rat kidneys were perfused at a constant perfusion pressure of 90 mmHg to study the natriuretic effects of atriopeptin III (AP-III) and to compare these effects with those of frusemide. AP-III (1 μg) or frusemide (1 mg) were added to the perfusate (100 ml) after two 15 min control collection periods.

2. Compared with the control group, AP-III and frusemide increased urinary sodium excretion (UNaV, 5.6 ± 1.1 and 4.6 ± 0.6 vs control 1.8 ± 0.3 μmol min−1 g−1, mean ± sem, P < 0.01 and P < 0.05, respectively), fractional sodium excretion (FENa, 4.8 ± 1.1 and 6.7 ± 0.8 vs control 2.0 ± 0.2%, P < 0.05 and P < 0.001, respectively) and potassium excretion (UKV, 3.2 ± 0.3 and 3.0 ± 0.3 vs control 1.5 ± 0.3 μmol min−1 g−1, both P < 0.01). However, AP-III, but not frusemide, increased glomerular filtration rate (820 ± 55 vs 590 ± 24 μl min−1 g−1, P < 0.01) and urine flow rate (V 97.5 ± 8.0 vs 44.1 ± 5.2 μl min−1 g−1, P < 0.001). Calculated distal delivery of sodium (CNa + CH2O, 76.6 ± 6.8 vs 30.7 ± 3.8 μl min−1 g−1, P < 0.005) as well as fractional distal delivery of sodium [(CNa + CH2O)/CIn, 9.4 ± 0.9 vs 5.1 ± 0.6%, P < 0.01] were increased by AP-III, but not frusemide. Fractional distal reabsorption of sodium [CH2O/(CNa + CH2O), 51.9 ± 6.5 vs 59.9 ± 2.7%, NS] was not affected by AP-III but was significantly reduced by frusemide (7.4 ± 3.0%, P < 0.001).

3. The natriuretic effects of the combination of AP-III and frusemide were additive even though the distal delivery was no greater than with AP-III alone. These data indicate that AP-III has a unique natriuretic effect different from frusemide, and that the main site of natriuretic action by AP-III is proximal to the ascending loop of Henle. Because of different nephron sites, the effects of AP-III and frusemide are additive, a finding of potential clinical importance.
Intracisternal administration of pergolide, a dopamine receptor agonist, triggers the release of an inhibitor of ouabain-sensitive sodium, potassium-dependent adenosine triphosphatase and enhances vascular reactivity in anaesthetized dogs
Authors: Jandhyala B. S. , Lokhandwala M. F. , Kivlighn S. D. , Ansari A. F. , De Feo M. L.
Published: August 2015

1. The present studies were undertaken to investigate whether intracisternal administration of pergolide, a dopamine-2 receptor agaonist, triggers the release of an inhibitor of ouabain-sensitive sodium, potassium-dependent adenosine triphosphatase into the circulation and whether such an effect is associated with increases in vascular reactivity in pentobarbital anaesthetized dogs. In different groups of animals, Na+-pump activity was estimated in the plantar and dorsal branches of the lateral saphenous veins by using the 86Rb-uptake method; vascular responsiveness to noradrenaline was studied in the denervated perfused hindlimb.

2. Na+-pump activity was significantly depressed in those blood vessels which were collected at 90 min after central administration of pergolide (12.5 μg/kg intracisternally). In perfused hindlimb studies, vascular responses to noradrenaline were significantly enhanced between 60 and 90 min after pergolide. Since the Na+-pump activity was evaluated in the hindlimb veins, and vascular reactivity was studied on the arterial circulation, the data suggest that the changes in both these variables could have been caused by a circulating substance.

3. In separate series of experiments, plasma samples were collected before and after intracisternal administration of pergolide. The Na+-pump activity was significantly inhibited in the segments of lateral saphenous veins which were incubated in the fresh plasma and/or boiled plasma supernatants, indicating that a heat stable pump inhibitor(s) is released into the circulation after pergolide administration.

4. Effects of pergolide demonstrated in the present study are qualitatively similar to those reported to occur after acute blood volume expansion. Hence it is proposed that central dopaminergic mechanisms may play an intermediary role in the release of the Na+-pump inhibitor(s). However, a non-specific action of pergolide cannot be ruled out at the present time.
Evaluation of mannitol, lactulose and 51Cr-labelled ethylenediaminetetra-acetate as markers of intestinal permeability in man
Authors: Elia M. , Behrens R. , Northrop C. , Wraight P. , Neale G.
Published: August 2015

1. Factors affecting the intestinal uptake and urinary excretion of mannitol, lactulose and 51Cr-labelled ethylenediaminetetra-acetate (51Cr-EDTA), have been investigated in normal subjects and three patients with ileostomy.

2. The distribution volume of markers within the body, the rate of disappearance from plasma and renal clearance were assessed after an intravenous injection of a mixture of mannitol (2 g), [14C]mannitol (10 μCi), lactulose (0.1 g) and 51Cr-EDTA (5 μCi).

