bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of skeletal muscle sodium pumps in the adaptation to potassium deprivation
Authors: McDONOUGH A. A. , THOMPSON C. B.
Published: November 2003

Skeletal muscle is specialized to lose K+ to the extracellular fluid during potassium deprivation which buffers the fall in plasma K+ concentration. While it remains to be determined whether K+ efflux from muscle is altered during K+ deprivation, active K+ uptake driven by sodium pumps is significantly depressed. The activity of sodium pumps in skeletal muscle does not increase during K+ depletion despite elevated intracellular Na+, a strong stimulus to increase activity in other cells. There is a decrease in the total pool size of sodium pump αβ heterodimers during potassium deprivation. The α2 (not the α1) sodium pump isoform is specifically decreased and β1 and/or β2 decreases in a muscle‐fibre‐dependent manner. The specific loss of K+ from skeletal muscle is probably a consequence of the fact that the α2 isoform predominates in this tissue. In tissues such as heart, where α2‐type pumps are only a minor fraction of the sodium pumps, the activity of the ubiquitous α1 isoform maintains intracellular Na+ and K+ at control levels, despite the fact that α2 levels decrease by 50%. Analysis of the time course of change in α2 mRNA vs. protein during K+ deprivation indicates that there is both a decrease in α2 synthesis and an increase in α2 degradation. The apparent time‐lag during potassium deprivation between the early decreases in both surface α2‐type sodium pump number (assessed by 3H‐ouabain binding) and intracellular K+, and the later decrease in total pool size of α2, suggests the hypothesis that there may be an early internalization of α2‐type sodium pumps to endosomal pools, followed by a degradation of these internalized pumps, contributing to the decrease in total α2 pool size. The signals mediating this specific response to hypokalemia, and those mediating the restoration of muscle K+ stores remain to be determined.
Membrane abnormalities and Ca homeostasis in muscles of the mdx mouse, an animal model of the Duchenne muscular dystrophy: a review
Authors: GILLIS J. M.
Published: November 2003

Muscles of the mdx mouse lack dystrophin, a cytoskeletal protein. Mdx fibres exhibit an increased fragility to hypo‐osmotic shock and to forced lengthening, an abnormal opening time of stretch‐sensitive calcium channels. The question of a chronic elevated [Ca2+]i value is a matter of controversy.

We have analysed Ca homeostasis in smooth and skeletal muscles from the adult mdx mouse. The wall of the vas deferens was loaded with the fluorescent Ca indicator Fura‐2‐AM (cell‐diffusible). Resting [Ca2+]i was measured after changes of the electrochemical potential for Ca2+ and after KCl or electrical stimulations. In no instance was a difference observed between these and similar muscles from control mice.

Single striated fibres were isolated by collagenase treatment of the flexor digitorum brevis muscle and loaded with Fura‐2‐AM. The value of resting [Ca2+]i was measured using an in situ calibration procedure which took account of Ca buffering by Fura‐2. A chronic increase of cytosolic Ca2+ was not confirmed.

The expression of the intracellular Ca‐binding protein, parvalbumin, was measured. It increased by about threefold in fast mdx muscles (tibialis anterior) but remained undetectable in the soleus. It is hypothesized that parvalbumin helps to maintain [Ca2+]i within normal values. This hypothesis will be discussed in connection with dystrophy phenotypes in mutant dogs and in human patients.
Ion transport in human skeletal muscle cells: disturbances in myotonic dystrophy and Brody's disease
Authors: BENDERS A. A. G. M. , WEVERS R. A. , VEERKAMP J. H.
Published: November 2003

After excitation of skeletal muscle, the disturbed ion homeostasis is restored by Na+, K+ ATPase of the sarcolemma and Ca2+ ATPase of the sarcoplasmic reticulum (SR). Contrary to Na+, K+ ATPase, the concentration and isoenzyme distribution of SR Ca2+ ATPase in human skeletal muscle depend on fibre type and age. In cultured human muscle cells the concentration and activity of Na+, K+ ATPase and SR Ca2+ ATPase increase with maturation.

In skeletal muscle and cultured muscle cells of patients suffering from myotonic dystrophy (MyD), the activity and the concentration of both Na+, K+ ATPase and SR Ca2+ ATPase are decreased by about 40%. In addition, we measured in cultured MyD muscle cells at rest an increased cytosolic Ca2+ concentration ([Ca2+]i) caused by active voltage‐operated Ca2+ channels, which are inactive in resting control cells. However, the restoration of a stimulus‐induced Ca2+ transient is unaffected. A differentiation‐related disturbance of membranes or a modulation defect of membrane proteins may play a role in MyD.

In skeletal muscle and cultured muscle cells of patients suffering from Brody's disease, which is characterized by impaired muscle relaxation, the SR Ca2+ ATPase activity is reduced by about 50%, but the concentrations of total SR Ca2+ ATPase and the predominant SERCA1 isoform are normal. Diseased muscle cells show a delayed restoration of [Ca2+]i after stimulation, which might be explained by structural modifications of SERCA1. Reduction of the Ca2+ release by drugs balances the excitation–relaxation cycle of the pathological cells.
Effects of thyroid hormones on contractility and cation transport in skeletal muscle
Authors: EVERTS M. E.
Published: November 2003

