bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissolved Urate Promotes Calcium Oxalate Crystallization: Epitaxy is Not the Cause
Authors: Grover Phulwinder K. , Ryall Rosemary L. , Marshall Villis R.
Published: August 2015

1. Increasing the concentration of dissolved urate promotes the crystallization of calcium oxalate from urine. The possibility was investigated that this effect may be caused by heterogeneous nucleation of calcium oxalate by particles of crystalline urate.

2. Urine samples were collected from 10 healthy men, centrifuged and filtered, and a solution of sodium urate was added to increase the medium urate concentration from 2.2 to 5.6 mmol/l. Calcium oxalate crystallization was induced by the addition of oxalate, followed by incubation for 90 min in a shaking waterbath at 37°C. The crystalline material was filtered out and the urate concentration was determined in the filtrate.

3. No difference in the urate concentration before and after induction of calcium oxalate crystallization was observed. These findings were confirmed by infra-red spectroscopy, X-ray powder diffraction and ultraviolet wet chemical analysis with detection limits of 5-10, 1.0 and 0.055%, respectively; urate was not detected in the calcium oxalate crystals.

4. In addition, three urine samples were collected and passed through 10 kDa ultrafiltration membranes to remove any colloidal particles which might have been present. The urate concentration was increased and an oxalate load was added as before, prior to incubation at 37°C in a shaking water bath for 5 min, followed by passage through 10 kDa ultrafiltration membranes. Scanning electron microscopy revealed no particles on the membranes thereby indicating that colloidal or crystalline urate was not formed early in the crystallization experiments.

5. It was concluded that the promotion of calcium oxalate crystallization by urate, and thereby the formation of calcium oxalate renal stones, is not caused by heterogeneous nucleation and subsequent epitaxial growth of calcium oxalate upon particles of urate.
Effects of Oral and Intravenous Calcitriol on Serum Calcium Oxalate Saturation in Dialysis Patients
Authors: Marangella Martino , Vitale Corrado , Cosseddu Domenico , Petrarulo Michele , Linari Franco
Published: August 2015

1. To determine whether the multiple changes in the blood chemistry profile induced by calcitriol may be conducive to secondary systemic oxalosis we have studied nine patients on regular dialysis treatment under three different regimens: (1) oral calcitriol, 0.25 μg/daily for at least 6 months. (2) off calcitriol, a 1-month withdrawal of the drug, taken as the baseline study period; (3) intravenous calcitriol, 1 μg three times weekly at the end of dialysis, with tests performed at 1 and 3 months from initiation.

2. Serum concentrations were measured pre- and post-dialysis at the end of each study period. The whole dialysate was used for the determination of the overall calcium and oxalate removal by dialysis. The degree of saturation with calcium oxalate mono-hydrate was estimated by a computer program. Serum calcitriol concentrations were also assessed.

3. Total and ionized serum calcium did not change on average, although mild hypercalcaemia developed in some patients on intravenous calcitriol. There was an increase in plasma level of oxalate during both oral and intravenous calcitriol treatment, but this was less pronounced during intravenous therapy. Removal of oxalate by dialysis was also greater in patients on oral calcitriol.

4. These increases were probably originated from intestinal absorption and secondary to hyper-absorption of dietary calcium. Consequently, the degree of saturation with calcium oxalate before dialysis rose during calcitriol treatment, irrespective of the route of administration.

5. These results emphasize that, in addition to soft tissue calcification due to calcium phosphates, ectopic calcium oxalate crystallization must also be viewed as a potential risk associated with long-term administration of calcitriol.
Potassium Channels in Hypokalaemic Periodic Paralysis: A Key to the Pathogenesis?
Authors: Links T. P. , Smit A. J. , Oosterhuis H. J. G. H. , Reitsma W. D.
Published: August 2015

1. A possible role for the ATP-sensitive potassium channels in the pathogenesis of hypokalaemic periodic paralysis was investigated.

2. We assessed insulin release and muscle strength after intravenous glucose loading with and without the potassium channel opener pinacidil and the potassium channel blocker glibenclamide in three patients with hypokalaemic periodic paralysis and in a pair of matched control subjects for each patient.

3. A significantly higher initial insulin response (1.5-30 min) was found in the patients with hypokalaemic periodic paralysis in comparison with the control subjects. During potassium channel blocking with glibenclamide the insulin release was more enhanced in patients than in control subjects. On the other hand, the potassium channel opener pinacidil impaired the insulin release in healthy control subjects but not in patients. The serum glucose levels showed no differences between patients and control subjects. In one of the patients with hypokalaemic periodic paralysis glucose loading resulted in a fall in muscle strength, which did not occur during the administration of pinacidil.

4. These findings suggest a disturbance in the ATP-sensitive potassium channel in patients with hypokalaemic periodic paralysis, which is not limited to pancreatic β cells, but may be also involved in the abnormal behaviour of skeletal muscle.
A New Calcitonin-Receptor-like Sequence in Rat Pulmonary Blood Vessels
Authors: Njuki F. , Nicholl C. G. , Howard A. , Mak J. C. W. , Barnes P. J. , Girgis S. I. , Legon S.
Published: August 2015

1. Two rat clones have been isolated which are similar to known calcitonin-receptor sequences. One of these does not have the distribution expected of a calcitonin receptor. It is widely distributed, with extremely high levels of expression in the lung, where it is associated with the blood vessels.