3. The urinary recovery of all the intravenously administered markers was close to 100%. Distribution volumes and patterns of excretion were virtually identical. Oxidation of intravenously administered mannitol accounted for only about 1% of the dose.

4. The passage of an orally administered mixture of markers was traced through the intestine and into urine. Transit time through the gastrointestinal tract was measured by the breath hydrogen method and by radionuclide scanning.

5. The passage of markers from mouth to the large bowel was essentially complete by 3.5 h. In some subjects the marker appeared in the large bowel as early as 30–40 min but in others it took three times as long.

6. After an oral dose the urinary excretion of mannitol fell progressively from 2 to 6 h, whereas the excretion of lactulose and 51Cr-EDTA increased slightly. As a consequence the lactulose/mannitol and 51Cr-EDTA/mannitol ratios in urine collected between 0 and 2 h were more than twofold higher than in urine collected between 4 and 6 h (P < 0.001). After 6 h, the urinary excretion of mannitol and lactulose declined rapidly in all subjects, and was similar to the pattern of excretion of 51Cr-EDTA in subjects with an ileostomy. In contrast, in normal subjects, the excretion of 51Cr-EDTA did not decline rapidly but continued for 24–48 h.

7. Differences in the excretion of mannitol, lactulose and 51Cr-EDTA after oral dosing is due to differences in the temporal pattern of absorption of these markers and not to differences in their distribution volume, oxidation or their clearance by the kidney.

8. The data suggest that the uptake of lactulose by the small intestine persists for longer than the uptake of mannitol, and show that 51Cr-EDTA is readily absorbed in the colon. This study indicates factors which must be considered in the design and interpretation of tests of small intestinal permeability.
Evidence for large intestinal control of potassium homoeostasis in uraemic patients undergoing long-term dialysis
Authors: Sandle G. I. , Gaiger E. , Tapster S. , Goodship T. H. J.
Published: August 2015

1. The role of the large intestine in the maintenance of K+ balance in uraemic patients established on long-term dialysis was studied with a rectal dialysis technique in 14 normal subjects, ten normokalaemic patients undergoing chronic ambulatory peritoneal dialysis (CAPD), and seven patients undergoing haemodialysis. Dietary K+ intakes in the normal subjects, CAPD patients and haemodialysis patients were 80–100 mmol/24 h, 70–80 mmol/24 h and 60–70 mmol/24 h, respectively.

2. At an initial intraluminal K+ concentration of 45 mmol/l, rectal K+ secretion in the CAPD patients (2.4 ± 0.4 μmol h−-1cm−-2) was greater than in normal subjects (1.2 ± 0.2 μmol h−-1 cm−-2, P < 0.02). Under similar conditions, rectal K+ secretion was also greater in the haemodialysis patients than in normal subjects, both pre-dialysis (3.7 ± 0.4 μmol h−-1 cm−-2, P < 0.001) and post-dialysis (2.4 ± 0.5 μmol h−-1 cm−-2, P < 0.05), even though haemodialysis decreased plasma K+ concentration from 5.3 ± 0.1 mmol/l to 3.5 ± 0.2 mmol/l (P < 0.001).

3. There were no significant differences in rectal Na+ absorption, rectal potential difference, plasma aldosterone concentration, or total body K+ content (measured by whole-body counting of 40K), between the normal subjects and either the CAPD or the haemodialysis patients.

4. These results indicate that K+ homoeostasis is maintained in uraemic patients undergoing long-term dialysis by a combination of K+ losses during dialysis, and enhanced large intestinal K+ excretion. The role of the large intestine appears to be particularly important at higher dietary K+ intakes, and the K+ secretory process is sensitive to changes in plasma K+ concentration.
Decreased systemic formation of prostaglandin E and prostacyclin, and unchanged thromboxane formation, in alcoholics during withdrawal as estimated from metabolites in urine
Authors: Förstermann Ulrich , Feuerstein Thomas J.
Published: August 2015

1. The rates of secretion into the circulation of prostaglandin E, prostacyclin, and thromboxane A2 were estimated in male alcoholics on the third day of withdrawal and in control subjects by measuring appropriate metabolites in urine.

2. Urinary levels of tetranor-5,11-diketo-7α-hydroxyprostane-1,16-dioic acid (the major urinary metabolite of prostaglandins E1 and E2), of 2,3-dinor-6-ketoprostaglandin F1α (the major urinary metabolite of prostacyclin) and of 6-keto-prostaglandin F1α (the stable hydrolysis product of prostacyclin) were significantly different from the normal subjects in the alcoholic group. In contrast, 2,3-dinor-thromboxane B2 (the major urinary metabolite of thromboxane A2) and thromboxane B2 (the stable hydrolysis product of thromboxane A2) were not significantly different between the groups.