Skeletal muscle is one of the major target organs for thyroid hormone. The muscles most commonly affected are those used during prolonged effort (slow‐twitch muscles). One of the major clinical features is the shortening of the Achilles‐tendon reflex time in hyperthyroidism and its prolongation in hypothyroidism. Most of the peripheral effects of the thyroid hormones can be ascribed to the action of triiodothyronine (T3), which is produced by de‐iodination of thyroxine (T4) in liver and kidney. From the plasma, T3 is actively transported into skeletal muscle. The Ca2+ ATPase in skeletal muscle is responsible for removal of Ca2+ ions from the cytosol into the sarcoplasmic reticulum (SR) during relaxation, and the Na+, K+ ATPase in the plasma membrane is responsible for restoration of the membrane potential after excitation. The concentrations of Ca2+ ATPase and Na+, K+ ATPase in rat skeletal muscle have been shown to increase four‐ and 10‐fold, respectively, in the transition from the hypothyroid to the hyperthyroid state. In humans, a linear correlation between the Na+, K+ ATPase concentration of skeletal muscle and the free T4 index was established. Significant effects of T3 on Ca2+ ATPase and Na+, K+ ATPase can be detected 24 h after a single injection. These effects are mediated by increased production of mRNA for the respective proteins, initiated by binding of T3 to nuclear receptors. Passive fluxes of Ca2+, Na+ and K+ also show a significant rise after T3 treatment. The increase in passive fluxes of Na+ and K+ can be detected before the rise in the concentration of Na+, K+ ATPase, suggesting that T3, in addition to its nuclear effects, may have a direct effect on the plasma membrane. Apart from their significance for muscle function in thyroid disease, the changes in Ca2+ ATPase and Na+, K+ ATPase will be important in other conditions where T3 and T4 levels show dramatic changes, i.e. during postnatal development, starvation and undernutrition, as well as in non‐thyroidal illness (low‐T3 syndrome).
Muscular function, metabolism and electrolyte shifts during prolonged repetitive exercise in humans
Authors: VØLLESTAD N. K. , VERBURG E.
Published: November 2003

Marked functional changes occur in human skeletal muscle during prolonged repetitive exercise. The maximum voluntary contraction force (MVC) falls gradually and may reach 50% of control within 30–60 min. The twitch tension declines faster and to a larger extent. During repetitive submaximal isometric contractions, the rate of relaxation increases progressively, in parallel with an increased energy cost of contraction. These functional changes are all slowly reversed in the post‐exercise period, as indicated by only minor changes over the first 30 min of recovery. Minor changes in substrates and metabolites, together with the slow rate of recovery, indicate that the alterations in contractile properties and energetics are independent of these metabolic factors. Alternative explanations may be related to electrolyte shifts over the sarcolemma or between cellular compartments. The total loss of K+ is small, and could not be detected by analysis of muscle biopsies. Only a slight initial rise in muscle content of calcium was found. The available data indicate that the increased energy cost of contraction is not connected to mitochondrial dysfunction, which might be caused by calcium accumulation. Rather, it seems that the ratio of ATP utilization to force is increased, and this could possibly be connected to the faster relaxation rate. Considering the low excitation rates during submaximal voluntary contractions, each motor unit generates an oscillating force closely associated with Ca2+ fluctuations between SR and cytosol. Increased relaxation rate might be caused by faster reuptake of Ca2+ into the SR, and this could contribute to the faster ATP turnover.
Potassium and fatigue: the pros and cons
Authors: SJØGAARD G.
Published: November 2003

A general finding is that muscle activity leads to potassium fluxes across the muscle membrane as well as to muscle fatigue, defined as a reduction in the force‐generating capacity of the muscle. However, much controversy exists regarding the causal role of potassium in fatigue development. The experimental model used is decisive in this context, e.g. whether we study intact in vivo organs in situ with voluntary contractions and reflex feedback for cardiorespiratory regulation, or whether we study in vitro isolated muscles or cells – or even skinned fibres. In the latter models, clear evidence has been presented that Ca2+ is the variable significant for force development and that K+ may be ignored. However, in the in situ situation the limiting link in the chain leading to muscle contraction may be one preventing the Ca2+ release from taking place. The sites are the triads, T‐tubules, and the surface membrane. The function of the latter two regarding action potential amplitude and propagation depends on [K+] gradients. Again, conflicting results exist regarding the electrophysiological changes and [K+] in fatigue. The activity pattern must then be taken into consideration. During high‐intensity (high‐frequency) activity the increased interstitial [K+] has been demonstrated to relate to fatigue, while in low‐intensity fatiguing protocols, the T‐tubule may be the limiting site. This fits with the concept of interstitial [K+] playing an essential role as a regulatory feedback mechanism, e.g. adjusting muscle blood flow to the metabolic load during muscle activity.
Modulation of muscle contractility during fatigue and recovery by ATP‐sensitive potassium channel
Authors: RENAUD J.‐M. , GRAMOLINI A. , LIGHT P. , COMTOIS A.
Published: November 2003

The activity of ATP‐sensitive potassium channels of skeletal muscle is controlled by changes in the bioenergetic state of the cell. These channels are inactive in unfatigued muscle and become activated during fatigue. It has been postulated that ATP‐sensitive potassium channels shorten the action potential duration, increase the potassium efflux and contribute to the decrease in force during fatigue. Although blocking ATP‐sensitive potassium channels during fatigue prolongs the action potential duration and decreases the potassium efflux as expected, it does not affect the rate of fatigue development, as observed from the decrease in tetanic force. Even though such results are not consistent with the hypothesis that ATP‐sensitive potassium channels contribute to the decrease in force during fatigue, a reduced capacity of skeletal muscles to recover their tetanic force following fatigue is also observed when ATP‐sensitive potassium channels are blocked during fatigue, suggesting that these channels have a myoprotective effect. It is thus possible that removing this myoprotection during fatigue results in deleterious effects which counteract the expected slower decrease in force. However, ATP‐sensitive potassium channel openers also fail to affect the rate of fatigue development. Therefore, the results obtained so far do not support the hypothesis that ATP‐sensitive potassium channels contribute to the decrease in force during fatigue.
Calcium uptake and release modulated by counter‐ion conductances in the sarcoplasmic reticulum of skeletal muscle
Authors: FINK R. H. A. , VEIGEL C.
Published: November 2003