2. This rat sequence may represent the receptor for calcitonin-gene-related peptide or islet amyloid polypeptide. Both have binding activity in the lung and are potent vasodilators. The gene represented by this sequence may therefore play an important role in the maintenance of vascular tone.
Cardiovascular and Sympatho-Adrenal Responses to Mental Stress in Primary Hypertension
Authors: Lindqvist Madeleine , Kahan Thomas , Melcher Anders , Hjemdahl Paul
Published: August 2015

1. Eleven untreated men with mild to moderate primary hypertension and 10 normotensive control subjects were studied at rest and during a mental stress test (Stroop colour word conflict test), which has previously been used in studies of hypertensive patients with regard to non-invasive cardiovascular variables and venous plasma catecholamine concentrations.

2. Heart rate, central cardiovascular pressures, cardiac output (thermodilution) and forearm blood flow (strain gauge plethysmography) were determined. Systemic and forearm vascular resistances were calculated. Arterial and venous plasma adrenaline and noradrenaline concentrations were measured by h.p.l.c., and arterial noradrenaline spillover and noradrenaline overflow from the forearm were assessed by isotope methodology ([3H]noradrenaline). Neuropeptide Y-like immunoreactivity was measured by radioimmunoassay.

3. In hypertensive patients heart rate, arterial blood pressure, cardiac output and forearm blood flow increased by 28%, 13%, 37% and 115%, respectively, and forearm and systemic vascular resistances decreased by 48% and 21%, respectively (P <0.001 for all responses), during stress. These responses were not different from those of the control group.

4. Arterial noradrenaline spillover rose by 63% and noradrenaline overflow from the forearm rose by 150% in the hypertensive patients in response to mental stress (P <0.001); no significant group differences could be demonstrated. However, the forearm noradrenaline overflow response to stress tended to be greater in the hypertensive group (P = 0.11). Arterial adrenaline concentrations doubled in both groups (P <0.001).

5. Arterial neuropeptide Y-like immunoreactivity increased slightly and similarly in the two groups (+7% in hypertensive patients and +9% in control subjects, P <0.05 for both) in response to mental stress. No net overflow of neuropeptide-Y-like immunoreactivity could be detected over the forearm.

6. It is concluded that the cardiovascular and sympatho-adrenal responses to mental stress evaluated in this study are similar in hypertensive patients and control subjects. Stress-induced vasodilatation occurs in the forearm despite signs of increased local sympathetic activity, indicating that powerful neurohormonal vasodilator mechanisms are activated by mental stress.
Effect of Noradrenaline on Renal Sodium and Water Handling in Euhydrated and Overhydrated Man
Authors: Lang Chim C. , Rahman Abdul R. , Balfour David J. K. , Struthers Allan D.
Published: August 2015

1. The renal effects of incremental doses of intravenously infused noradrenaline were evaluated in normal subjects during two different water loads, 5 ml/kg (n = 6) and 20 ml/kg (n = 9), producing conditions of euhydration and overhydration, respectively.

2. Noradrenaline infusion rates ranged from 0.015 to 0.075 μg min−1 kg−1. In the euhydrated subjects, noradrenaline caused a dose-dependent fall in urinary sodium excretion and an increase in urinary flow rate. During overhydration similar doses of noradrenaline caused a fall in urinary sodium excretion but a decrease in urinary flow rate.

3. Although there was no detectable change in glomerular filtration rate, a dose-dependent fall in effective renal plasma flow was observed in both hydration states during noradrenaline infusion.

4. Noradrenaline infusion was associated with a dose-dependent increase in proximal tubular sodium reabsorption as assessed by the lithium clearance method. Fractional reabsorption of sodium by the distal nephron was, however, unchanged by noradrenaline in both hydration states.

5. Plasma vasopressin concentration was unchanged by noradrenaline in euhydrated subjects. The renin-angiotensin-aldosterone axis was stimulated by noradrenaline in both euhydrated and overhydrated subjects.

6. Thus we conclude that plasma circulating noradrenaline has a dose-dependent antinatriuretic effect in man. The antinatriuretic effect of noradrenaline is mediated mainly at the proximal tubule in man. We have also shown that during overhydration, noradrenaline decreased urinary flow rate. In contrast, in euhydrated subjects, noradrenaline increased urinary flow rate with no accompanying changes in plasma vasopressin concentration, which suggests a direct effect of noradrenaline on the renal tubular permeability to water.
Can Ultrafiltration Occur with a Hypo-Osmolar Solution in Peritoneal Dialysis?: The Role for ‘Colloid’ Osmosis
Authors: Mistry Chandra D. , Gokal Ram
Published: August 2015

1. In peritoneal dialysis the removal of excess body water (ultrafiltration) is traditionally achieved by means of dialysis solution made hypertonic to plasma by the addition of an osmotic agent. In vitro, the osmotic flow may be directed against the osmolality gradient by using a hypo-osmolar solution, but this phenomenon has not previously been applied to clinical peritoneal dialysis.

2. The ultrafiltration performances of hypo-osmolar dialysis solutions containing a high-molecular-weight glucose polymer (weight average molecular weight 22 000), isolated by fractionation of hydrolysed corn starch, were compared with those of hypertonic glucose solutions over a 12 h exchange in 11 patients well established on continuous ambulatory peritoneal dialysis.

3. Five per cent (272 +1.1 mosmol/kg) and 7.5% (277 + 2.0 mosmol/kg) glucose polymer solutions produced net ultrafiltration of 243 +53 and 526 +59 ml that were significantly greater than the ultrafiltration of −48 +96 and 223 +84 ml associated with 1.36% (339 +1.9 mosmol/kg) and 2.27% (393 +3.2 mosmol/kg) glucose solutions, respectively. The net ultrafiltration with 10% glucose polymer (284 +2.0 mosmol/kg) and 3.86% glucose (482 + 1.6 mosmol/kg) solutions were similar (699 +48 versus 708 +82 ml).