3. These data suggest that the ratio of the vasodilator prostanoids prostaglandin E and prostacyclin and the vasoconstrictor prostanoid thromboxane A2 is lower than in normal subjects, in alcoholics during withdrawal. This may be one causal factor for the higher incidence of hypertension observed in withdrawing alcoholics compared with control subjects.
Adaptation to exercise-induced muscle damage
Authors: Clarkson Priscilla M. , Byrnes William C. , Gillisson Eva , Harper Elizabeth
Published: August 2015

1. Serum creatine kinase (CK) and muscle soreness, common indicators of muscle damage, were assessed in 16 subjects after performance of two bouts of eccentric exercise spaced 7 days apart. The purpose was (1) to examine rapid muscle adaptation when the ipsilateral limb was exercised on the second bout and (2) to investigate possible central adaptations when the contralateral limb was exercised on the second bout.

2. The LSL group (n = 7) and the LOL group (n = 9) performed the exercise with the ipsilateral and the contralateral limb, respectively. Careful attention was paid to stabilization of the subject so that the contralateral limb was not active in isometric stabilization.

3. For the LSL group, a lower CK and soreness response was found on bout 2 compared with bout 1. For the LOL group, no significant difference in CK response and soreness was found between bout 1 and bout 2.

4. No repeat bout effect was found when the contralateral limb was exercised; therefore central adaptation from performance of the first exercise was minimal. Because a lower repeated bout effect was found after bout 2 using the ipsilateral limb, it was concluded that an experimental design using ipsilateral muscle groups should provide a good model to study rapid muscle adaptation to exercise damage.
Impaired insulin-mediated erythrocyte magnesium accumulation in essential hypertension
Authors: Paolisso Giuseppe , Passariello Nicola , Sgambato Saverio , Torecca Roberto , Buoninconti Raffaello , Varricchio Michele , D'Onofrio Felice
Published: August 2015

1. This study was designed to investigate variations in erythrocyte magnesium in the presence of insulin (0.1 unit/l) in hypertensive subjects.

2. Plasma and erythrocyte magnesium levels were found to be significantly lower in hypertensive than in normotensive subjects.

3. The impaired response to insulin (0.1 units/l) of erythrocytes from hypertensive patients was not reversed by elevated extracellular Mg2+ (3.6 mmol/l).

4. Erythrocytes of hypertensive subjects showed an increased membrane microviscosity compared with normotensive subjects.

5. Lidocaine decreased erythrocyte membrane microviscosity and increased erythrocyte magnesium levels in the presence of insulin.
Familial pseudohyperkalaemia: Inhibition of erythrocyte K+ efflux at 4°C by quinine
Authors: James David R. , Stansbie David
Published: August 2015

1. Mechanisms responsible for increased erythrocyte K+ efflux in vitro have been investigated in a patient with familial pseudohyperkalaemia. Mean net K+ efflux (4°C) was 108 nmol h−1 10−9 erythrocytes, seven times greater than the mean for controls (15.2 nmol h−1 10−9 erythrocytes). Net K+ efflux was not increased at 22°C or 37°C and losses at 4°C were reversed by subsequent incubation at 37°C.

2. Erythrocyte glucose consumption (4°C) was 14 nmol h−1 10−9 erythrocytes, similar to the mean for controls of 16.8 nmol h−1 10−9 erythrocytes. This suggests that the increased net K+ efflux (4°C) was not associated with abnormal energy consumption and was therefore unlikely to be due to an abnormality of the Na+, K+-pump.

3. Incubation of erythrocyte suspensions with ouabain (0.1 mmol/l) or frusemide (1 mmol/l) at 4°C or 37°C resulted in no differences in K+ efflux between patient and controls. Incubation with quinine (2 mmol/l), an inhibitor of the erythrocyte Ca2+-dependent K+ channel, reduced net K+ efflux at 4°C, but the effect persisted in Ca2+-depleted erythrocytes, implying that quinine was acting in a non-specific fashion.

4. Chemical pathologists and clinicians must be aware of this condition if inappropriate treatment of pseudohyperkalaemia is to be avoided.
The kidney and cardiovascular system in obstructive jaundice: Functional and metabolic studies in conscious rats
Authors: Heidenreich Stefan , Brinkema Erich , Martin Andreas , Düsing Rainer , Kipnowski Jochen , Kramer Herbert J.
Published: August 2015

1. The effects of jaundice on renal and circulatory function were investigated in chronic bile duct ligated (CBDL). rats 6 days after surgery. Sham operated (SO) animals served as controls.

2. Body weight was significantly reduced, whereas blood pressure remained unaltered, 6 days after bile duct ligation when serum bilirubin had risen to 169 ± 18 (SEM) as compared with 2.8 ± 0.3 μmol/l in SO rats. When compared with control values before surgery, urinary volume had significantly increased and absolute excretion of sodium, potassium, chloride and phosphate had decreased on day 6 after CBDL. Endogenous creatinine clearance was markedly depressed when compared with SO rats. Whereas fractional excretion of potassium remained unaltered, fractional excretion of sodium and of phosphate was significantly increased.

3. Except for a significant increase in urinary thromboxane B2 (TXB2) excretion in CBDL rats, no significant changes were observed in urinary excretion of prostaglandin (PG) E2, in the synthesis of PGE2, 6-keto-PGF1α and TXB2 by isolated aortic tissue in vitro, nor in renal and cardiac adenosine triphosphatase activities or renal cortical mitochondrial function.

