Reducing neonatal morbidity by discontinuing oxytocin during the active phase of first stage of labor: a multicenter randomized controlled trial STOPOXY.

BACKGROUND: Oxytocin is effective in reducing labor duration, but can be associated with fetal and maternal complications such as neonatal acidosis and post-partum hemorrhage. When comparing discontinuing oxytocin in the active phase with continuing oxytocin infusion, previous studies were underpowered to show a reduction in neonatal morbidity. Thus, we aim at evaluating the impact of discontinuing oxytocin during the active phase of the first stage of labor on the neonatal morbidity rate. METHODS: STOPOXY is a multicenter, randomized, open-label, controlled trial conducted in 20 maternity units in France. The first participant was recruited January 17th 2020. The trial includes women with a live term (≥37 weeks) singleton, in cephalic presentation, receiving oxytocin before 4 cm, after an induced or spontaneous labor. Women aged < 18 years, with a lack of social security coverage, a scarred uterus, a multiple pregnancy, a fetal congenital malformation, a growth retardation <3rd percentile or an abnormal fetal heart rate at randomization are excluded. Women are randomized before 6 cm when oxytocin is either continued or discontinued. Randomization is stratified by center and parity. The primary outcome, neonatal morbidity is assessed using a composite variable defined by an umbilical arterial pH at birth < 7.10 and/or a base excess > 10 mmol/L and/or umbilical arterial lactates> 7 mmol/L and/or a 5 min Apgar score < 7 and/or admission in neonatal intensive care unit. The primary outcome will be compared between the two groups using a chi-square test with a p-value of 0.05. Secondary outcomes include neonatal complications, duration of active phase, mode of delivery, fetal and maternal complications during labor and delivery, including cesarean delivery rate and postpartum hemorrhage, and birth experience. We aim at including 2475 women based on a reduction in neonatal morbidity from 8% in the control group to 5% in the experimental group, with a power of 80% and an alpha risk of 5%. DISCUSSION: Discontinuing oxytocin during the active phase of labor could improve both child health, by reducing moderate to severe neonatal morbidity, and maternal health by reducing cesarean delivery and postpartum hemorrhage rates. TRIAL REGISTRATION: Clinical trials NCT03991091 , registered June 19th, 2019.

Assessment of Polygonum odoratum Lour. Leaf Extract on Rat's Ileum Contraction and the Mechanisms Involved.

Vietnamese coriander (Polygonum odoratum Lour.) is a plant native to northern Thailand. The biological activities of P. odoratum Lour. extract (POE) include antibacterial, antiviral, and expectorant. However, the effect of POE on intestinal smooth muscle motility is unclear. The aim of this study was to evaluate the relaxant effects of POE on isolated rat ileum. Propranolol (1 µM), calcium chloride (1-20 mM), and Nω-nitro-l-arginine methylester (l-NAME, 100 µM) were used to investigate the mechanisms of action. The results showed that POE (0.01-5 mg/mL) reduced KCl-induced contraction. In addition, POE (1 mg/mL) reduced the contraction by propranolol and l-NAME and attenuated CaCl2-induced contractions. Our results indicate that the relaxation effect of POE on ileum contractions seems to involve nitric oxide and ß-adrenergic pathways, and blockade of calcium influx. These findings provide a pharmacological basis for the traditional use of POE to treat gastrointestinal disorders such as irritable bowel syndrome or diarrhea.

Muscle contractile properties of cancer patients receiving chemotherapy: Assessment of feasibility and exercise effects.