4. The transperitoneal absorption of glucose polymer was substantially lower than that of glucose solutions as was the potential calorie load per millilitre of ultrafiltrate.

5. The addition of 0.35% glucose (molecular weight 180) to 7.5% glucose polymer solution raised the dialysate osmolality to an iso-osmolar level (299 +0.8 mosmol/kg) and produced ultrafiltration which was 29% greater than with 7.5% glucose polymer solution alone.

6. The demonstration of ultrafiltration with hypo-osmolar dialysate represents an important advance towards the formulation of a physiological iso-osmolar dialysis solution, which may have long-term benefits over the conventional hypertonic solutions. The iso-osmolar combination of ‘colloid’ and ‘crystalloid’ osmotic agents looks promising with a potential for a wide range of ultrafiltration capabilities as well as metabolic correction.
CD45RA+ T Cells: Not Simple Virgins
Authors: Lightstone Liz , Marvel Jacqueline
Published: August 2015

1. The T cells which mediate immunological memory remain elusive. Identification of such cells would open the door to increasingly specific immunotherapy in areas such as transplantation and autoimmunity.

2. Over the last few years attempts have been made to identify phenotypic markers which can distinguish naive or virgin T cells from primed or memory ones. In humans, great hopes were raised when it was shown that the level of expression of the higher-molecular-mass isoforms (CD45RA) of the tyrosine phosphatase, CD45, correlated with previous exposure to antigen.

4. However, our studies in the mouse and more recent studies in rat and human suggest that expression of CD45RA more closely correlates with the state of responsiveness of the T cell.

5. Thus, with time, activated/memory T cells return to a state of quiescence or hypo-responsiveness and express high levels of CD45RA. Hence, not all CD45RA+ T cells are virgins.
A Novel Antiserum Specific to Apolipoprotein B-48: Application in the Investigation of Postprandial Lipidaemia in Humans
Authors: Peel Andrew S. , Zampelas Antonios , Williams Christine M. , Gould Barry J.
Published: August 2015

1. Apolipoprotein B-48, the transport protein for chylomicrons, is identical with apolipoprotein B-100 for the first 48% of its sequence. No antiserum has yet been reported that can recognize apolipoprotein B-48, but not apolipoprotein B-100.

2. In the present study an antiserum was raised to the C-terminal sequence of apolipoprotein B-48, using specific chemical reactions to ensure that the charged carboxyl group of the C-terminal isoleucine residue was free. In a Western blot the antiserum was shown to bind to a protein band having the characteristics of apolipoprotein B-48, but not to apolipoprotein B-100.

3. In the early evening 11 subjects were given a test meal which contained 40 g of mixed oil and retinyl palmitate. Blood samples were collected over 9 h. Chylomicron-enriched fractions were prepared and analysed for triacylglycerol, retinyl palmitate and apolipoprotein B-48, the latter after separation using SDS/PAGE and visualization by chemiluminescence on a Western blot. Both triacylglycerol and apolipoprotein B-48 showed an early peak at 1 h, which was not seen with retinyl palmitate. All three substances gave a broader peak between 5 and 6 h post-prandially. Retinyl palmitate concentrations declined rapidly during the late (6-9 h) postprandial period, but apolipoprotein B-48 concentrations remained elevated.

4. This study has shown that an antiserum has been produced which is specific for apolipoprotein B-48. This has enabled measurement of postprandial concentrations of the protein that revealed features of chylomicron metabolism which have not been reported previously.
Antecedent Insulin Level and Pattern of Induction of Acute Hypoglycaemia do Not Affect Subsequent Counterregulatory Responses in Healthy Subjects
Authors: Moriarty K. T. , Simpson E. J. , Mullinger R. N. , MaCdonald I. A. , Tattersall R. B.
Published: August 2015

1. This study was designed to determine whether the duration and pattern of prior insulin exposure modulate the symptomatic and counterregulatory responses to hypoglycaemia.

2. Ten healthy non-obese subjects (five males/five females age 25 + 1 years, mean + SEM) were made hypoglycaemic in three ways: (i) a hyperinsulinaemic (60 m-units min−1 m−2; plasma insulin concentration 95 m-units/l) clamp, with 1 h of euglycaemia, blood glucose level 4.5 mmol/l, followed by 30 min of hypoglycaemia, at a stable glucose nadir of 2.0 mmol/l (i.e. euglycaemic then hypoglycaemic clamp: E+HC); (ii) an identical hypoglycaemic clamp without preceding hyperinsulinaemic euglycaemia (i.e. a hypoglycaemic clamp: HC); (iii) insulin infusion only, discontinued at a blood glucose level of 3.0 mmol/l (II). Blood glucose level reached the same nadir as on E+HC and HC, and did not fall further. At the glucose nadir, and 15 and 30 min after, the plasma insulin concentration was 23, 7 and 4 m-units/l, respectively, on the II visit.

3. At the glucose nadir, plasma glucagon level, plasma adrenaline level, sweating rate, heart rate, blood pressure, and overall and individual symptom scores (using visual analogue scales) were the same on E+HC, HC and II.

4. There were no significant differences in neurohormonal response between E+HC and HC, but more subjects felt hypoglycaemic on E+HC on arrival at the glucose nadir (P <0.05). There was significantly more blurring of vision (1.3+0.5 versus 0.2+0.1 cm) and tingling (1.2+0.4 versus 0.2+0.1 cm) 30 min after arriving at the glucose nadir on E+HC than HC (P <0.05, analysis of variance).