4. The adenosine triphosphate content of kidney cortex and cardiac mitochondrial function were significantly depressed in CBDL rats.

5. The results demonstrate that jaundice in CBDL rats is associated with functional and metabolic disturbances of the kidney and cardiac muscle, which may contribute to the renal and haemodynamic characteristics observed in jaundiced animals and humans.
Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism
Authors: Clements M. R. , Davies M. , Fraser D. R. , Lumb G. A. , Mawer E. Barbara , Adams P. H.
Published: August 2015

1. The elimination half-time of 25-hydroxyvitamin D in plasma was estimated after intravenous injection of the radioactively labelled metabolite in seven patients with primary hyperparathyroidism before and after excision of a parathyroid adenoma.

2. The elimination half-time of 25-hydroxyvitamin D was significantly shortened in primary hyperparathyroidism and reverted towards normal after parathyroidectomy.

3. The increased metabolic clearance of 25-hydroxyvitamin D in primary hyperparathyroidism was accounted for by an increased excretion of vitamin D-derived inactivation products in the faeces.

4. Enhanced hepatic inactivation of 25-hydroxyvitamin D may be important in the development of vitamin D deficiency in primary hyperparathyroidism.
An increase in cerebral benzodiazepine receptors induced by a subacute administration of ammonia, mercaptans and short-chain fatty acids in rats
Authors: Baraldi M. , Zeneroli M. L. , Ventura E. , Vezzelli C.
Published: August 2015

1. In the search to identify peripheral toxins which could be responsible for the supersensitivity of brain benzodiazepine receptors in experimental models of hepatic encephalopathy, [3H]diazepam-binding studies have been performed on brain tissues of normal rats treated with ammonium chloride, dimethyldisulphide and octanoic acid administered alone or in combination.

2. The subacute administration of the three toxins in combination induced a 30% increase in the number of benzodiazepine recognition sites. The administration of these toxins alone or in combination showed that this increase was mainly linked to the synergistic action of dimethyldisulphide or octanoic acid with ammonia, since dimethyldisulphide plus octanoic acid was ineffective.

3. These observations seem to reinforce the suggestion that these three toxins are able to induce neurochemical derangements similar to those described in experimental hepatic encephalopathy.
Relationship between glomerular filtration rate and renal blood flow at different levels of protein-induced hyperfiltration in man
Authors: Rodríguez-Iturbe Bernardo , Herrera Josē , García Rafael
Published: August 2015

1. We studied the relationship between changes in glomerular filtration rate (GFR) determined as inulin clearance (CIn), and changes in renal blood flow (RBF), determined as p-aminohippurate clearance (CPAH), after the ingestion of a large (1.35±sem 0.04 g/kg, n = 9), moderate (1.08±0.03 g/kg, n = 10) or mild (0.55±0.02 g/kg, n = 8) protein load given as a meat meal. Control subjects (n = 10) received a carbohydrate meal.

2. CIn and CPAH increased after a protein meal. Two hours after eating the test meal, GFR levels were (mean ± sem) 160.0±13.8 (P < 0.05), 141 ± 7.69 and 127.8 ±9.07 ml/min in the groups that received a large, moderate and mild protein load, respectively. Peak CIn values after the meal were 211.6 ±sem 14.92 (P < 0.001), 177.5±10.88(P < 0.01)and 129.0±8.72 ml/min after a large, moderate and mild protein load, respectively.

3. At peak GFR levels after the meal, filtration fraction (FF) (CIn × 100/CPAH) increased significantly (P < 0.02) with the large and with the moderate protein load, but not with the mild protein load.

4. There was a significant (P < 0.001) positive relationship between increments of FF and increments of CIn, but not CPAH, whether the values were expressed as post-meal/pre-meal ratios or as absolute changes.

5. We conclude that hyperfiltration induced by a large protein load is associated with increments in GFR which are proportionally larger than the increments in RBF and, therefore, cannot be explained by simple vasodilatation. Factors capable of increasing FF operate in the physiological response to a protein meal.
Is alveolar carbon monoxide an unreliable index of carboxyhaemoglobin changes during smoking in man?
Authors: Guyatt Andrew R. , Kirkham Andrew J. T. , Mariner Derek C. , Cumming Gordon
Published: August 2015

1. We measured alveolar carbon monoxide (CO) after a 20 s breath-holding period and carboxyhaemoglobin both before and after smoking a cigarette on 500 occasions (101 individuals). The two measurements were closely correlated but there was a marked difference in the change or ‘boost’ after smoking one cigarette. The mean relative boosts ([post value—pre value]/[pre + post]/2) for alveolar CO and carboxyhaemoglobin were 7.7% and 20.3%, while negative boosts (fall rather than the expected rise) were seen in 103 of 500 and three of 500 occasions respectively. In 140 studies a third alveolar CO reading taken 5 min later was slightly larger, but the difference was insignificant.