The sarcoplasmic reticulum (SR) plays the central role in regulating the free myoplasmic Ca2+ level for the contractile activation of skeletal muscle. The initial stages of the voltage‐controlled Ca2+ release mechanism are known in molecular detail. However, there is still very little known about the later stages of Ca2+ uptake and total Ca2+ turnover in the contraction–relaxation cycle under normal physiological conditions or under conditions influenced by fatigue or disease. Ca2+ uptake and release are both accompanied by ‘counter‐ion’ movements across the SR membrane which prevent or reduce the generation of SR membrane potentials and balance for electroneutrality in the SR lumen. The SR membrane is permeable for the cations K+, Na+, H+ and Mg2+ and the anion Cl‐. Using electron‐probe X‐ray microanalysis, it has been shown that during tetanic stimulation the Ca2+ release was mainly balanced by uptake of K+ and Mg2+, leaving a charge deficit that was assumed to be neutralized via H+ ion or organic counter‐ion movement. The low time resolution of electron‐probe X‐ray microanalysis leaves the possibility of other transient concentration changes in the SR, e.g. for Cl‐ ions. Possible physiological roles of the SR counter‐ion conductances can be tested using skinned muscle fibre preparations with intact sarcoplasmic reticulum and removed or chemically permeabilized outer sarcolemma. In skinned fibres, the SR K+ conductance can be effectively reduced with SR K+ channel blockers such as 4‐aminopyridine, tetraethylammonium and decamethonium. Interestingly, these blockers increase Ca2+ loading as well as Ca2+ release, whereas other less specific blockers, such as 1.10‐bis‐quanidino‐n‐decane, seem to reduce Ca2+ release, possibly also via blocking Ca2+ release channels. Thus, it seems very important also to test the effects of counter‐currents carried by K+, Mg2+, H+ or Cl‐ ions on intact and voltage‐clamped single‐fibre preparations.
Role of l‐arginine in preventing myocardial and endothelial injury following ischaemia/reperfusion in the rat isolated heart
Authors: LI X.‐S. , URIUDA Y. , WANG Q.‐D. , NORDLANDER R. , SJÖQUIST P.‐O. , PERNOW J.
Published: November 2003

The protective effect of l‐arginine on ischaemia/reperfusion‐induced myocardial injury was investigated in the rat isolated Langendorff perfused heart. Six groups of hearts subjected to 30 min global ischaemia and 30 min reperfusion received either vehicle, d‐arginine, l‐arginine, the nitric oxide (NO)‐donor S‐Nitroso‐N‐Acetyl‐d, l‐Penicillamine (SNAP), the inhibitor of NO formation NG‐nitro‐l‐arginine (l‐NNA), or l‐arginine plus l‐NNA. The recoveries of left ventricular double product and coronary flow at the end of reperfusion were significantly higher in the l‐arginine group (85±5 and 75±6%, respectively) than in the vehicle group (37±6 and 34±5%, respectively, P<0.05). During both the ischaemic and reperfusion periods, left ventricular end diastolic pressure was lower in the l‐arginine group than in the vehicle group. Creatine kinase outflow and the area of no‐reflow were smaller in the l‐arginine treated hearts (P<0.01). There were no differences between vehicle and d‐arginine treated groups. l‐NNA did not affect recovery per se but abolished the protective actions of l‐arginine. SNAP produced the same protective effects as l‐arginine. Acetylcholine‐induced endothelium‐dependent vasodilation was reduced after ischaemia and reperfusion in the vehicle group but not in the l‐arginine group. It is concluded that l‐arginine reduces ischaemia/reperfusion‐induced myocardial and endothelial injury. The results suggest that the beneficial effects of l‐arginine are related to preserved synthesis and release of NO.
Effects of sympathetic inhibition on blood pressure and renal responses to central hypervolaemia in normal humans
Authors: KREUTZ R. , KRUSE H.‐J. , OVERLACK A. , STUMPE K. O. , KOLLOCH R. E.
Published: November 2003

The purpose of this study was to evaluate the effects of short‐term sympathetic inhibition with clonidine on blood pressure and renal responses to central hypervolaemia induced by thermoneutral head‐out water immersion. Eleven healthy subjects were randomly studied on two occasions, during a 1 h pre‐immersion period, 2 h of water immersion and a 1 h post‐immersion period, after either placebo or clonidine treatment. Clonidine caused a significant suppression of plasma adrenaline, plasma noradrenaline, urinary noradrenaline excretion and mean arterial blood pressure. Blood pressure remained constant during water immersion after both placebo and clonidine, compared with the respective pre‐immersion control values. The suppression pattern of plasma catecholamines and urinary noradrenaline in response to water immersion during placebo was similar after clonidine treatment. Renal volume excretion was not affected by clonidine. In contrast, clonidine caused a significant attenuation of the immersion‐induced stimulation of natriuresis (maximum ‐33±12%, P<0.01, compared with placebo). These data indicate that the renal capacity to excrete sodium is impaired during moderate blood pressure reduction by short‐term sympathetic inhibition with clonidine, whereas the regulation of arterial blood pressure in response to central hypervolaemia is maintained.
Effects of acute and chronic unilateral renal denervation on the tubuloglomerular feedback mechanism
Authors: THORUP C. , KURKUS J. , OLLERSTAM A. , PERSSON A. E. G.
Published: November 2003