5. Significant differences were only found between E+HC or HC and the II visit 15 min after arriving at the glucose nadir, when the blood glucose level had risen significantly to 2.9 mmol/l, and 30 min after arrived at the glucose nadir, by which time the blood glucose level had recovered to 3.8 mmol/l.

6. A 1 h run-in period of euglycaemic hyperinsulinaemia does not affect the hormonal or physiological response to an identical degree of hypoglycaemia, but appears to cause increased symptoms of neuroglycopenia during subsequent stable hypoglycaemia.

7. A difference in plasma insulin level within the physiological range does not affect the magnitude of symptomatic, hormonal or physiological responses to the same degree of hypoglycaemia.
Induction of Enhanced Responsiveness of Human Articular Chondrocytes to Extracellular ATP by Tumour Necrosis Factor-α
Authors: Leong Weng S. , Graham R. , Russell G. , Caswell Alison M.
Published: August 2015

1. We have observed previously that extracellular ATP acting at P2-purinoceptors promotes the production of prostaglandin E2 by human articular chondrocytes, and that this response is enhanced synergistically by interleukin-1β. Since other cytokines that influence the metabolism of articular cartilage may have a similar effect, we have investigated whether tumour necrosis factor-α also modulates the stimulation of the production of prostaglandin E2 in these cells by ATP.

2. Tumour necrosis factor-α enhanced the response of cultured human articular chrondrocytes to a maximally stimulating concentration of ATP (100 μmol/l). This effect was present when the cells were co-incubated with tumour necrosis factor-α and ATP for 4 h, was augmented when the cells were also preincubated with the cytokine for 24 h, and remained constant or declined on extending the preincubation period to 72 h. The enhancement of responsiveness to ATP by tumour necrosis factor-α was dose-dependent, and the minimum effective concentration (6 pmol/l) did not consistently increase prostaglandin E2 production when the cytokine was tested alone. The presence of tumour necrosis factor-α during the incubation with ATP was required for maximum enhancement of the response. Tumour necrosis factor-α did not alter the minimum concentration of ATP that stimulated production of prostaglandin E2.

3. Cytokines such as interleukin-1 and tumour necrosis factor-α are involved in the pathogenesis of some forms of arthritis, and these data provide additional evidence that their actions in articular cartilage may be modulated by other agents which originate from chondrocytes. Moreover, although both these cytokines enhance responsiveness of human articular chondrocytes to extracellular ATP, differences in their effects were observed which suggest that they may act independently.
Control of Sodium Excretion in Patients with Cranial Diabetes Insipidus Maintained on Desamino-[8-d-Arginine]Vasopressin
Authors: Sutters M. , Brace C. , Hatfield E. , Whitehurst A. , Lightman S. L. , Peart W. S.
Published: August 2015

1. We have studied the response of six patients with cranial diabetes insipidus and six age-matched control subjects to dietary sodium restriction during constant administration of the synthetic vasopressin analogue desamino-[8-D-arginine]vasopressin.

2. Urine flow increased on the first low salt day in the normal control subjects but not in the patients with cranial diabetes insipidus. Body weight fell 1.35 kg in the control subjects but was constant in the patients with cranial diabetes insipidus.

3. Urinary sodium excretion fell at the same rate in both groups. Diurnal variation of urinary sodium excretion and creatinine clearance was present in the control subjects but not in the patients with cranial diabetes insipidus.

4. Changes in plasma sodium concentration and osmolality were similar. Plasma protein concentration increased more in the control subjects (from 69.1 + 13 to 73 + 1.2 versus from 71.7 + 1 to 73.2 + 1.1 g/l). The responses of plasma atrial natriuretic peptide, plasma renin activity and salivary aldosterone concentration were similar between the two groups. Salivary aldosterone concentration levels were consistently higher in the patients with cranial diabetes insipidus.

5. We confirm that the low salt diuresis is triggered by release from the antidiuretic activity of arginine vasopressin. In the patients with cranial diabetes insipidus extracellular fluid osmoregulation appeared to be achieved by the movement of water out of and sodium into the extracellular fluid.

6. Absent posterior pituitary function and hypothalamic disturbances did not alter renal sodium conservation. Total extracellular fluid sodium appeared to be lower in the patients with cranial diabetes insipidus than in the control subjects. Disturbances of hypothalamic and pituitary function may have caused resetting of overall sodium balance and altered diurnal cycles of urinary sodium excretion and creatinine clearance.
Modulation of Small-Intestinal Secretion and Absorption in Chronic Vitamin E Deficiency: Studies in Rat Jejunum in vitro
Authors: Lindley K. J. , Muller D. P. R. , Milla P. J.
Published: August 2015

1. A vicious cycle of malabsorption and malnutrition has been implicated in the pathogenesis of protracted diarrhoeal disease in infancy. Vitamin E deficiency is common in malnourished infants with protracted diarrhoea. We have studied the effects of chronic vitamin E deficiency on small-inestinal secretion and absorption in the rat.

2. Weanling rats were fed vitamin E-sufficient or -deficient diets for 21 weeks. Jejunal function was studied in vitro in an Ussing chamber after this period.

3. Steady-state isotopic flux experiments in unstimulated tissues demonstrated net Na+ and Cl−secretion in vitamin E-deficient jejuna but net Na+ and Cl− absorption in vitamin E-sufficient jejuna.

4. Basal intestinal short-circuit current was the same in both groups.

5. Cyclic nucleotide and maximal non-neuronal acetylcholine-mediated electrogenic secretion were increased in vitamin E-deficient jejuna.