2. In seven subjects where the carboxyhaemoglobin level was raised by breathing a 2% CO gas mixture, the alveolar CO and carboxyhaemglobin boosts were similar (71.7% and 75.2% respectively), and they fell sharply subsequently rather than increasing further as occurred after smoking.

3. We conclude that alveolar CO measurements give a useful estimate of carboxyhaemoglobin level if the subject has not smoked for at least half an hour but that measurements of alveolar CO boost are useless since the act of smoking interferes with alveolar sampling. We postulate that cigarette smoking induces a transient change in pulmonary gas exchange.
Genetic co-segregation of renal haemodynamics and blood pressure in the spontaneously hypertensive rat
Authors: Harrap S. B. , Doyle A. E.
Published: August 2015

1. To determine the relevance of renal circulatory abnormalities found in the immature spontaneously hypertensive rat (SHR) to the genetic hypertensive process, glomerular filtration rate and renal blood flow were measured in conscious F2 rats, derived from crossbreeding SHR and normotensive Wistar–Kyoto rats (WKY), at 4, 11 and 16 weeks of age by determining the renal clearances of 51Cr-ethylenediaminetetra-acetate and 125I-hippuran respectively. Plasma renin activity was measured at 11 and 16 weeks of age.

2. Mean arterial pressure, glomerular filtration rate and renal blood flow increased between 4 and 11 weeks of age. Between 11 and 16 weeks the mean glomerular filtration rate and renal blood flow did not alter, although the mean arterial pressure rose significantly. At 11 weeks of age, during the developmental phase of hypertension, a significant negative correlation between mean arterial pressure and both glomerular filtration rate and renal blood flow was noted. However, by 16 weeks when the manifestations of genetic hypertension were more fully expressed, no correlation between mean arterial pressure and renal blood flow or glomerular filtration rate was observed. Plasma renin activity was negatively correlated with both glomerular filtration rate and renal blood flow, but the relationship was stronger at 11 than at 16 weeks of age.

3. These results suggest that the reduction in renal blood flow and glomerular filtration rate, found in immature SHR, is genetically linked to the hypertension and may be of primary pathogenetic importance. It is proposed that the increased renal vascular resistance in these young animals stimulates the rise of systemic arterial pressure which returns renal blood flow and glomerular filtration rate to normal.
Degradation by bacterial enzymes of colonic mucus from normal subjects and patients with inflammatory bowel disease: The role of sialic acid metabolism and the detection of a novel O-acetylsialic acid esterase
Authors: Corfield Anthony P. , Williams Andrew J. K. , Clamp John R. , Wagner Susan A. , Mountford Richard A.
Published: August 2015

1. The activities of enzymes degrading human colonic mucin were examined in faecal specimens from healthy subjects and patients with inflammatory bowel disease.

2. The activity of sialidase was measured using a new physiological substrate related to mucus glycoproteins. In addition, acylneuraminate pyruvate-lyase (N-acetylneuraminate lyase; EC 4.1.3.3.) and a novel O-acetylsialic acid esterase (sialate O-acetylesterase; EC 3.1.1.35) were detected.

3. The O-acetylsialic acid esterase activity was readily detectable in partially purified fractions after Sephadex G-100 chromatography.

4. Patients with inflammatory bowel disease showed significant increases in acylneuraminate pyruvate-lyase and proteinase activity but sialidase activity did not differ from normal. The activity of these enzymes in neutrophils could not account for the differences observed.
Unaltered dopaminergic modulation of aldosterone secretion in cirrhosis
Authors: Bernardi M. , De Palma Rossana , Trevisani F. , Malatesta R. , Baraldini M. , Cursaro Carmela , Gasbarrini G.
Published: August 2015

1. The responses of plasma aldosterone and plasma prolactin concentrations to metoclopramide (10 mg intravenously) were evaluated over 2 h in eight healthy controls and in 23 patients with cirrhosis (10 without and 13 with ascites). Plasma renin activity, glomerular filtration rate and renal sodium excretion were also determined.

2. Metoclopramide did not significantly influence plasma renin activity, whereas both plasma aldosterone and plasma prolactin rose significantly. The incremental areas under the curves did not differ among controls and cirrhotic patients without and with ascites. No significant correlations between plasma prolactin and aldosterone, either under basal conditions or after metoclopramide administration, were found in either controls or patients.

3. Glomerular filtration rate did not change after metoclopramide. Renal sodium excretion in controls and cirrhotic patients without ascites was also unaffected, whereas it decreased significantly in cirrhotic patients with ascites. In the latter, renal sodium excretion was inversely correlated with plasma aldosterone both under basal conditions and after metoclopramide administration.

4. The dopaminergic control of aldosterone secretion does not appear to be significantly altered in cirrhosis. Metoclopramide administration to cirrhotic patients with ascites leads to an increase in plasma aldosterone that may enhance renal sodium retention.
Why does vasodilatation occur during syncope?
Authors: Robinson B. J. , Johnson R. H.
Published: August 2015

1. Syncopal or near syncopal episodes have been observed in five subjects who stood or were tilted and in whom blood samples were being taken.