We recently observed a time‐dependent resetting of the tubuloglomerular feedback (TGF) sensitivity to a subnormal level after acute unilateral renal denervation (aDNX). The present investigation compares the effects of aDNX with those of chronic unilateral renal denervation (cDNX), i.e one week after aDNX. All experiments were performed in anaesthetized rats prepared for micropuncture. cDNX led to increases in urine, sodium and potassium excretion in denervated kidneys, while contralateral kidneys showed reduced excretion of these parameters. GFR was increased in denervated kidneys, but unchanged on the contralateral side. TGF activity was determined by measuring the maximal stop‐flow pressure response (ΔPsf) and the tubular flow rate at which 50% of the maximal response occurred (turning point; TP). cDNX decreased TGF sensitivity, as indicated by an increased TP from 19.1 nL/min in sham‐DNX to 26.1 nL/min. Concomitantly, TP in contralateral kidneys was significantly decreased to 15.9 nL/min. aDNX led to a greater sensitivity reduction; TP increased from 19.8 to 34.0 nL/min and contralaterally TP decreased to 14.0 nL/min. ΔPsf in cDNX increased by 63% compared to sham‐DNX, while on the contralateral side this was unchanged. No difference in ΔPsf was found between control, DNX and contralateral kidneys in the aDNX group. In summary, these experiments show that the previously reported decrease in TGF sensitivity in aDNX kidneys still persists after one week, although less pronounced. As a result of the decreased TGF sensitivity, GFR is kept on a high level in cDNX kidneys. Contralateral kidneys show reversed resetting.
The relationship between interstitial fluid pressure and volume in rat trachea
Authors: WOIE K. , REE R. K
Published: November 2003

A change of interstitial fluid volume (IFV) will normally change the interstitial fluid pressure (Pif) so as to counteract further fluid movement across the capillaries and changes in IFV. Contrary to this, several acute inflammatory reactions in the trachea are associated with increased negativity of Pif, which will interstitial fluid balance in the trachea, interstitial compliance (ΔIFV/ΔPif) was measured in pentobarbital anaesthetized rats. IFV was measured as the plasma equivalent extravascular distribution space of [51Cr]EDTA. Pif was measured in the same animal with sharpened glass pipettes (diameter 3–6 μm) connected to a servocontrolled counterpressure system. In dehydration (30 mL saline i.v., n=10) interstitial compliance was 0.083 mL g dry wt‐1 mmHg‐1. Since control IFV was 1.046 mL g dry wt‐1 (n=10) the interstitial compliance is 8% of IFV per mmHg. In overhydration (30 mL NaCl, n=10) and dextran anaphylaxis (1 mL dextran 70, n=10) compliance remained the same for the first 15% increase in IFV and then increased several‐fold since Pif did not increase more than 2 mmHg above control level. The increased negativity of Pif by ‐10 mmHg associated with acute inflammation will require a reduction of IFV by 80% when interstitial compliance is 8% per mmHg. A more likely explanation is therefore that structural rearrangements are responsible for the events leading to increased negativity of Pif in acute inflammation.
Local vascular responses to elevation of an organ above the heart
Authors: ASGEIRSSON B. , GRÄNDE P.‐O.
Published: November 2003

Elevation of an organ above the heart reduces the arterial and venous hydrostatic pressures in proportion to the height of elevation. Intact autoregulation protects organs, such as the brain and skeletal muscle, from significant alterations in blood flow and hydrostatic capillary pressure due to the decrease in arterial inflow pressure during such a manoeuvre. However, the consequences of the decreased hydrostatic pressure on the venous side are far from clarified.

The present study analyses the local haemodynamic effects of the decrease in arterial and venous hydrostatic pressures that occur during vertical elevation of an organ above the heart at atmospheric and raised tissue pressures (0, 10 and 30 mmHg). A sympathectomized cat skeletal muscle enclosed in a plethysmograph and perfused from the animal was used as the experimental model.

The results show that elevation of the muscle above the heart at atmospheric tissue pressure created a variable vascular resistance starting at the venous outlet of the organ, and related to the difference between tissue pressure and venous outflow pressure. This resistance completely protects the organ from the hydrostatic pressure alterations on the venous side. The results also show that arterial pressure variations will exert the same haemodynamic influences on the organ as tissue pressure variations, except for the formation of the venous outflow resistance at raised tissue pressure.

The application of these results to normal and injured organs, e.g. normal and injured skeletal muscle and brain, with various tissue pressures, is discussed.
The effect of lesions of the sympathoadrenal system on training induced adaptations in adipocytes and pancreatic islets in rats
Authors: STALLKNECHT B. , ROESDAHL M. , VINTEN J. , CAPITO K. , GALBO H.
Published: November 2003

