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Introduction Restorative therapies such as Low-intensity Shockwave Lithotripsy (LiSWT) for erectile dysfunction (ED) have generated substantial interest. Despite growing popularity, a paucity of data exists to confirm efficacy in reversing underlying pathophysiologies of ED. Objective We evaluated the efficacy of the Storz® Duolith™ to determine whether active versus sham treatment is superior for treatment of ED. Methods We performed a two-arm stratified, single-blinded, randomized controlled clinical trial. Inclusion/exclusion criteria are listed in table 1. A total of 31 patients were enrolled, with 15 randomized to the sham group and 16 to the treatment group. Patients underwent LiSWT with the Duolith™ device delivered twice weekly for 3 weeks, comprising 3000 shockwaves at 0.1 mJ/mm2 delivered to the distal penis, base of penis, and crura. Outcomes included absolute change in IIEF/SHIM score and change in EHS score. Changes in SHIM scores were compared between the treatment arms using Student’s t-test, while changes in EHS scores were compared using Wilcoxon rank-sum test. Results Demographic and baseline clinical characteristics were similar between arms. At one-month post-treatment, SHIM scores improved by 3.4 points in the LiSWT arm while no improvement was seen in the sham arm (-3.4 vs. 0.7, p=0.014). This corresponded to a 42.1% improvement in the LiSWT arm and a 0.1% decline in the sham arm. No significant differences were observed in EHS change scores between treatment arms. No adverse outcomes were reported. Conclusions The present interim analysis shows improvement in SHIM scores in men undergoing LiSWT for ED. Additional recruitment and follow-up is in ongoing to further demonstrate efficacy and sustainability of LiSWT in the treatment of ED. Disclosure No

The Galactic Centre contains a supermassive black hole with a mass of 4 million suns within an environment that differs markedly from that of the Galactic disk. While the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings. Also, while the levels of star formation in the Galactic Centre have been approximately constant over the last few hundred Myr, there is evidence of elevated short-duration bursts, strongly influenced by interaction of the black hole with the enhanced gas density present within the ring-like Central Molecular Zone at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200 pc region is characterized by large amounts of warm molecular gas, a high cosmic ray ionization rate, unusual gas chemistry, enhanced synchrotron emission, and a multitude of radio-emitting magnetised filaments, the origin of which has not been established. Here we report radio imaging that reveals bipolar bubbles spanning 1 degree x 3 degrees (140 parsecs x 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 x 10^52 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities., 25 pages, 3 figures, 3 tables, authors' version of a Letter published in Nature on 11 September 2019

New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a quiescent state since at least early 2015, reactivated between 2017 March 19 and April 5. The radio flux density, while variable, is approximately 100x larger than during its dormant state. The X-ray flux one month after reactivation was at least 800x larger than during quiescence, and has been decaying exponentially on a 111+/-19 day timescale. This high-flux state, together with a radio-derived rotational ephemeris, enabled for the first time the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV pulsed fraction is comparable to the smallest observed for magnetars. The overall pulsar geometry inferred from polarized radio emission appears to be broadly consistent with that determined 6-8 years earlier. However, rotating vector model fits suggest that we are now seeing radio emission from a different location in the magnetosphere than previously. This indicates a novel way in which radio emission from magnetars can differ from that of ordinary pulsars. The torque on the neutron star is varying rapidly and unsteadily, as is common for magnetars following outburst, having changed by a factor of 7 within six months of reactivation., Comment: Published in ApJ (2018 April 5); 13 pages, 4 figures

Enhanced tendon and ligament repair would have a major impact on orthopaedic surgery outcomes, resulting in reduced repair failures and repeat surgeries, more rapid return to function, and reduced health care costs. Scaffolds have been used for mechanical and biologic reinforcement of repair and regeneration with mixed results. This review summarizes efforts made using biologic and synthetic scaffolds using rotator cuff and ACL as examples of clinical applications, discusses recent advances that have shown promising clinical outcomes, and provides insight into future therapy.