2. In all subjects bradycardia and hypotension developed before the onset of symptoms. Increases in plasma adrenaline concentrations occurred in all subjects, beginning before the faint. Changes in plasma noradrenaline concentrations were variable: in three subjects there was a marked fall and in the other two subjects an increase. Plasma vasopressin increased in all subjects.

3. Increases in plasma adrenaline may be contributing to the vasodilatation and arterial hypotension which occur during syncope.
Caffeine clearance and biotransformation in patients with chronic liver disease
Authors: Scott Nigel R. , Stambuk Drago , Chakraborty J. , Marks Vincent , Morgan Marsha Y.
Published: August 2015

1. The clearance and biotransformation of caffeine (1,3,7-trimethylxanthine) were investigated in eight healthy control subjects and 16 patients with cirrhosis, by measuring serial serum caffeine concentrations and recoveries of methylxanthine metabolites in urine for 48 h after a 400 mg oral caffeine load.

2. In the control group, the mean (± sd) serum caffeine clearance was 1.3 ± 0.4 ml min−1 kg−1 and a mean of 56.4 ± 16.5% of the administered caffeine was recovered from the urine over 48 h as methyluric acids and methylxanthines. The majority of the metabolites were excreted in the first 24 h period and only 2.0 ± 1.4% of the administered caffeine was excreted unchanged.

3. Patients with compensated cirrhosis (n = 10) metabolized caffeine similarly to the control subjects. Thus the mean serum caffeine clearance was 1.4 ± 1.2 ml min−1 kg−1 and a mean of 57.2 ± 11.7% of the administered caffeine was recovered from the urine over 48 h. The majority of the metabolites were excreted in the first 24 h; the pattern of metabolic excretion was unaltered and only 2.2 ± 0.9% of the administered caffeine was excreted unchanged.

4. In the patients with decompensated cirrhosis (n = 6), significant changes were observed in caffeine metabolism. The mean serum caffeine clearance (0.4 ± 0.2 ml min−1 kg−1) was significantly impaired compared with controls (P < 0.01) and a significant delay was observed in metabolite excretion in the urine. Thus the mean recovery of metabolites in the urine during the first 24 h (25.0 ± 11.2%) was significantly reduced compared with controls (44.1 ± 12.4%, P = 0.03), whereas the mean urinary metabolite recovery in the second 24 h (20.9 ± 10.5%) was insignificantly increased compared with controls (12.3 ± 7.8%). Overall, the mean recovery of metabolites in the urine in 48 h (45.9 ± 15.4%) was similar to that in the control group. The overall recovery of unchanged caffeine was significantly greater than in controls (5.0 ± 2.8% vs 2.0 ± 1.4%, P = 0.04), but the pattern of metabolite excretion was otherwise unchanged.

5. In the patients with liver disease there were significant linear correlations between the degree of hepatocellular dysfunction and the serum caffeine elimination half-life (r = 0.774; P < 0.01) and the total recovery of methylxanthine metabolites in the urine, in the 0–24 h (r = 0.702; P = 0.002) and 0–48 h (r = 0.581; P = 0.018) periods.

6. Caffeine clearance is impaired in patients with decompensated cirrhosis either because of a reduction in hepatic caffeine uptake or else because of a reduction in ‘functioning hepatocyte mass’. However, the biotransformation of caffeine is unaltered in the presence of hepatic dysfunction.
Effects of the anabolic steroid stanozolol on cells derived from human bone
Authors: Vaishnav R. , Beresford J. N. , Gallagher J. A. , Russell R. G. G.
Published: August 2015

1. In this study, cells derived from explants of human trabecular bone were treated with the anabolic steroid stanozolol in order to determine whether the potential therapeutic effect of this agent might be explained by direct effects on skeletal tissue.

2. Stanozolol at a concentration of 10−10 mol/l to 10−6 mol/l consistently stimulated the incorporation of [3H]thymidine into DNA of human bone cells and increased proliferation.

3. Stanozolol had variable effects on the expression of two other markers of the osteoblast phenotype, namely the bone-specific vitamin-K-dependent protein osteocalcin, and the enzyme alkaline phosphatase. Although stanozolol tended to increase the values, this was not seen in all experiments.

4. We conclude that human bone cells respond to stanozolol. The effects of this agent on cell proliferation may be important in understanding the mode of action of this drug in the treatment of osteopenic disorders.
α-Methyldopa selectively reduces alae nasi activity
Authors: Lahive K. C. , Weiss J. W. , Weinberger S. E.
Published: August 2015

1. Sedatives such as the benzodiazepines and alcohol reduce upper airway muscle activity. We hypothesized that a sedating antihypertensive, α-methyldopa, might have similar effects. To investigate this hypothesis we studied the effect of α-methyldopa on alae nasi electromyographic (EMG) activity during hypercapnia.