Physical training increases insulin stimulated glucose uptake in adipocytes and decreases insulin secretion from pancreatic islets. The mechanism behind these adaptations is not known. Because in acute exercise adrenergic activity influences both adipocytes and pancreatic islets, the sympathetic nervous system was examined as the possible mediator. Rats were either adrenodemedullated or sham adrenodemedullated and underwent either unilateral abdominal sympathectomy or were sham sympathectomized. Resting plasma adrenaline concentration in adrenodemedullated rats was 32% of the concentration in sham adrenodemedullated rats (P<0.0001) and muscle noradrenaline content in sympathectomized leg was 9% of content in sham sympathectomized leg (P<0.0001). After operations rats were either swim trained for 10 weeks or remained sedentary. Insulin stimulated 3‐O‐[14C]methylglucose transport was measured in adipocytes from epididymal fat pads, and insulin secretion and glucose metabolism were measured in glucose stimulated pancreatic islets. Training increased insulin stimulated glucose transport in adipocytes (P<0.0001) and decreased their size (P<0.0001), but neither adrenodemedullation nor sympathetic denervation affected these parameters significantly. Training decreased insulin secretion (P<0.01) and increased glucose oxidation (P=0.02) and utilization (P=0.08) in pancreatic islets, but none of these parameters was affected significantly by adrenodemedullation. It is concluded that adrenergic activity is not important for the training induced decrease in size and increase in insulin stimulated glucose transport of adipocytes. Neither is an intact adrenal medulla necessary for training‐induced adaptations in pancreatic beta cell function. Finally, in response to training, β cell insulin secretion and glucose metabolism changed in opposite directions.
The influence of extracellular Ca2+ on the time course of isovolumetric pressure development in the guinea‐pig urinary bladder
Authors: GROEN J. , VAN MASTRIGT R. , BOSCH R.
Published: November 2003

Isovolumetric contractions were induced electrically in five guinea‐pig bladders in a 1.8 mm Ca2+ buffer solution at two different volumes. The rate of pressure development was studied by analysis of phase‐plots, which are plots of the rate of change of intravesical pressure as a function of pressure. At relatively large volumes the rate of pressure development showed a biphasic nature, suggesting that two different processes were involved in different phases of contraction. Extracellular Ca2+ was manipulated to identify these processes. Removal of extracellular Ca2+ led to an 85% reduction of the maximum isovolumetric pressure in subsequent stimulations, but pressure developed faster. The biphasic nature of pressure development at large volumes tended to disappear. It was concluded that at large bladder volumes pressure development in this type of smooth muscle is determined by the release of intracellularly stored Ca2+ in the early phase of contraction. In the final phase the rate of pressure development is limited by the extracellular Ca2+ influx. At small bladder volumes the Ca2+ influx takes place at a higher rate, so that the contribution of intracellular Ca2+ release to pressure development could not be identified at these volumes.
Central command increases cardiac output during static exercise in humans
Authors: WILLIAMSON J. W. , OLESEN H. L. , POTT F. , MITCHELL J. H. , SECHER N. H.
Published: November 2003

Neural control of the circulation during static two‐leg exercise was evaluated in 10 subjects. External compression of the legs was employed to assess muscle mechano‐receptor influence by achieving the same intramuscular pressure (80 mmHg) as developed during exercise. The muscle metabo‐reflex contribution was assessed by post‐exercise muscle ischaemia, and the influence from higher centres in the central nervous system (‘central command’) was taken as the part of the response that could not be accounted for by the two reflex contributions. During static exercise, mean arterial pressure was higher (26±3 mmHg; P<0.01) as compared with leg compression (10±2 mmHg) and with post‐exercise muscle ischaemia (11±2 mmHg). Heart rate (25±4 b.p.m.) and cardiac output (0.8±0.3 L min‐1) were increased only during static exercise (P<0.05). Increase in total peripheral resistance were similar during static exercise, post‐exercise muscle ischaemia and leg compression. The pressor response to static exercise with a large muscle group was equally attributable to mechanical and metabolic stimulation of afferent nerves; and the two influences were redundant in their effect on total peripheral resistance. In contrast, the influence from central command was directed to the heart with elevation of its rate and minute volume.
Do we still need dipyridamole?
Authors: Gibbs Christopher R. , Lip Gregory Y. H.
Published: November 2003

There is limited evidence that dipyridamole is generally an effective antithrombotic agent when used alone, nor is there convincing evidence that the combination of aspirin and dipyridamole is more effective than aspirin alone, except perhaps in cerebrovascular disease. There is no consistent evidence to support the routine use of dipyridamole after coronary artery bypass grafting and in patients with occlusive peripheral vascular disease, although these remain common reasons for its use. Dipyridamole is a useful agent in ‘pharmacological stress’ testing in nuclear cardiology imaging and may be valuable when combined with warfarin in certain patient groups, such as those with prosthetic heart valves. When combined with aspirin, dipyridamole may be of value in the secondary prophylaxis of cerebrovascular disease, although further studies are clearly needed. In a significant proportion of cases, evidence‐based medicine cannot support the current widespread continued prescription of dipyridamole in cardiological practice, but the jury is still out on cerebrovascular disease.
Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man
Authors: Kupferschmidt Hugo H. T. , Fattinger Karin E. , Ha Huy Riem , Follath Ferenc , Krähenbühl Stephan
Published: November 2003

Aims
 Saquinavir is a potent HIV protease inhibitor whose effectiveness is limited in vivo by its low bioavailability. Since saquinavir is metabolized by CYP3A4, the effect of grapefruit juice, an inhibitor of CYP3A4, was investigated on its bioavailability.

Methods
 After an overnight fast, eight healthy volunteers were treated with either 400 ml grapefruit juice or water before intravenous (12 mg) or oral saquinavir (600 mg) was administered. Serial blood samples were obtained over the following 24 h and standardized meals were served 5 and 10 h after the administration of saquinavir. The plasma concentrations of saquinavir were determined by high‐performance liquid chromatography and pharmacokinetic parameters were calculated by routine methods.

Results
 The AUC was not affected by grapefruit juice after intravenous administration, but it increased significantly from 76±96 (water, mean (s.d.) to 114±70 (μg l−1 h (grapefruit juice) after oral saquinavir. Similarly, the oral bioavailability of saquinavir increased by a factor of 2 with grapefruit juice (from 0.7% to 1.4%). In contrast, clearance, volume of distribution and elimination half‐life of saquinavir were not affected by grapefruit juice. After oral, but not after intravenous administration, the plasma concentration‐time curve showed a second peak after lunch irrespective of pretreatment, suggesting enhancement of absorption by food.