BACKGROUND: This pilot trial explores the feasibility of measuring muscle contractile properties in patients with cancer, effects of exercise during chemotherapy on muscle contractile properties and the association between changes in contractile muscle properties and perceived fatigue. METHOD: Patients who received (neo)adjuvant chemotherapy for breast or colon cancer were randomized to a 9-12 week exercise intervention or a waitlist-control group. At baseline and follow-up, we measured knee extensor strength using maximal voluntary contraction (MVC), contractile muscle properties of the quadriceps muscle using electrical stimulation, and perceived fatigue using the Multidimensional Fatigue Inventory. Feasibility was assessed by the proportion of patients who successfully completed measurements of contractile muscle properties. Exercise effects on muscle contractile properties were explored using linear regression analyses. Between-group differences >10% were considered potentially relevant. Pearson correlation (rp ) of changes in contractile muscle properties and changes in perceived fatigue was calculated. RESULTS: Twenty two of 30 patients completed baseline and follow-up assessments. Measurements of contractile properties were feasible except for muscle fatigability. We found a potentially relevant between-group difference in the rate of force development favoring the intervention group (1192 N/s, 95% CI = -335; 2739). Change in rate of force development was negatively correlated with change in perceived general (rp  = -0.54, P = .04) and physical (rp  = -0.59, P = .02) fatigue. CONCLUSION: Chemotherapy induces a decrease in the rate of force development, which may reflect a larger loss in type II muscle fibers. This may be attenuated with (resistance) exercise. The increase in the rate of force development was related to a decrease in perceived fatigue.

Assessment of Inhibitory Effects of Hypnotics on Acetylcholine-Induced Contractions in Isolated Rat Urinary Bladder Smooth Muscle.

The present study aimed to investigate the potential inhibitory effects of 21 clinically available hypnotics on acetylcholine (ACh)-induced contractions in rat urinary bladder smooth muscle (UBSM) in order to predict whether these hypnotics could induce voiding impairment. ACh-induced contraction in rat UBSM was inhibited only by diphenhydramine (a histamine H1 receptor antagonist) at a concentration that was clinically relevant. ACh-induced contraction was also significantly inhibited by flurazepam (a benzodiazepine hypnotic) and suvorexant (an orexin receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. These three drugs (at 10-5 M) also inhibited high-KCl (80 mM) Locke-Ringer solution-induced contractions. In contrast to the effects of the abovementioned hypnotics, ACh-induced contractions were not significantly affected by triazolam, etizolam, brotizolam, lormetazepam, estazolam, flunitrazepam, nitrazepam (benzodiazepine hypnotics), thiopental, thiamylal, pentobarbital, amobarbital, secobarbital, phenobarbital (barbiturate hypnotics), zolpidem (an imidazopyridine hypnotic), zopiclone (a cyclopyrrolone hypnotic), ramelteon (a melatonin receptor agonist), bromovalerylurea, and chloral hydrate. These findings suggest that most clinically used hypnotics are not likely to result in anticholinergic-induced dysuria within their clinically achievable blood concentration ranges. Diphenhydramine may, however, induce voiding impairment, an action attributable to diminished UBSM contractility within its clinical dose range.

Assessment of the Airway Smooth Muscle Relaxant Effect of Drotaverine.

BACKGROUND: Drotaverine, a type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, blocks the degradation of 3',5'-cyclic adenosine monophosphate. However, published receptor binding data showed that drotaverin also binds to the L-type voltage-operated calcium channel (L-VOCC). Based on these molecular mechanisms of action, a direct and indirect (by blocking the constrictor response) relaxant effect on airway smooth muscle can be predicted, which has not yet been assessed. SUMMARY: Accordingly, drotaverine and reference agents were tested both on the histamine-, methacholine-, or KCl-induced contraction response and on precontracted guinea pig tracheal preparations. It was found that drotaverine not only relaxed the precontracted tracheal preparations but also decreased mediator-induced contraction. These effects of drotaverine were concentration dependent, with a significantly higher potency on the KCl-induced response, than on either the histamine or methacholine induced one. A similar result was noted for nifedipine. The PDE inhibitor, theophylline, also relaxed the precontracted preparations but was ineffective on the mediator-induced contraction in a physiologically relevant concentration range. Moreover, theophylline did not show selectivity and was the least potent relaxant among the 3 tested molecules. Key Message: These results show that drotaverine is a more potent airway smooth muscle relaxant molecule than theophylline. This enhanced potency on relaxation and inhibition of the constrictor response, at least partly, may be explained by the combined L-VOCC blocking and PDE inhibitory potential of drotaverine.