6. Exogenous 5-hydroxytryptamine (serotonin) induced a smaller increment in electrogenic secretion in vitamin E-deficient jejuna.

7. Vitamin E-deficient jejuna were less responsive to exogenous noradrenaline, resulting in a smaller α2-adrenergic-mediated decrease in intestinal short-circuit current.

8. Fasting for 72 h produced a greater increment in intestinal short-circuit current in vitamin E-deficient jejuna.

9. Chronic vitamin E deficiency is prosecretory in the small intestine and may predispose to the perpetuation of protracted diarrhoeal diseases.
Occurrence of Presyncope in Subjects without Ventricular Innervation
Authors: Lightfoot J. Timothy , Rowe Stuart A. , Fortney Suzanne M.
Published: August 2015

1. To determine whether activation of the left ventricular C-fibre mechanoreceptors initiates the vasodepressor reflex that often causes syncope, we exposed six orthotopic cardiac transplant patients and six matched, healthy control subjects to progressively increasing lower body negative pressure until the onset of vasodepressor responses.

2. There was no significant difference (P = 0.78) between the central hypovolemia tolerances of the cardiac transplant and the control groups.

3. The decrease in systolic blood pressure before the onset of vasodepressor reflexes was greater in the cardiac transplant group. The cardiac transplant group did not maintain diastolic blood pressure during central hypovolaemia. From baseline to the onset of vasodepression, there were no differences in leg circumference, forearm blood flow and forearm vascular resistance responses between the two groups.

4. We conclude that the left ventricular mechanoreceptors may not be the primary afferent trigger for syncope.
Role of Haematocrit in Mediating the Actions of Chronic Erythropoietin Treatment on Blood Pressure and Renal Haemodynamics in the Rat
Authors: Huang Chunlong , Davis Gerard , Johns Edward J.
Published: August 2015

1. This investigation aimed to study the effect of chronic administration of human recombinant erythropoietin on haematocrit, blood pressure, renal cortical and papillary resistances and vascular responsiveness to vasoconstrictor agents.

2. Rats were treated with placebo or 25, 50 or 100 units/kg erythropoietin subcutaneously, every other day for 3 weeks. Animals were then anaesthetized with sodium pentobarbitone and were prepared for laser-Doppler flowmetry measurement in the renal cortex and papilla.

3. Haematocrit in the placebo-treated group was 48.0 + 0.5% and was raised to 52.5 + 0.7, 55.9 + 0.8 and 62.4 + 1.1% (all P <0.05) by the chronic administration of 25, 50 and 100 units/kg doses of the hormone, respectively. Blood pressure was 107 + 1 mmHg in the placebo-treated group and was elevated to 116 + 2 and 130 + 1 mmHg (both P <0.05), respectively, by the two highest doses of erythropoietin. Cortical and papillary perfusions were reduced at the highest dose of erythropoietin, but calculated resistances were increased by 15 and 40% (P <0.05) at 50 and 100 units/kg doses of the hormone, respectively.

4. Infusion of the vasopressor hormones vasopressin and phenylephrine caused increases in blood pressure and decreases in renal cortical and papillary perfusion, the magnitudes of which were only marginally changed by the highest dose of the erythropoietin. Angiotensin II increased blood pressure and decreased cortical perfusion, and the magnitudes of these responses were unchanged by the chronic treatment with erythropoietin.

5. Acute graded increases in haematocrit resulted in significantly (P <0.05) raised blood pressure above a value of 58%. However, renal cortical and papillary perfusions decreased and resistances were increased significantly (P <0.05) when the haematocrit was raised above 56%.

6. The acute transfusion study demonstrated that elevations in blood pressure and renal vascular resistances occurred at haematocrit values somewhat higher than when it was raised by chronic erythropoietin treatment. Thus this would be consistent with the suggestion that erythropoietin has some direct action on the vasculature beyond that resulting from the raised haematocrit. These data show that a low dose regimen of erythropoietin can modestly increase haematocrit without other cardiovascular changes becoming apparent. The findings add weight to the recent clinical practice of using very low doses of the hormone in the treatment of chronic renal failure.
Effect of Induced Bronchoconstriction on Nasal Airflow Resistance in Patients with Asthma
Authors: Yap J. C. H. , Pride N. B.
Published: August 2015

1. Reflex bronchial changes have been demonstrated after nasal stimulation in both man and experimental animals. The existence of a pulmonary-nasal reflex is less established. We have examined whether induced narrowing of the intrathoracic airways leads to increases in nasal airflow resistance (R naw) in patients with asthma.

2. We have used a non-invasive forced oscillation method to measure total respiratory resistence (R rs) at 8 Hz during tidal breathing sequentially via the nose (R rs, na) and via the mouth (R rs, mo) and derived R naw by subtracting R rs, mo from R rs, na. We examined whether changes in R naw occurred when increases in R rs, mo were induced by inhaling histamine aerosol via the mouth with the nose occluded in 11 patients with stable, mild asthma (six males, age 28.1 + 2.1 years, forced expiratory volume in 1 s 97 +6% of predicted, means +SEM). Six of the patients had a history of rhinitis. The patients were first challenged with doubling concentrations of histamine via a dosimeter to establish the dose which reduced the forced expiratory volume in 1 s by ≧ 20%. Two hours later when the forced expiratory volume in 1 s had returned to baseline, they were challenged with saline and again 2 h later with the concentration of histamine that had earlier caused a ≧ 20% fall in the forced expiratory volume is 1 s.