Conclusions
 The studies demonstrate that grapefruit juice increases the bioavailability of saquinavir without affecting its clearance, suggesting that inhibition of intestinal CYP3A4 may contribute. Since the antiretroviral effect of saquinavir is dose‐dependent, inhibition of CYP3A4 may represent a way to enhance its effectiveness without increasing the dose.
Integrating clinical pharmacology teaching with general practice
Authors: Shenfield Gillian M.
Published: November 2003

Aims
 To make Clinical Pharmacology teaching relevant and introduce students to therapeutic problems relevant to general practice.

Methods
 Six topics in the ‘core curriculum’ for Clinical Pharmacology were taught jointly by a Clinical Pharmacologist and General Practitioners (GPs). Formal teaching was reduced by issuing handouts containing copies of the overheads used. At least half the time was spent on interactive discussion of case histories.

Results
 Students rated the sessions more highly than other Clinical Pharmacology teaching and were not disadvantaged in examinations. All participants enjoyed and learnt from the experience and the GPs gained confidence in their ability to teach.

Conclusions
 This simple method is ideal for teaching Clinical Pharmacology and Therapeutics.
Are altered pharmacokinetics of non‐steroidal anti‐inflammatory drugs (NSAIDs) a risk factor for gastrointestinal bleeding?
Authors: Wynne H. A. , Long A. , Nicholson E. , Ward A. , Keir D.
Published: November 2003

Aims
 We hypothesised that pharmacokinetic factors might go some way to explaining the risk of major gastrointestinal haemorrhage with non‐steroidal anti‐inflammatory drugs (NSAIDs), with bleeders exhibiting a reduced clearance of NSAIDs compared with non‐bleeders and set out to investigate this.

Methods
 Fifty patients presenting to hospital with acute gastrointestinal bleeding while taking piroxicam, indomethacin, diclofenac or naproxen and age, sex, musculoskeletal disease and drug matched community dwelling controls, up to two for each index case, who had not bled were recruited. Clinical details including duration of therapy were recorded. Bleeders discontinued the implicated NSAID at presentation, controls at least five half‐lives before the study. Bleeders were contacted by letter 1 month after discharge and invited to take part and were studied after a median delay of 5 months. Subjects received an oral dose of their respective NSAID and venous blood was sampled, over a period determined by the half‐life of the NSAID. Plasma concentrations were determined by high performance liquid chromatography.

Results
 The median length of treatment for the index patients was 1 year (range 2 weeks—28 years) and for the control patients 2 years (1 month—25 years), P<0.0005. There were no significant differences in peak plasma concentration, time to peak plasma concentration or area under the plasma concentration‐time curve between bleeders or controls for any of the NSAIDs studied, apart from piroxicam Cmax being lower in bleeders at 2.07 mg l−1 than in controls at 3.21 mg l−1, mean difference (95% CI) −1.14 (−1.83–−0.48), P<0.005.

Conclusions
 The data failed to support the hypothesis that reduced clearance of NSAIDs, which results in higher plasma concentrations, is a risk factor for acute gastrointestinal haemorrhage.
Indicators for Drug and Therapeutics Committees
Authors: Weekes Lynn M. , Brooks Colleen , Day Richard O.
Published: November 2003

Aims
 This study describes development and field testing of a set of indicators for drug and therapeutics committees (DTCs) in hospitals. It was intended that these indicators should be accessible, useful and relevant in the Australian setting.

Methods
 Candidate indicators were written following consultation and data collection. A framework of outcome, impact and process indicators was based on DTC goals, objectives and strategies. The candidate indicators were field tested over a 2 month period in teaching, city non‐teaching, rural and private hospitals. The field tests provided response data for each indicator and evaluation of the indicators against criteria for accessibility, relevance, usefulness, clarity and resource utilisation. Consensus on which indicators to accept, modify or reject was reached at a workshop of stakeholders and experts, taking account of the field test results.

Results
 Thirty‐five candidate indicators were tested in 16 hospitals. Twenty‐two had a response from >80% of sites, 23 had a mean relevance rating >3.5, 19 had a mean usefulness rating >3.5, 27 were correctly interpreted by >90% of sites and 25 could be collected in an acceptable time. The most acceptable indicators required least data collection or provided data deemed useful for purposes other than the field test. At the consensus workshop 13 indicators were accepted with no or minor change, nine were accepted after major modification and eight were discarded. It was recommended that a further five indicators should be merged or subsumed into one indicator.

Conclusions
 This study has developed and field tested a set of indicators for DTCs in Australia. The indicators have been taken up enthusiastically as a first attempt to monitor DTC performance but require ongoing validation and development to ensure continuing relevance and usefulness.
Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole
Authors: Andersson Tommy , Holmberg Johan , Kerstin Röhss  , Walan Anders
Published: November 2003

Aims
 To study the pharmacokinetics of three proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole, as well as any potential influence on CYP1A2 activity (measured by means of rate of caffeine metabolism) of these compounds at single dose and repeated dose administration.

Methods
 Fourteen healthy males, classified as 12 extensive metabolizers (EMs) and two poor metabolizers (PMs) according to the urinary S/R mephenytoin ratio, completed this open, randomized, three‐way cross‐over study. In each of the three 7‐day treatment periods either omeprazole (20 mg), lansoprazole (30 mg) or pantoprazole (40 mg) in therapeutically recommended doses was administered once daily, and the pharmacokinetics of the proton pump inhibitors as well as the rate of caffeine metabolism was measured on days 1 and 7.