2. We studied ten healthy subjects and three subjects with obstructive sleep apnoea during CO2-stimulated breathing. In a preliminary study four subjects demonstrated a fall in alae nasi EMG activity 4 h after the ingestion of 500 mg of α-methyldopa during CO2 rebreathing.

3. In six additional normal subjects and three subjects with obstructive sleep apnoea, we studied the alae nasi EMG activity during steady-state hypercapnia with PCO2 held constant 5 torr (0.7 kPa) above baseline. On 2 separate days we studied subjects before and 2 h after they had ingested 750 mg of α-methyldopa or placebo.

4. In the normal subjects the mean alae nasi EMG activity fell by 34% 2 h after ingestion of α-methyldopa (P < 0.05) without a change in other ventilatory parameters.

5. In the sleep apnoea group the individual mean alae nasi EMG activity fell 16–49%, with ventilation and tidal volume falling in one patient.

6. We conclude that α-methyldopa selectively reduces upper airway motor activity.
Muscle fatigue and pain after eccentric contractions at long and short length
Authors: Newham D. J. , Jones D. A. , Ghosh G. , Aurora P.
Published: August 2015

1. The effect of muscle length on the development of muscle pain and fatigue has been studied.

2. Eight normal young adults performed maximal eccentric contractions of the elbow flexors. The muscles of one arm were exercised at short length, and the contralateral muscle at long length. Each contraction lasted approximately 1 s, and was repeated once every 10 s for 30 min.

3. Muscle strength and frequency-force characteristics were measured from isometric contractions before, immediately after and at 24 h intervals for the next 4 days. Muscle tenderness was assessed daily.

4. The muscle strength was reduced by approximately 10% by exercise at short length, and by 30% by exercise at long length.

5. The 20:100 ratio (force generated by stimulation at 20 Hz/force generated at 100 Hz) fell by 30% after exercise at short length and had recovered after 24 h. Exercise at long length reduced this ratio by 65% and the muscles had not fully recovered 4 days later.

6. Muscle pain developed after both exercise regimens, but was slightly worse after that at long length.

7. It is concluded that there is a length-dependent component in the development of pain and fatigue after eccentric exercise, which had previously been thought to be caused solely by high force generation.
Effect of sodium chloride and sodium bicarbonate on blood pressure in stroke-prone spontaneously hypertensive rats
Authors: Luft F. C. , Steinberg H. , Ganten U. , Meyer D. , Gless K. H. , Lang R. E. , Fineberg N. S. , Rascher W. , Unger Th. , Ganten D.
Published: August 2015

1. To test the hypothesis that NaCl increases blood pressure, while NaHCO3 does not, we measured the effect of an NaHCO3-containing mineral water on blood pressure in stroke-prone spontaneously hypertensive (SHR-SP) and Wistar–Kyoto (WKY) rats. We compared mineral water with equimolar amounts of NaCl and demineralized drinking water in six groups of 20 rats each over 24 weeks.

2. NaCl consistently increased blood pressure in both SHR-SP and WKY compared with demineralized water, while mineral water did not.

3. We studied the possible role of sodium-regulating hormones. Sodium, potassium-dependent adenosine triphosphatase activity was decreased by NaCl and by age, but not by mineral water. The concentration of atrial natriuretic peptide was greater in SHR-SP, but was not influenced by the two regimens. Components of the renin–angiotensin–aldosterone system and 18-hydroxy-deoxycorticosterone tended to decrease with NaCl, but not with mineral water.

4. Plasma pH values in the six groups of rats were not different; however, SHR-SP had consistently lower Pco2 and HCO−3 values and higher anion gap values than WKY rats. These values were not influence by the two regimens.

5. NaCl elevates blood pressure in SHR-SP while NaHCO3 does not. The changes in hormones regulating sodium homoeostasis suggest that NaCl induces volume expansion while NaHCO3 does not. The effect may be related to influences on renal sodium reabsorption by chloride and bicarbonate. The possible role of increased proton excretory activity in SHR-SP remains to be determined.
Magnesiuric and calciuric effects of terbutaline in man
Authors: Bos W. J. W. , Postma D. S. , van Doormaal J. J.
Published: August 2015

1. The effect of terbutaline infusion over 4 h on serum levels of potassium, ionized calcium, phosphate and magnesium and urinary excretion of potassium, calcium, magnesium and adenosine 3′:5′-cyclic monophosphate was studied in six healthy volunteers.

2. Serum levels of potassium, calcium, phosphate and magnesium decreased. Urinary excretion of potassium decreased, whereas those of calcium, magnesium and adenosine 3′:5′-cyclic monophosphate increased.

3. These results indicate that the hypocalcaemic and hypomagnesaemic effects of terbutaline can, at least partly, be explained by enhanced urinary excretion of calcium and magnesium. This may have important implications for the short-term terbutaline treatment of patients with, for example, cardiac disease.
Transport and metabolism of 6-thioguanine and 6-mercaptopurine in mouse small intestine
Authors: Bronk J. R. , Lister Norma , Shaw M. I.
Published: August 2015

1. The transport of 6-thioguanine and 6-mercaptopurine has been studied with isolated jejunal loops of mouse small intestine. H.p.l.c. was used to identify and quantify the thiopurines and their metabolites in the serosal secretions.