Skeletal Muscle Metabolic Dysfunction in Patients With Malignant Hyperthermia Susceptibility.

BACKGROUND: Malignant hyperthermia (MH), a pharmacogenetic disorder of skeletal muscle, presents with a potentially lethal hypermetabolic reaction to certain anesthetics. However, some MH-susceptible patients experience muscle weakness, fatigue, and exercise intolerance in the absence of anesthetic triggers. The objective of this exploratory study was to elucidate the pathophysiology of exercise intolerance in patients tested positive for MH with the caffeine-halothane contracture test. To this end, we used phosphorus magnetic resonance spectroscopy, blood oxygen level-dependent functional magnetic resonance imaging (MRI), and traditional exercise testing to compare skeletal muscle metabolism in MH-positive patients and healthy controls. METHODS: Skeletal muscle metabolism was assessed using phosphorus magnetic resonance spectroscopy and blood oxygen level-dependent functional MRI in 29 MH-positive patients and 20 healthy controls. Traditional measures of physical capacity were employed to measure aerobic capacity, anaerobic capacity, and muscle strength. RESULTS: During 30- and 60-second exercise, MH-positive patients had significantly lower ATP production via the oxidative pathway compared to healthy controls. MH-positive patients also had a longer recovery time with blood oxygen level-dependent functional MRI compared to healthy controls. Exercise testing revealed lower aerobic and anaerobic capacity in MH-positive patients compared to healthy controls. CONCLUSIONS: Results of this exploratory study suggest that MH-positive patients have impaired aerobic metabolism compared to healthy individuals. This could explain the exercise intolerance exhibited in MH-susceptible patient population.

Capsiate supplementation reduces oxidative cost of contraction in exercising mouse skeletal muscle in vivo.

Chronic administration of capsiate is known to accelerate whole-body basal energy metabolism, but the consequences in exercising skeletal muscle remain very poorly documented. In order to clarify this issue, the effect of 2-week daily administration of either vehicle (control) or purified capsiate (at 10- or 100-mg/kg body weight) on skeletal muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in mice. Mechanical performance and energy metabolism were assessed strictly non-invasively in contracting gastrocnemius muscle using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Regardless of the dose, capsiate treatments markedly disturbed basal bioenergetics in vivo including intracellular pH alkalosis and decreased phosphocreatine content. Besides, capsiate administration did affect neither mitochondrial uncoupling protein-3 gene expression nor both basal and maximal oxygen consumption in isolated saponin-permeabilized fibers, but decreased by about twofold the Km of mitochondrial respiration for ADP. During a standardized in vivo fatiguing protocol (6-min of repeated maximal isometric contractions electrically induced at a frequency of 1.7 Hz), both capsiate treatments reduced oxidative cost of contraction by 30-40%, whereas force-generating capacity and fatigability were not changed. Moreover, the rate of phosphocreatine resynthesis during the post-electrostimulation recovery period remained unaffected by capsiate. Both capsiate treatments further promoted muscle mass gain, and the higher dose also reduced body weight gain and abdominal fat content. These findings demonstrate that, in addition to its anti-obesity effect, capsiate supplementation improves oxidative metabolism in exercising muscle, which strengthen this compound as a natural compound for improving health.

Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol.

BACKGROUND: To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously. METHODS/DESIGN: We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT. DISCUSSION: The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02045667.

Effect of caffeine on intrinsic mechanical properties of normal and malignant hyperthermia-susceptible muscle.