Results
 In the EMs there was an increase in AUC from day 1 to day 7 for omeprazole. In the PMs the AUC of both omeprazole and lansoprazole was unchanged during repeated dosing, while for pantoprazole there was a tendency to a slight decrease. The AUC at steady state was for all three proton pump inhibitors 5 fold higher in PMs compared with EMs, indicating that the same proportion of the dose, irrespective of compound, is metabolized by CYP2C19. No induction of CYP1A2 was evident for any of the compounds in either EMs or PMs.

Conclusions
 The ∼5 fold difference in AUC between EMs and PMs indicates that approximately 80% of the dose for all three proton pump inhibitors is metabolized by the polymorphically expressed CYP2C19. None of the three proton pump inhibitors, administered in therapeutically recommended doses, is an inducer of CYP1A2—neither in PMs nor in EMs.
Effect of food on the pharmacokinetics of ropinirole in parkinsonian patients
Authors: Brefel C. , Thalamas C. , Rayet S. , Lopez‐Gil A. , Fitzpatrick K. , Bullman S. , Citerone D. R. , Taylor A. C. , Montastruc J. L. , Rascol O.
Published: November 2003

Aims
 Ropinirole is a specific non‐ergoline dopamine D2‐receptor agonist with antiparkinsonian properties.The pharmacokinetic parameters of ropinirole taken in the fasted condition were compared with those when it was co‐administered with food.

Methods
 This was an open, randomized, two sessions cross over study in 12 patients with Parkinson’s disease, comparing the steady‐state pharmacokinetic profiles of ropinirole on two different study days: ‘fasted’ and ‘fed’.

Results
 The mean Cmax was lower in the ‘fed’ regimen than in the ‘fasted’ one (−25%, P=0.002). The median tmax was observed 2.6 h later in the ‘fed’ regimen than in the ‘fasted’ regimen (P<0.05). There was a slight but significant decrease in AUC(0,8 h) in the ‘fed’ regimen (P=0.03).

Conclusions
 Food decreases the rate of absorption of ropinirole, but has little effect on the extent of absorption.
Mutual exclusion of t(11;18)(q21;q21) and numerical chromosomal aberrations in the development of different types of primary gastric lymphomas
Authors: Schreuder Max I. , Hoeve Marieke A. , Hebeda Konnie M. , Verdijk Marian A. , Ligtenberg Marjolijn J. , Bot Frederik J. , Chott Andreas , Van Krieken J. Han J. M.
Published: November 2003

Summary.  Gastric non‐Hodgkin's lymphomas can be divided histologically into mucosa‐associated lymphoid tissue (MALT) lymphoma (ML) and diffuse large cell lymphoma (DLCL) with or without evidence of preceding/accompanying ML (DLCL + ML). We studied the incidence of the most frequent structural chromosomal aberration in ML, t(11;18)(q21;q21), and numerical aberrations of seven chromosomes in 36 ML, 39 DLCL + ML and ten gastric DLCL cases, by dual‐colour interphase fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT‐PCR). t(11;18)(q21;q21) was exclusively detected in ML (FISH 22%; RT‐PCR 24%), being completely absent in DLCL + ML and DLCL. No other translocations involving 11q21 or 18q21 and other partner chromosomes were detected by FISH. In lymphomas harbouring t(11;18)(q21;q21), this translocation was the sole genetic abnormality. In contrast, 45% of the t(11;18)(q21;q21)‐negative ML showed trisomies, especially of chromosome 3 and 18. In DLCL + ML with separate small and large cell components, trisomies were either detected in both components or occurred exclusively in large tumour cells. Our results suggest that ML can be divided in lymphomas characterized by the t(11;18)(q21;q21), which are unlikely to transform into high‐grade tumours, and t(11;18)(q21;q21)‐negative ML that may develop into DLCL + ML after the acquisition of additional genetic aberrations.
Oral anticoagulation in surgical procedures: risks and recommendations
Authors: Torn Marieke , Rosendaal Frits R.
Published: November 2003

Summary.  Surgery in anticoagulated patients is problematic. Coumarin therapy is often discontinued or reversed to reduce the perioperative bleeding risk. Meanwhile, the thromboembolic risk is enhanced. We sought to determine the frequency of bleeding and thromboembolism in anticoagulated patients undergoing routine surgery and to investigate the role of patient characteristics and the level of anticoagulation. We studied patients who attended the Leiden Anticoagulation Clinic for treatment relating to mechanical heart valve prostheses, atrial fibrillation or myocardial infarction and underwent surgery at the Leiden University Medical Centre between 1994 and 1998. Outcome events were bleeding and thromboembolism in the perioperative period. Seventy‐two complications occurred in 603 interventions, yielding an overall frequency of 11·9% [95% confidence interval (CI): 9·3–14·9], 9·5% (n = 57) for haemorrhage and 2·5% (n = 15) for thromboembolism. Younger patients tended to have more complications [odds ratio (OR) for >65 years of age: 0·5, 95% CI 0·3–1·0] as did patients with atrial fibrillation (OR for atrial fibrillation versus mechanical heart valve prostheses: 1·8, 95% CI 0·8–4·2). High postoperative levels of anticoagulation were associated with a slightly increased risk of complications [OR international normalized ratio (INR) > 3 vs. INR < 2: 1·3, 95% CI 0·6–3·0]. We conclude that routine surgery in anticoagulated patients yields a high perioperative bleeding and thromboembolic risk. While neither patient characteristics nor the level of anticoagulation appeared to play a major role in the occurrence of complications, the risk was clearly associated to the type of surgery, with the highest risk in thoracic surgery.
HTLV‐1 carriers with B‐cell lymphoma of localized stage head and neck: prognosis, clinical and immunopathological features
Authors: Suefuji Hiroaki , Ohshima Koichi , Hayabuchi Naofumi , Nakamura Katsumasa , Kikuchi Masahiro
Published: November 2003