Peripheral neuropathic pain (PNP) poses a significant clinical challenge. The long-term efficacy of delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray was investigated in this 38-week open-label extension study. In total, 380 patients with PNP associated with diabetes or allodynia entered this study from two parent randomised, controlled trials. Patients received THC/CBD spray for a further 38 weeks in addition to their current analgesic therapy. Neuropathic pain severity was the primary efficacy measure using a pain 0-10 numerical rating scale (NRS). Additional efficacy, safety and tolerability outcomes were also investigated. In total, 234 patients completed the study (62 %). The pain NRS showed a decrease in score over time in patients from a mean of 6.9 points (baseline in the parent studies) to a mean of 4.2 points (end of open-label follow-up). The proportion of patients who reported at least a clinically relevant 30 % improvement in pain continued to increase with time (up to 9 months); at least half of all patients reported a 30 % improvement at all time points. Improvements were observed for all secondary efficacy outcomes, including sleep quality 0-10 NRS scores, neuropathic pain scale scores, subject global impression of change and EQ-5D questionnaire scores. THC/CBD spray was well tolerated for the study duration and patients did not seek to increase their dose with time, with no new safety concerns arising from long-term use. In this previously difficult to manage patient population, THC/CBD spray was beneficial for the majority of patients with PNP associated with diabetes or allodynia.

Background: Peripheral neuropathic pain (PNP) associated with allodynia poses a significant clinical challenge. The efficacy of Δ9‐tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray, a novel cannabinoid formulation, was investigated in this 15‐week randomized, double‐blind, placebo‐controlled parallel group study. Methods: In total, 303 patients with PNP associated with allodynia were screened; 128 were randomized to THC/CBD spray and 118 to placebo, in addition to their current analgesic therapy. The co‐primary efficacy endpoints were the 30% responder rate in PNP 0–10 numerical rating scale (NRS) score and the mean change from baseline to the end of treatment in this score. Various key secondary measures of pain and functioning were also investigated. Results: At the 30% responder level, there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis (intention‐to‐treat) dataset [p = 0.034; 95% confidence interval (CI): 1.05–3.70]. There was also a reduction in mean PNP 0–10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group, but which failed to reach statistical significance. Secondary measures of sleep quality 0–10 NRS score (p = 0.0072) and Subject Global Impression of Change (SGIC) (p = 0.023) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment. Conclusions: These findings demonstrate that, in a meaningful proportion of otherwise treatment‐resistant patients, clinically important improvements in pain, sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray. THC/CBD spray was well tolerated and no new safety concerns were identified.

Circinus X-1 is a bright and highly variable X-ray binary which displays strong and rapid evolution in all wavebands. Radio flaring, associated with the production of a relativistic jet, occurs periodically on a ~17-day timescale. A longer-term envelope modulates the peak radio fluxes in flares, ranging from peaks in excess of a Jansky in the 1970s to an historic low of milliJanskys during the years 1994 to 2007. Here we report first observations of this source with the MeerKAT test array, KAT-7, part of the pathfinder development for the African dish component of the Square Kilometre Array (SKA), demonstrating successful scientific operation for variable and transient sources with the test array. The KAT-7 observations at 1.9 GHz during the period 13 December 2011 to 16 January 2012 reveal in temporal detail the return to the Jansky-level events observed in the 1970s. We compare these data to contemporaneous single-dish measurements at 4.8 and 8.5 GHz with the HartRAO 26-m telescope and X-ray monitoring from MAXI. We discuss whether the overall modulation and recent dramatic brightening is likely to be due to an increase in the power of the jet due to changes in accretion rate or changing Doppler boosting associated with a varying angle to the line of sight., 7 pages, 5 figures, accepted for publication in MNRAS 14 May 2013

The construction of the seven-dish Karoo Array Telescope (KAT-7) array in the Karoo region of the Northern Cape in South Africa was intended primarily as an engineering prototype for technologies and techniques applicable to the MeerKAT telescope. This paper looks at the main engineering and scientific highlights from this effort, and discusses their applicability to both MeerKAT and other next-generation radio telescopes. In particular, we found that the composite dish surface works well, but it becomes complicated to fabricate for a dish lacking circular symmetry; the Stirling cycle cryogenic system with ion pump to achieve vacuum works but demands much higher maintenance than an equivalent Gifford-McMahon cycle system; the ROACH (Reconfigurable Open Architecture Computing Hardware)-based correlator with SPEAD (Streaming Protocol for Exchanging Astronomical Data) protocol data transfer works very well and KATCP (Karoo Array Telescope Control Protocol) control protocol has proven very flexible and convenient. KAT-7 has also been used for scientific observations where it has a niche in mapping low surface-brightness continuum sources, some extended H I haloes and OH masers in star-forming regions. It can also be used to monitor continuum source variability, observe pulsars, and make Very Long Baseline Interferometry observations.