3. Between 0.5 and 10 min after histamine inhalation, a sustained increase in R rs, mo was achieved with mean increases averaging 68–77% above baseline over this period (P <0.001). This was associated with a slower rise in mean R naw which reached a maximum of 53% above baseline at 5 min after histamine inhalation. The rise in R naw varied between patients, but was sustained for 10 min in eight of the patients; the extent of rise was not related to a history of rhinitis.

4. The results suggest that, in some asthmatic patients, bronchoconstriction results in an increase in R naw, probably due to a pulmonary-nasal reflex. Further studies are required to investigate the mechanisms of this increase.
Effect of Local Inhibition of Nitric Oxide Synthesis on Forearm Blood Flow and Dorsal Hand Vein Size in Patients with Alcoholic Cirrhosis
Authors: Calver Alison , Harris Adam , Maxwell J. Douglas , Vallance Patrick
Published: August 2015

1. Nitric oxide (NO) is a potent endogenous vasodilator and plays a role in the control of resting vascular tone. Patients with cirrhosis have a hyperdynamic circulation with reduced blood pressure and decreased peripheral resistance, and it is possible that increased production of NO due to induction of NO synthase may be involved in maintaining this vasodilatation. We have examined this possibility by studying the effects of local infusions of NG-monomethyl-l-arginine (an inhibitor of NO synthase) in the forearm arteriolar bed and the superficial dorsal hand veins of patients with alcoholic cirrhosis.

2. Drugs were either infused locally into the brachial artery and forearm blood flow was measured by venous occlusion plethysmography, or into a vein on the back of the hand and vein diameter was measured using a linear displacement technique.

3. Basal forearm blood flow was increased and vascular resistance was decreased in the patients with alcoholic cirrhosis compared with healthy control subjects. Noradrenaline and NG-monomethyl-l-arginine caused dose-dependent falls in forearm blood flow in both healthy control subjects and patients with cirrhosis. There was no significant difference in the responses to either noradrenaline or NG-monomethyl-l-arginine between the two groups.

4. In the superficial hand veins there was no change in vein size in response to NG-monomethyl-l-arginine infused alone, and venoconstriction to local infusion of noradrenaline was unaffected by co-infusion with NG-monomethyl-l-arginine.

5. Our results confirm that patients with alcoholic cirrhosis are vasodilated compared with healthy control subjects. Our findings show that basal NO-mediated vasodilatation occurs in the forearm arterial bed, but not the superficial hand veins, of these patients. However, since the response to local NO synthesis inhibition was similiar in the two groups, increased production of NO due to induction of NO synthase is unlikely to account fully for the vasodilatation seen in patients with mild to moderate alcoholic cirrhosis.
Altered Dynamics of the Circadian Relationship between Systemic Arterial Pressure and Cardiac Sympathetic Drive Early on in Mild Hypertension
Authors: Guzzetti S. , Dassi S. , Balsamà M. , Ponti G. B. , Pagani M. , Malliani A.
Published: August 2015

1. This study was designed to test the hypothesis that simultaneous non-invasive assessment of the circadian variations in both intermittent arterial pressure and the continuous 24 h changes of spectral markers of cardiac neural control could provide new information on cardiovascular regulatory mechanisms, in hypertensive patients and normotensive subjects. To test this hypothesis we studied 18 subjects with mild hypertension and 11 normotensive subjects in whom we recorded simultaneously non-invasive intermittent arterial pressure and Holter electrocardiogram for 24 h. We also studied the same subjects during resting and standing conditions in the clinical laboratory.

2. The normalized power of the low-frequency (∼0.1 Hz) spectral component of R-R interval variability, considered mainly a marker of sympathetic drive to the sino-atrial node, was, at rest, significantly higher in the hypertensive than in the normotensive subjects, as already reported. Moreover, the values of the low-frequency component at rest recorded in the clinical laboratory were significantly correlated with those obtained from ambulatory recording during night rest. The decrease in the values of arterial pressure during the night-time was accompanied by a reduction in the power of the low-frequency component only in the case of normotensive subjects. Accordingly, the slope of the regression of the low-frequency component as a function of systolic arterial pressure during ambulatory recordings was steep in normotensive subjects and flat in hypertensive subjects.

3. The computer analysis of Holter recordings combined with ambulatory arterial pressure monitoring seems to provide a new method with which to quantify the early changes in cardiovascular regulatory mechanisms that could help to identify individuals at higher risk.
Involvement of Nitric Oxide in the Vasodilatory Response to Parathyroid Hormone-Related Peptide in the Isolated Rabbit Kidney
Authors: Simeoni Umberto , Massfelder Thierry , Saussine Christian , Judes Clément , Geisert Jean , Helwig Jean-Jacques
Published: August 2015

1. The present study was designed to explore the role of NO derived from l-arginine in the vasodilatory response to synthetic human parathyroid hormone-related peptide-(1–34) in the isolated rabbit kidney perfused in the presence of indomethacin (10 μmol/l) and preconstricted with noradrenaline (7.2 nmol/min).

2. Under control conditions, bolus administrations of acetylcholine (10 μmol/l), an NO-dependent renal vasodilator, verapamil (0.1 mmol/l), an NO-independent renal vasodilator, and parathyroid hormone-related peptide (87 nmol/l) decreased the preconstriction pressure, by 31%, 71% and 43%, respectively.

3. Bolus administration of 100 μmol/l NG-nitro-l-arginine-methyl ester caused a 20% increment in the perfusion pressure of the noradrenaline-preconstricted kidney. NG-nitro-l-arginine methyl ester inhibited the vasodilatory effect of acetylcholine and parathyroid hormone-related peptide, by 68% and 44%, respectively, but did not alter the verapamil-induced vasodilatation.