Summary. Human T‐lymphotropic virus type I (HTLV‐I) is closely associated with T‐cell lymphoma/leukaemia, which always shows monoclonal HTLV‐1 provirus DNA integration. HTLV‐1 is not associated with B‐cell lymphoma. The relationship between B‐cell lymphoma and HTLV‐1 was analysed retrospectively in early stage B‐cell non‐Hodgkin's lymphoma (NHL) according to HTLV‐1 infection and pathological features. We analysed 198 cases of head and neck B‐cell NHL treated with radiotherapy and/or chemotherapy; 21 were seropositive and 177 were seronegative for HTLV‐1. We also immunostained 26 cases of diffuse large B‐cell lymphoma (DLBL), including 12 seropositive and 14 seronegative for HTLV‐1 respectively, for CD20, CD3, CD4, CD8, CD56, MIB‐1 and T‐cell‐restricted intracellular antigen (TIA‐1) to examine the phenotype, immunity and proliferation activity. The 5‐year overall survival rates were 78% and 49% (P = 0·007, log rank test) for HTLV‐1 seronegative and seropositive cases respectively. Infection with HTLV‐1 was significantly associated with poor survival in patients with B‐cell lymphoma by multivariate analysis. For DLBL, HTLV‐1 infection was not a significant factor, but the overall survival curve was similar to that of the 21 seropositive B‐cell lymphoma cases. Lymphoma cells were negative for TIA‐1, but the background lymphocytes were positive for this marker. The number of TIA‐1‐positive cells was higher in HTLV‐1‐negative cases than in‐positive cases. In conclusion, patients with B‐cell‐NHL (B‐NHL) who are also HTLV‐1 carriers have a poorer prognosis than non‐carriers. HTLV‐1 does not seem to be associated with lymphomagenesis of the B phenotype itself, but correlates with host immunity by reducing the number of cytotoxic T‐cells.
Pamidronate is an effective treatment for osteoporosis in patients with beta‐thalassaemia
Authors: Voskaridou Ersi , Terpos Evangelos , Spina Giovanna , Palermos John , Rahemtulla Amin , Loutradi Aphroditi , Loukopoulos Dimitris
Published: November 2003

Summary.  Osteoporosis in beta‐thalassaemia is multifactorial; increased osteoclast function seems to play an important role in its pathogenesis. The aim of this study was to evaluate the effect of pamidronate on the osteoporosis of thalassaemia. To this effect we studied 26 patients who received this drug in doses of 30 or 60 mg i.v. once a month over 12 months. The effects were monitored by measuring bone mineral density (BMD) in association with markers of osteoclast function [soluble receptor activator of nuclear factor‐kappa B ligand (sRANKL), osteoprotegerin (OPG)] and of bone remodelling [N‐telopeptide of collagen type‐I (NTX), tartrate‐resistant acid phosphatase isoform‐5b (TRACP‐5b), bone‐alkaline phosphatase (bALP), and osteocalcin (OC)]. Thirty healthy individuals were also studied, as controls. NTX, TRACP‐5b, bALP and OC levels were significantly higher in thalassaemic patients compared with controls; in contrast, OPG levels were significantly lower, while the levels of sRANKL varied within normal limits. Administration of pamidronate was followed by a clear decrease of NTX, TRACP‐5b, OPG, and OC, and by a significant increase in the BMD of the lumbar spine, which was similar in patients of both treatment groups. These data suggest that pamidronate, at a monthly dose of 30 mg, is an effective treatment for thalassaemic osteoporosis.
High prevalences of vitamin B12 and folic acid deficiency in elderly subjects in Israel
Authors: Figlin Elizabeth , Chetrit Angela , Shahar Avner , Shpilberg Ofer , Zivelin Ariella , Rosenberg Nurit , Brok‐Simoni Frida , Gadoth Nathan , Sela Ben‐Ami , Seligsohn Uri
Published: November 2003

Summary.  The prevalences of vitamin B12 and folic acid deficiency in the general Israeli population of elders has not been assessed. We measured plasma cobalamin and folic acid concentrations in 418 subjects from four institutions for the aged, 749 subjects attending 19 geriatric day centres and 104 healthy controls. Methylmalonic acid (MMA) and/or homocysteine concentrations were determined in subjects who had a cobalamin concentration <221 pmol/l or folic acid concentration <11 nmol/l respectively. The prevalences of vitamin B12 deficiency (cobalamin <147 pmol/l and MMA ≥0·24 μmol/l), and folic acid deficiency (folic acid <11 nmol/l and homocysteine of >15 μmol/l) in subjects from day centres were 12·6% and 16·4% respectively, and in subjects from institutions 1·2% and 2·2% respectively (P < 0·001). Multiple logistic regression analysis indicated that the relative risk of living at home versus institutions for the aged was highly significant, with odds ratios (OR) of 6·8 [95% confidence interval (CI) 2·6–18·0] for vitamin B12 deficiency and 6·6 (95% CI 2·9–13·1) for folic acid deficiency. Analysis of data for day centre patients showed that folic acid deficiency was a significant risk factor of vitamin B12 deficiency (adjusted OR 3·68, 95% CI 2·27–5·98), and vitamin B12 deficiency was a significant risk of folic acid deficiency (adjusted OR 3·69, 95% CI 2·27–6.01). These data suggest that malnutrition is a major cause of the highly prevalent deficiencies of vitamin B12 and/or folic acid in elderly Israeli subjects dwelling at home.