Central neuropathic pain (CNP) occurs in many multiple sclerosis (MS) patients. The provision of adequate pain relief to these patients can very difficult. Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (USAN name, nabiximols; Sativex, GW Pharmaceuticals, Salisbury, Wiltshire, UK), to alleviate CNP. Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment, in a double-blind manner, for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain. This parallel-group phase of the study was then followed by an 18-week randomized-withdrawal study (14-week open-label treatment period plus a double-blind 4-week randomized-withdrawal phase) to investigate time to treatment failure and show maintenance of efficacy. A total of 339 patients were randomized to phase A (167 received THC/CBD spray and 172 received placebo). Of those who completed phase A, 58 entered the randomized-withdrawal phase. The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met, with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo (p = 0.234). However, an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point (p = 0.046). During the randomized-withdrawal phase, the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray, with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group (p = 0.04). The mean change from baseline in Pain Numerical Rating Scale (NRS) (p = 0.028) and sleep quality NRS (p = 0.015) scores, both secondary endpoints in phase B, were also statistically significant compared to placebo, with estimated treatment differences of -0.79 and 0.99 points, respectively, in favor of THC/CBD spray treatment. The results of the current investigation were equivocal, with conflicting findings in the two phases of the study. While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period, the primary endpoint was not met due to a similarly large number of placebo responders. In contrast, there was a marked effect in phase B of the study, with an increased time to treatment failure in the THC/CBD spray group compared to placebo. These findings suggest that further studies are required to explore the full potential of THC/CBD spray in these patients.

Background: Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design. Methods: A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4 weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase. Results: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4 weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P = 0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols. Conclusions: The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.

Alanine and N-methylation scans together with molecular modelling were implemented in order to propose a binding conformation of the minimum active fragment of bombesin (BB), Ac-BB[7-14], to the gastrin releasing peptide (GRP) and neuromedin B (NMB) receptors. These data are also used to critically evaluate the previously proposed binding conformations such as alpha-helix and antiparallel beta-sheets. This shows that the previously reported conformations do not satisfy the experimental data. A new binding conformation of Ac-BB[7-14] is proposed consisting of three consecutive gamma-turns followed by a bend and finishing with two gamma-turns. This low energy conformation (analogous to a fragment of thymidylate synthase, 2TSC) of bombesin stabilized by five internal hydrogen bonds, and with the side chains of residues Trp8 and Leu13 held on the same side of the peptide, is in agreement with the experimentally observed data. This and the results of molecular modelling may aid in the synthesis of conformationally restricted high affinity bombesin analogues and/or high affinity template-based GRP or NMB receptor agonists and antagonists.

Symptoms relating to spasticity are common in multiple sclerosis (MS) and can be difficult to treat. We have investigated the efficacy, safety and tolerability of a standardized oromucosal whole plant cannabis-based medicine (CBM) containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), upon spasticity in MS. A total of 189 subjects with definite MS and spasticity were randomized to receive daily doses of active preparation (n = 124) or placebo (n = 65) in a double blind study over 6 weeks. The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity. Secondary endpoints included a measure of spasticity (Ashworth Score) and a subjective measure of spasm. The primary efficacy analysis on the intention to treat (ITT) population (n = 184) showed the active preparation to be significantly superior (P = 0.048). Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance. The responder analysis favoured active preparation, 40% of subjects achieved >30% benefit (P = 0.014). Eight withdrawals were attributed to adverse events (AEs); six were on active preparation and two on placebo. We conclude that this CBM may represent a useful new agent for treatment of the symptomatic relief of spasticity in MS.

Earlier papers, based on a computer model of European air traffic, deal with the probability of conflicts arising between pairs of aircraft operating under free-flight rules. This paper discusses the problems of resolving these conflicts. When a potential collision takes place in the neighbourhood of other intruding aircraft, these must be taken into account when choosing an escape manoeuvre. A suggestion is made that may ease the problem.

Die Therapie des peripheren neuropathischen Schmerzes ist auch heutzutage eine schmerztherapeutische Herausforderung. Das Ziel, eine optimale medikamentose Wirkung-Nebenwirkung-Relation zu erzielen, ist Grundvoraussetzung fur die erwunschte Patientencompliance. Der Einsatz von Cannabis ist dabei eine oft diskutierte Medikamentenoption.