INTRODUCTION: Malignant hyperthermia (MH) is a potentially lethal anesthesic complication. Pathological symptoms develop after exposure to triggering substances. It remains uncertain whether cellular alterations pre-exist. Mechanical properties of isolated muscle bundles were examined before and after exposure to a triggering substance. METHODS: With prior written consent, muscle bundles of 12 MH-susceptible (MHS) and 56 MH-nonsusceptible (MHN) individuals were examined before and after exposure to incremental doses of caffeine. Mechanical properties (baseline tension, peak tension, time to peak tension, and relaxation time) were measured. Contraction and relaxation derivatives and contraction-relaxation coupling were calculated and analyzed. RESULTS: Mechanical properties were not different between the groups before caffeine application. Caffeine increased peak tension in both groups and baseline tension only in MHS muscle bundles; relaxation time/derivative and contraction-relaxation coupling were prolonged. CONCLUSIONS: Cellular changes seen in MH are not pre-existing. Exposure to triggering substance impairs relaxation in MHS muscle.

In vitro evaluation of ureteral contractility: a comparative assessment of human, porcine and sheep ureteral response to vardenafil.

OBJECTIVES: Basic science studies of ureteral physiology and pathophysiology are commonly performed on animal ureters due to several limitations associated with human ureteral sampling. In this work we question whether animal ureters are good replicas of human ureteral behavior for pharmacological studies. MATERIALS AND METHODS: Ureteral rings from human, porcine and ovine ureters underwent the same organ bath protocol. After stimulation with KCl, ureters were subjected to different doses of vardenafil. Basic contractility and ureteral response to vardenafil were analyzed. RESULTS: A different pattern of basic contractility was evidenced between species. Vardenafil administration induced a dose-dependent reduction in KCl-induced amplitude increase in human ureters and a dose-dependent reduction in autonomic contractile rhythm of porcine and ovine ureters. Although animal ureters could predict the relaxant response of human samples to vardenafil, its effect would have been overestimated using only animal models. CONCLUSIONS: Human ureteral investigations cannot entirely be replaced by existing animal models since results of the latter will vary significantly according to the tested pharmaceutical agent.

Defining uremic arterial functional abnormalities in patients recently started on haemodialysis: combined in vivo and ex vivo assessment.

Endothelial dysfunction is a key initiating event in vascular disease in chronic kidney disease (CKD) patients and haemodialysis (HD) patients exhibit significant vascular abnormalities. To understand this further, we examined how ex vivo intrinsic function in isolated arteries correlates with in vivo assessments of cardiovascular status in HD patients. Abdominal fat biopsies were obtained from 11 HD patients and 26 non-uremic controls. Subcutaneous arteries were dissected and mounted on a wire myograph, and cumulative concentration-response curves to noradrenalin, endothelin-1, a thromboxane A2 agonist (U46619), angiotensin II, vasopressin, bradykinin (BK), acetylcholine (ACh) and sodium nitroprusside (SNP) were constructed. Pulse wave velocity and blood pressure were measured in HD patients. Enhanced (P<0.05-0.0001) maximal contractile responses (Rmax) to all spasmogens (particularly vasopressin) were observed in arteries from HD patients compared to controls, and this effect was more pronounced in arteries with an internal diameter>600 µm. The potency (pEC50) of U46619 (P<0.01) and vasopressin (P<0.001) was also increased in arteries>600 µm of HD patients. The maximal relaxant response to the endothelium-dependent dilators ACh and BK were lower in HD patients (P<0.01-P<0.0001) (worse for ACh than BK); however the endothelium-independent dilator SNP was similar in both groups. PWV was significantly correlated with the vasoconstrictor response to vasopressin (P = 0.042) in HD patients. HD patients are primed for hypertension and end organ demand ischaemia by a highly sensitised pressor response. The failure of arterial relaxation is mediated by endothelial dysfunction. Intrinsic vascular abnormalities may be important in sensitising HD patients to recurrent cumulative ischaemic end organ injury.

In vitro muscle contracture investigations on the malignant hyperthermia like episodes in myotonia congenita.