4. Unlike l-arginine, the bolus administration of 1 μmol/l of a mono-substituted l-arginine derivative, N-α-benzoyl-l-arginine ethyl ester, durably decreased the noradrenaline/NG-nitro-l-arginine methyl ester-induced preconstriction by 57%.

5. Both l-arginine and N-α-benzoyl-l-arginine ethyl ester effectively reversed the inhibition induced by NG-nitro-l-arginine methyl ester on the vasodilatation elicited by acetylcholine and parathyroid hormone-related peptide.

6. In conclusion, the formation of NO from l-arginine contributes a substantial part to the vasodilatory action of parathyroid hormone-related peptide. Therefore, parathyroid hormone-related peptide appears to have a place among the renal haemodynamically active substances, whose vasodilatory actions are tuned by NO.
Ethanol Decreases Nocturnal Plasma Levels of Atrial Natriuretic Peptide (ANP 99-126) but Not the N-Terminal Fragment of Pro-Atrial Natriuretic Peptide (ANP 1-98) in Man
Authors: Ekman Ann-Charlotte , Vakkuri Olli , Vuolteenaho Olli , Leppäluoto Juhani
Published: August 2015

1. The aim of this study was to elucidate the role of atrial natriuretic peptides in the regulation of water and electrolyte balance after alcohol intake. To this end we measured the plasma concentrations of ethanol, atrial natriuretic peptide 99–126 and the N-terminal fragment of pro-atrial natriuretic peptide (atrial natriuretic peptide 1–98), serum osmolality and serum sodium concentration, and urine output, urine osmolality and urinary sodium excretion for 12 h after administration of ethanol (0, 0.5 and 1.0 g body weight/kg) and placebo drinks to nine healthy subjects according to a double-blind cross-over design.

2. Intake of ethanol (at 19.00–19.45 hours) inhibited the nocturnal increase in the plasma atrial natriuretic peptide 99–126 level dose-dependently (P < 0.05), but had no effect on the plasma atrial natriuretic peptide 1–98 level. Serum osmolality and serum sodium concentration were elevated dose-dependently for 2–5 h after the ethanol intake. Urine volume increased after the higher ethanol dose (net loss of 0.6 litre of water).

3. Since the plasma atrial natriuretic peptide 1–98 level was not changed after ethanol intake, we propose that the alcohol-induced inhibition of the nocturnal rise in the plasma atrial natriuretic peptide 99–126 level is not caused by an inhibition of release, but may rather reflect an increased peripheral elimination of atrial natriuretic peptide 99–126.
α- and β-Cell Function in Obese Zucker (fa/fa) Rats: A Study with the Isolated Perfused Pancreas
Authors: Hirose Dr Hiroshi , Maruyama Hiroshi , Kido Koichi , Ito Katsuhiko , Koyama Kazunori , Tashiro Yukio , Saruta Takao
Published: August 2015

1. The effects of various stimuli, including changes in glucose concentration, arginine, tyramine and noradrenaline, on insulin and glucagon secretion were investigated using isolated perfused pancreata of obese and lean male Zucker rats at 12 months of age.

2. In Zucker fatty rats, the insulin secretion rate was significantly (P < 0.01) higher than that of lean rats at all glucose concentrations tested (8.3, 16.7 and 1.4 mmol/l). However, the integrated insulin secretory response to raising the glucose concentration from 8.3 to 16.7 mmol/l was almost absent in these rats. The glucagon secretion rates were significantly lower at 8.3 and 1.4 mmol/l glucose (P < 0.001 for both), and in responses to 10 μg/ml tyramine and 0.1 μmol/l noradrenaline (P < 0.05 for both), in Zucker fatty rats. Integrated insulin and glucagon responses to 10 mmol/l arginine were identical in the two groups.

3. Histopathological and immunochemical studies revealed hyperplasia of β-cells and scattered α-cells in the enlarged islets of Zucker fatty rats.

4. These results suggest that, in Zucker fatty rats, the decreased glucagon secretion in the isolated perfused pancreas is attributable to changes in the environment of α-cells and/or the inhibitory effects of hypersecreted insulin.
Assessment of Insulin Sensitivity in Man: A Comparison of Minimal Model- and Euglycaemic Clamp-Derived Measures in Health and Heart Failure
Authors: Swan Jonathan W. , Walton Christopher , Godsland Ian F.
Published: August 2015

1. Simplified protocols for the measurement of insulin resistance will facilitate studies of this potentially important variable.

2. Using the euglycaemic clamp as the reference technique, we have assessed the validity of the insulin sensitivity index (inversely related to insulin resistance) obtained using a high-dose (500 mg/kg), unmodified intravenous glucose tolerance test with a 16 point sampling schedule and analysis using the minimal model of glucose disappearance. The two methods were compared in 10 clinically normal subjects and five patients with severe heart failure secondary to coronary heart disease.

3. The insulin sensitivity index of the minimal model was compared with four clamp-derived measures. Correlation coefficients of 0.72–0.92 (P < 0.01−P < 0.001) were obtained between the two methods over a wide range of insulin sensitivity [model values 1.03–14.63 min−1/(pmol/l) × 10−5]. Patients with heart failure had the lowest measures of insulin sensitivity.