2. When the lumen of the intestinal loops contained either 6-thioguanine or 6-mercaptopurine at a concentration of 1 mmol/l, the concentration of unmetabolized drug in the serosal secretions reached a maximum of 0.13 ± 0.02 mmol/l (mean ± sem).

3. Analysis of the serosal secretions from the perfusions with either of the drugs revealed the appearance of an unknown compound which had the characteristics of a thiopurine and the same time course of appearance as the unmetabolized drug. Thus 6-thioguanine and 6-mercaptopurine are significantly metabolized during absorption in mouse intestine.

4. The unknown compound was identified as 6-thiouric acid, and with 1 mmol/l 6-thioguanine or 6-mercaptopurine in the lumen the concentration of this metabolite in the serosal secretions rose to a maximum of 0.13 ± 0.01 and 0.18 ± 0.03 mmol/l, respectively. At luminal drug concentrations of 0.1 mmol/l, the metabolite accounted for approximately 90% of the serosal thiopurine.

5. After an initial lag period of 20 min, linear rates of appearance in the serosal secretions were obtained for both the unmetabolized drugs and 6-thiouric acid.

6. Addition of the xanthine oxidase inhibitor oxypurinol at a luminal concentration of 0.3 mmol/l prevented the formation of 6-thiouric acid from 6-thioguanine. However, the inhibitor reduced the rate of 6-thioguanine appearance in the serosal secretions by 50%.

7. The conversion of 6-mercaptopurine to 6-thiouric acid was prevented when allopurinol or oxypurinol were added to the lumen. At a luminal drug concentration of 1 mmol/l, allopurinol increased the rate at which 6-mercaptopurine appeared in the serosal secretions by 90% compared with an increase of only 50% with oxypurinol.

8. The transport of water and glucose by the mouse intestinal loops was unaffected by 6-thioguanine or the xanthine oxidase inhibitors. However, 6-mercaptopurine caused significant reductions in the rate of water transport (30%) and glucose transport (39%). These effects were observed at a luminal drug concentration of 0.1 mmol/l and there was no further increase at a drug concentration of 1 mmol/l.
Sodium transport in the diseased human gallbladder and the effects of indomethacin
Authors: Jacyna M. R. , Ross P. E. , Hopwood D. , Bouchier I. A. D.
Published: August 2015

1. Sodium ion (Na+) transport, a principal function of the gallbladder epithelium, was studied by measuring the flux of 22Na across isolated, inflamed human gallbladder mucosa maintained in a modified ‘Ussing’ flux chamber. Tissue was obtained from cholecystectomy specimens in symptomatic patients with cholelithiasis.

2. In 30 gallbladders studied, 57% had a net Na+ flux from mucosa to serosa (Na+ absorption), while 23% had a net Na+ flux from serosa to mucosa (Na+ secretion). The remaining 20% showed no overall net Na+ flux.

3. Indomethacin added to the serosal fluid reversed the direction of net Na+ flux in secreting gallbladders and caused an absorption of Na+. In Na+-absorbing gallbladders, indomethacin caused a slight reduction in Na+ absorption. No change in Na+ flux was induced in gallbladders with no initial net Na+ flux.

4. These results demonstrate that instead of absorbing Na+, some inflamed human gallbladders may secrete Na+. As this secretion can be reversed to the more usual absorption by indomethacin, it is likely that this secretion is mediated by prostaglandins.
Endocrine and renal response to water loading and water restriction in normal man
Authors: Shore Angela C. , Markandu Nirmala D. , Sagnella Giuseppe A. , Singer Donald R. J. , Forsling Mary L. , Buckley Martin G. , Sugden A. Louise , MacGregor Graham A.
Published: August 2015

1. Nine normal subjects (eight male, one female) on a fixed daily intake of 150 mmol of sodium and 80 mnol of potassium, were randomized to receive either 3 days of 1.0 litre total water intake/24 h (food + fluid) or 4 days of 6.8 litres total water intake/24 h, and were then crossed over after a 3 day control period (2.7 litres water/24 h).

2. During water restriction, urine volume fell from 1.94 litres/24 h to less than 1 litre/24 h by the first day and was 0.77 litre/24 h on the final day. Plasma atrial natriuretic peptide levels were unchanged from baseline despite a large increase in plasma vasopressin and plasma and urine osmolality. Urinary sodium was unaltered throughout, while urinary potassium was increased on the final 2 days of water restriction.

3. During water loading, urine volume increased from 1.85 litres/24 h to 5.44 litres/24 h on the first day and remained at approximately 6 litres/24 h for the final 3 days. Plasma atrial natriuretic peptide showed no change. Plasma vasopressin and plasma and urine osmolality were reduced. Urinary sodium and potassium output were unchanged from baseline.

4. These results suggest that changes in plasma atrial natriuretic peptide are unlikely to be involved in the normal homoeostatic response to changes in water balance in man.