BACKGROUND: A common form of congenital myotonia, myotonia congenita (MC), is caused by mutations in the skeletal muscle Cl(-) channel gene type 1 (CLCN1). Due to the reduced Cl(-) conductance of the mutated channels, the patients may develop generalized muscle rigidity and hypermetabolism during general anaesthesia. The clinical symptoms resemble malignant hyperthermia (MH), which may lead to mistreatment of the patient. METHODS: Muscle specimens of ADR mice (an animal model of MC) as well as of human individuals were used and exposed to potent ryanodine receptor type 1 (RyR1) activators and increasing K(+) concentration. Muscle force was monitored by a standardized diagnostic method for MH, the so-called in vitro contracture test. RESULTS: Neither muscle of ADR mice nor MC muscle (murine and human myotonic muscle) showed pathological contractures after exposure to the potent RyR1 agonists caffeine and halothane. Increasing concentrations of K(+) had a dose-dependent preventive effect on myotonic stiffness. CONCLUSION: We conclude that the adverse anaesthetic MH-like episodes observed in MC patients do not primarily originate from an altered Ca(2+) release in skeletal muscle. In MC muscle, this hypermetabolism is facilitated by a (pharmacologically induced) sustained depolarization due to an instable membrane potential. The in vitro results suggest that these patients benefit from tight K(+) monitoring because of the membrane potential stabilizing effect of K(+) .

Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial.

BACKGROUND: Previous studies suggested intravenous or nebulised magnesium sulphate (MgSO(4)) might improve respiratory function in patients with acute asthma. We aimed to determine whether intravenous or nebulised MgSO(4) improve symptoms of breathlessness and reduce the need for hospital admission in adults with severe acute asthma. METHODS: In our double-blind, placebo-controlled trial, we enrolled adults (aged ≥16 years) with severe acute asthma at emergency departments of 34 hospitals in the UK. We excluded patients with life-threatening features or contraindication to study drugs. We used a central randomisation system to allocate participants to intravenous MgSO(4) (2 g in 20 min) or nebulised MgSO(4) (three 500 mg doses in 1 h) alongside standard therapy including salbutamol, or placebo control plus standard therapy alone. We assessed two primary outcome measures in all eligible participants who started treatment, according to assigned treatment group: the proportion of patients admitted to hospital within 7 days and breathlessness measured on a 100 mm visual analogue scale (VAS) in the 2 h after initiation of treatment. We adjusted for multiple testing using Simes's method. The trial stopped before recruitment was completed because funding expired. This study is registered, number ISRCTN04417063. FINDINGS: Between July 30, 2008, and June 30, 2012, we recruited 1109 (92%) of 1200 patients proposed by the power calculation. 261 (79%) of 332 patients allocated nebulised MgSO(4) were admitted to hospital before 7 days, as were 285 (72%) of 394 patients allocated intravenous MgSO(4) and 281 (78%) of 358 controls. Breathlessness was assessed in 296 (89%) patients allocated nebulised MgSO(4), 357 (91%) patients allocated intravenous MgSO(4), and 323 (90%) controls. Rates of hospital admission did not differ between patients treated with either form of MgSO(4) compared with controls or between those treated with nebulised MgSO(4) and intravenous MgSO(4). Change in VAS breathlessness did not differ between active treatments and control, but change in VAS was greater for patients in the intravenous MgSO(4) group than it was in the nebulised MgSO(4) group (5·1 mm, 0·8 to 9·4; p=0·019). Intravenous or nebulised MgSO(4) did not significantly decrease rates of hospital admission and breathlessness compared with placebo: intravenous MgSO(4) was associated with an odds ratio of 0·73 (95% CI 0·51 to 1·04; p=0·083) for hospital admission and a change in VAS breathlessness of 2·6 mm (-1·6 to 6·8; p=0·231) compared with placebo; nebulised MgSO(4) was associated with an odds ratio of 0·96 (0·65 to 1·40; p=0·819) for hospital admission and a change in VAS breathlessness of -2·6 mm (-7·0 to 1·8; p=0·253) compared with placebo. INTERPRETATION: Our findings suggest nebulised MgSO(4) has no role in the management of severe acute asthma in adults and at best suggest only a limited role for intravenous MgSO(4) in this setting. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Assessment of the pharmacological properties of 5-methoxyindole derivatives at 5-HT4 receptors.