4. The high-dose, unmodified intravenous glucose tolerance test with minimal model analysis is a straightforward and economical clinical procedure and provides a valid measure of insulin sensitivity, in health and disease.
Production of Interleukin-6 and Tumour Necrosis Factor-α in Vitro Is Reduced in Whole Blood of Severely Malnourished Children
Authors: Doherty J. F. , Golden M. H. N. , Remick D. G. , Griffin G. E.
Published: August 2015

1. Cytokine production in vitro was assessed in 16 malnourished children, before and after nutritional recovery.

2. Tumour necrosis factor-α and interleukin-6 were measured in whole blood after lipopolysaccharide stimulation.

3. The total amount of both cytokines was significantly less after 24 h incubation among malnourished children when compared with the same children after nutritional rehabilitation.

4. Cytokine production in vitro is impaired in severely malnourished children.
Acute Sodium Loading in Patients with Uncomplicated Diabetes Mellitus: Renal and Hormonal Effects
Authors: Beretta-Piccoli Carlo , Elshater-Zanetti Francesca , Shaw Sidney , Cusi Daniele , Weidmann Peter
Published: August 2015

1. Diabetes mellitus is associated with high body sodium, but the pathogenetic mechanism is still unknown. The possibility that an abnormal renal handling of sodium, an abnormal responsiveness of sodium-modulating factors or a shift in the set point for sodium metabolism may contribute to or be associated with sodium retention was tested with an acute saline infusion.

2. A consecutive sample of 33 patients with stable non-azotaemic diabetes mellitus (24 insulin-dependent patients) and 30 normal control subjects was studied. Two litres of a 0.9% NaCl infusion were infused over 4 h. The urinary sodium excretion during the infusion and the next 18 h was analysed in relation to blood pressure, creatinine and lithium clearances, Na+−K+ co-transport, Na+−Li+ countertransport, plasma levels of renin, angiotension II, aldosterone, noradrenaline, adrenaline, atrial natriuretic factor and digoxin-like factor.

3. Diabetic patients and control subjects did not differ in blood pressure, body mass index, clearances of creatinine, sodium or lithium, intracellular sodium, Na+−K+ co-transport and Na+−Li+ countertransport, urinary and plasma levels of digoxin-like factor, plasma renin activity, angiotensin II, aldosterone, noradrenaline, adrenaline and atrial natriuretic factor. The intravenous saline infusion caused a similar natriuresis in diabetic patients and normal subjects; the renin—angiotension-aldosterone system was suppressed to a higher degree in diabetic patients than in normal subjects, whereas atrial natriuretic factor was stimulated to a similar extent; plasma digoxin-like activity was unchanged in both groups.

4. The natriuretic response to saline infusion was comparable between patients with insulin-dependent and non-insulin-dependent diabetes mellitus, those with lower or higher HbA1c levels and those with positive or negative family history of essential hypertension.

5. Using an acute saline infusion to study sodium-modulating factors, no abnormality can be detected which could represent a pathogenetic mechanism for sodium retention in diabetes mellitus. The normal natriuretic response to acute sodium loading in diabetic patients indicates that the set point for sodium homoeostasis may be normal despite the presence of high exchangeable sodium.
Acute Effects of Intravenous Ouabain in Healthy Volunteers
Authors: Pidgeon G. B. , Richards A. M. , Nicholls M. G. , Lewis L. K. , Yandle T. G.
Published: August 2015

1. The influence of single-dose intravenous ouabain on haemodynamics, renal function and vasoactive hormones was investigated in healthy subjects.

2. After ouabain injection there was a significant reduction in minimum and average hourly heart rates. Diastolic blood pressure fell immediately after ouabain, without a significant change in systolic blood pressure.

3. There was no change in renal blood flow, glomerular filtration rate, hourly urine volume or sodium and potassium excretion.

4. Ouabain injection was associated with a fall in plasma angiotensin II levels and a rise in plasma adrenaline levels, but plasma noradrenaline levels were unchanged. Both plasma atrial and brain natriuretic peptide levels were increased after ouabain administration.

5. The present study demonstrates that ouabain has significant although minor, acute effects on plasma levels of vasoactive hormones. It fails, however, to confirm that ouabain is an acute pressor or natriuretic substance. If it has an important influence on electrolyte and haemodynamic homoeostasis, its actions are likely to be slowly developed.
Effects of Vasopressin V1 and V2 Receptor Antagonists on Progressive Renal Failure in Rats
Authors: Okada Hirokazu , Suzuki Hiromichi , Kanno Yoshihiko , Yamamura Yoshitaka , Saruta Takao
Published: August 2015

1. The relationship between vasopressin and the progression of renal failure has been proposed, but not intensively investigated because of a lack of orally available, selective vasopressin antagonists.

2. The effects of novel, orally available vasopressin V1 and V2 receptor antagonists on several indices of the progression of chronic renal failure, i.e. blood pressure, urinary protein excretion, sodium balance and renal histopathology, were investigated by using Wistar rats with adriamycin-induced nephropathy accelerated by deoxycorticosterone acetate-salt hypertension. Groups 2 and 3 were treated with V1 and V2 antagonists, respectively, while the untreated group 1 served as the control. To block the effects of vasopressin efficaciously, V1 and V2 antagonists were simultaneously administered (group 4).

3. At week 6, 2 weeks after the beginning of administration of deoxycorticosterone acetate-salt and vasopressin antagonists after the second injection of adriamycin, V1 and V2 antagonists given either alone or in combination significantly reduced the systolic blood pressure as compared with the control, and urine volume was increased in groups 3 and 4. The proteinuria was also decreased at week 10 in groups 2, 3 and 4. Differences in sodium excretion between all groups were not significant. Histopathological alterations in the kidneys of group 4 were significantly ameliorated.

4. These results suggest that a combination of V1 and V2 antagonists can have therapeutic effects in certain types of chronic renal failure.