OBJECTIVES: The aim was to examine the biological activity of 5-methoxytryptamine derivatives at the 5-hydroxytryptamine (5-HT)(4) receptor to explore the effect of substitution on the aliphatic amine of the 5-methoxyamine scaffold. METHODS: Three compounds were tested for affinity at the 5-HT(4) receptor by radioligand binding and functional activity using guinea-pig ileum and human colon circular muscle preparations and also in the mouse whole gut transit test. KEY FINDINGS: The three compounds all had agonist properties at the 5-HT(4) receptor but their efficacy differed in the different functional tests. Compound 3 had the highest affinity for the 5-HT(4) receptor and was a full agonist at relaxing human colon circular muscle with efficacy closest to 5-HT. Compounds 1 and 2 were partial agonists in this assay with lower efficacies; compound 2 was a full agonist in the guinea-pig ileum assay whereas compound 3 was a partial agonist. Compounds 1 and 2 also showed activity in the mouse gut transit assay while compound 3 had no activity. CONCLUSIONS: Of the compounds tested, compound 3 was the most promising 5-HT(4) receptor agonist and the results highlight the value of using human tissue in functional tests when assessing compounds for potential activity.

Assessment of biological activity of novel peptide analogues of angiotensin IV.

OBJECTIVES: Angiotensin IV (Ang IV) is a metabolite of angiotensin II which acts on specific AT(4) receptors identified as the enzyme insulin regulated aminopeptidase (IRAP). The transduction process of these receptors is unresolved, but Ang IV inhibits the aminopeptidase activity. Ang IV improves cognition in animal models thus there is a desire to develop metabolically stable analogues for further development. METHODS: Peptide analogues of Ang IV were obtained commercially or synthesised. Each peptide was tested in vitro for its ability to inhibit the aminopeptidase activity (IRAP) of mouse brain homogenates and for its effects on isolated rat uterine smooth muscle. KEY FINDINGS: [Des-Val(1) ]-Ang IV, acetylated-Ang IV-amide, Ang IV-amide and [des-His(4) ]-Ang IV all inhibited IRAP. [Sar(1) , Ile(8) ]-Angiotensin II (10 µm) had an effect greater than that of Ang IV or any of the other analogues studied. In isolated uterine smooth muscle, angiotensins II and IV induced contractions, which could be antagonised by an AT(1) -receptor antagonist. None of the novel peptides induced uterine smooth muscle contractions, but [Sar(1) , des Arg(2) -Gly(8) ]-angiotensin II showed significant antagonism of the contractile effects of angiotensin II and carboxyamide-terminated Ang IV-NH(2) showed antagonism of Ang IV-induced contractions. CONCLUSIONS: This study provides five novel inhibitors of IRAP worthy of assessment in behavioural models of learning and memory. The analogues are devoid of AT(1) receptor agonist properties, and the carboxyamide analogue presents an opportunity to elucidate the mechanism of action of Ang IV as, like Ang IV, it inhibits IRAP, but antagonises the effects of Ang IV on isolated smooth muscle.

Acute L-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise tolerance.

It has recently been reported that dietary nitrate (NO(3)(-)) supplementation, which increases plasma nitrite (NO(2)(-)) concentration, a biomarker of nitric oxide (NO) availability, improves exercise efficiency and exercise tolerance in healthy humans. We hypothesized that dietary supplementation with L-arginine, the substrate for NO synthase (NOS), would elicit similar responses. In a double-blind, crossover study, nine healthy men (aged 19-38 yr) consumed 500 ml of a beverage containing 6 g of l-arginine (Arg) or a placebo beverage (PL) and completed a series of "step" moderate- and severe-intensity exercise bouts 1 h after ingestion of the beverage. Plasma NO(2)(-) concentration was significantly greater in the Arg than the PL group (331 ± 198 vs. 159 ± 102 nM, P < 0.05) and systolic blood pressure was significantly reduced (123 ± 3 vs. 131 ± 5 mmHg, P < 0.01). The steady-state O(2) uptake (VO(2)) during moderate-intensity exercise was reduced by 7% in the Arg group (1.48 ± 0.12 vs. 1.59 ± 0.14 l/min, P < 0.05). During severe-intensity exercise, the Vo(2) slow component amplitude was reduced (0.58 ± 0.23 and 0.76 ± 0.29 l/min in Arg and PL, respectively, P < 0.05) and the time to exhaustion was extended (707 ± 232 and 562 ± 145 s in Arg and PL, respectively, P < 0.05) following consumption of Arg. In conclusion, similar to the effects of increased dietary NO(3)(-) intake, elevating NO bioavailability through dietary L-Arg supplementation reduced the O(2) cost of moderate-intensity exercise and blunted the VO(2) slow component and extended the time to exhaustion during severe-intensity exercise.

Assessment of urodynamic and detrusor contractility variables in patients with overactive bladder syndrome treated with botulinum toxin-A: is incomplete bladder emptying predictable?

OBJECTIVE: To assess whether incomplete bladder emptying and the need for clean intermittent self-catheterization (CISC) is predictable, by analysing urodynamic and detrusor contractility variables in patients treated with botulinum toxin-A (BTX-A) for refractory idiopathic detrusor overactivity (IDO). PATIENTS AND METHODS: Sixty-seven patients (mean age 50.3) with IDO, from two centres, had bladder injections of 200 U BTX-A. Patients with difficulty in emptying their bladder and/or persistent overactive bladder symptoms, with postvoid residual volumes (PVR) of >150 mL after treatment were started on CISC. Urodynamics were conducted at baseline, 4 and 12-16 weeks after injection with BTX-A. Detrusor contractility was assessed using the projected isovolumetric pressure (PIP1) in women and bladder contractility index (BCI) in men. RESULTS: There were improvements in the mean maximum cystometric capacity, bladder compliance and maximum detrusor pressures during filling cystometry after BTX-A injections. The PVR was significantly increased at 4 but not at 12 weeks. Nineteen patients required CISC and when compared with those not needing CISC their pretreatment maximum flow rate (15 vs 22 mL/s, P = 0.003), PIP1 (43 vs 58, P = 0.02) and BCI (113 vs 180, P = 0.001) were lower. Receiver operator characteristic curve analysis suggested that a PIP1 of < or =50 in women (sensitivity 0.83; specificity 0.70; area under the curve 0.822) and BCI < or =120 (sensitivity 0.7; specificity 0.79; area 0.879) might predict the need for CISC. CONCLUSION: The maximum flow rate, PIP1 and BCI were significantly lower in patients who required CISC after BTX-A treatment than in those who did not. A PIP1 of < or =50 in women and a BCI of < or =120 might be predictive of a need for CISC in this setting, and might help when counselling patients.

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation.

Eosinophils are multifunctional leukocytes that degrade and remodel tissue extracellular matrix through production of proteolytic enzymes, release of proinflammatory factors to initiate and propagate inflammatory responses, and direct activation of mucus secretion and smooth muscle cell constriction. Thus, eosinophils are central effector cells during allergic airway inflammation and an important clinical therapeutic target. Here we describe the use of an injectable MMP-targeted optical sensor that specifically and quantitatively resolves eosinophil activity in the lungs of mice with experimental allergic airway inflammation. Through the use of real-time molecular imaging methods, we report the visualization of eosinophil responses in vivo and at different scales. Eosinophil responses were seen at single-cell resolution in conducting airways using near-infrared fluorescence fiberoptic bronchoscopy, in lung parenchyma using intravital microscopy, and in the whole body using fluorescence-mediated molecular tomography. Using these real-time imaging methods, we confirmed the immunosuppressive effects of the glucocorticoid drug dexamethasone in the mouse model of allergic airway inflammation and identified a viridin-derived prodrug that potently inhibited the accumulation and enzyme activity of eosinophils in the lungs. The combination of sensitive enzyme-targeted sensors with noninvasive molecular imaging approaches permitted evaluation of airway inflammation severity and was used as a model to rapidly screen for new drug effects. Both fluorescence-mediated tomography and fiberoptic bronchoscopy techniques have the potential to be translated into the clinic.

Assessment of the effectiveness of nontransdermal energy patches on muscle endurance and power.

Claims of recently developed energy patches suggest that organic nanoscale biomolecular "antennas" produced by L and D-stereoisomers resonate at frequencies in unison with molecules in the cells inducing electron flow to assists in recruiting calcium ions, allowing greater muscle fiber recruitment during muscle contraction. The purpose of the study was to assess the efficacy of energy patches in the performance of selected muscle power and endurance measures. After a 5-minute warm-up and stretch, 41 college varsity football players (age, 20.37 +/- 1.24 years; height, 169.91 +/- 7.44 cm; weight, 109.45 +/- 19.85 kg) were pre-tested on 102-kg maximal bench press repetitions, standing vertical jump, grip strength, peak torque, torque to body weight, total work, average power, and average torque as measured by 50 repetitions of leg extensions at 180 degrees .s. The following week, the players were randomly assigned the experimental or placebo patches. After placement of the patches, the participants again completed a 5-minute warm-up, followed by the identical pre-test protocol. Repeated-measures ANOVAs were used to compare resultant data. No significant group interaction effects were found between experimental and placebo patches for maximal bench press repetitions (p = 0.48), vertical jump distance (p = 0.39), grip strength (p = 0.29), total work (p = 0.26), torque to body weight (p = 0.05), average peak torque (p = 0.08), and average power (p = 0.05). A significant increase occurred in the experimental group for peak torque (p = 0.04). It was concluded that the energy patches significantly improved performance over placebo patches in one of the eight variables tested and registered near significance in two additional variables. However, inconsistency in overall results demands further studies to determine the reliability in improvement of performance in the presence of energy patches.

Comparison between acceleromyography and visual assessment of train-of-four for monitoring neuromuscular blockade in horses undergoing surgery.

OBJECTIVE: To compare acceleromyography (AMG) with visual assessment of train-of-four (TOF) for monitoring neuromuscular blockade and detecting residual muscle paralysis in horses receiving atracurium. STUDY DESIGN: Prospective, controlled clinical study. ANIMALS: Nine adult, client-owned horses weighing 577 (436, 727) kg (median, minimum, maximum) and ASA physical status I-II, admitted for surgery. METHODS: An electrical nerve stimulator was used to stimulate the peroneal nerve with TOFs at 1 minute intervals. Before and after atracurium administration (0.15 mg kg(-1), IV), the number of twitches observed (TOF count, or TOFc) was assessed visually. When four twitches were seen (i.e., TOFc = 4) presence or absence of fade by visual assessment was recorded. Simultaneously, the response to each TOF was assessed by AMG; this measured TOFc, and twitch fade using TOF ratio (TOFR; ratio of fourth to first twitch). The anesthetist performing the visual evaluation was blinded to the AMG readings. Recovery from neuromuscular blockade was defined as the absence of fade by visual inspection or a TOFR > or =90% by AMG. RESULTS: During onset of action of the drug, fade was first detected 4 (1, 8) minutes earlier by AMG (p = 0.008). Maximal blockade started at 6 (3, 17) minutes by visual assessment and 9 (3, 25) minutes by AMG (not significantly different). Only four horses achieved complete neuromuscular blockade (TOFc of zero by both methods); in those four horses AMG did not detect the start of the return of neuromuscular transmission before visual assessment. Visual assessment indicated the return of four twitches with no fade 12 (8, 42) minutes before AMG gave a TOFR of > or =90% (p = 0.004). CONCLUSION AND CLINICAL RELEVANCE: There was no substantial advantage for AMG in detecting the onset of atracurium-induced neuromuscular blockade. However, AMG detected residual blockade when visual assessment of TOF did not. Application of AMG is likely to reduce the incidence of residual blockade.