In a randomised double-blind, placebo-controlled study, the respiratory effects of intravenous tramadol (1 mg or 2 mg.kg-1) were compared with intravenous pethidine 1 mg.kg-1 under halothane anaesthesia. Children, ASA 1-2 between 2 and 10 years, presenting for inguinal surgery were studied. Once a steady state for halothane was reached, baseline recordings of end-tidal carbon dioxide, oxygen saturation, respiratory rate, tidal volume, minute volume, blood pressure and pulse rate were recorded. Intravenous tramadol 1 mg.kg-1 (T1) or 2 mg.kg-1 (T2) or pethidine 1 mg.kg-1 (PE) or placebo (PL) was then given according to a computer-generated randomisation. Further sets of recordings were taken at 5-min intervals for 20 min prior to commencement of surgery. The rate of recovery was assessed according to Aldrete scoring and the time and need for further analgesia were noted. The postoperative pain intensity was scored by means of a five-point verbal rating scale hourly for 6 h. Eighty-eight children, 22 per group, were studied. The mean age, weight and height were similar in each group. There was a statistically significant difference between the maximum decrease in respiratory rate and increase in end-tidal carbon dioxide between group PE and groups T1/T2 (p < 0.001). Thirteen episodes of apnoea occurred in the PE group, 11 requiring naloxone. The mean respiratory rate was lowest 5 min after injection in all groups. There was a slow increase in respiratory rate until incision in groups T1 and T2. Respiratory rate remained almost unchanged in PL until incision. The decreases in respiratory rate were reflected by increases in end-tidal carbon dioxide, the highest being recorded in the PE group. A lower intensity of pain in the first 2 h was noted in the three opioid groups. During the first 6 h, the proportion of patients requiring a further dose of analgesia was highest in PL and lowest in T2. Tramadol appears safe for use in children.

The design and synthesis of a structural motif which can mimic protein-protein interactions is described. These moieties, termed asdendroids (Greekdendron, a tree), are low-molecular-weight structures which are based on self-organising dendritic polymers.

As part of a program to investigate the structure-activity relationships of Gabapentin (Neurontin), a number of alkylated analogues were synthesized and evaluated in vitro for binding to the Gabapentin binding site located on the alpha2delta subunit of a calcium channel. A number of other bridged and heterocyclic analogues are also reported along with their in vitro data. Two compounds showing higher affinity than Gabapentin were selected for evaluation in an animal model of epilepsy. One of these compounds, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexyl)acetic acid hydrochloride (19), was shown to be effective in this model with a profile similar to that of Gabapentin itself.

A series of conformationally restricted Gabapentin analogues has been synthesised and used to propose the preferred conformation of Gabapentin for it to bind to the α 2 δ subunit of a calcium channel.

A targeted set of 256 aromatic α-amino acid derivatives is described to provide new lead compounds for biological screening. The utility is exemplified by identification of ligands for the human neuromedin B (hNMB) receptor, such as compound 3 (Ki hNMB 37nM).

Peripheral neuropathic pain (PNP) associated with allodynia poses a significant clinical challenge. The efficacy of Δ(9) -tetrahydrocannabinol/cannabidiol (THC/CBD) oromucosal spray, a novel cannabinoid formulation, was investigated in this 15-week randomized, double-blind, placebo-controlled parallel group study.In total, 303 patients with PNP associated with allodynia were screened; 128 were randomized to THC/CBD spray and 118 to placebo, in addition to their current analgesic therapy. The co-primary efficacy endpoints were the 30% responder rate in PNP 0-10 numerical rating scale (NRS) score and the mean change from baseline to the end of treatment in this score. Various key secondary measures of pain and functioning were also investigated.At the 30% responder level, there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis (intention-to-treat) dataset [p = 0.034; 95% confidence interval (CI): 1.05-3.70]. There was also a reduction in mean PNP 0-10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group, but which failed to reach statistical significance. Secondary measures of sleep quality 0-10 NRS score (p = 0.0072) and Subject Global Impression of Change (SGIC) (p = 0.023) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment.These findings demonstrate that, in a meaningful proportion of otherwise treatment-resistant patients, clinically important improvements in pain, sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray. THC/CBD spray was well tolerated and no new safety concerns were identified.

In an earlier paper, the writer attempted a quantitative study of a flow-planning system for aircraft intending to fly across Europe. This paper aims to offer each aircraft a clearance giving a reasonable expectation that, throughout cruising flight at least, there will be no conflict with other traffic. Such a clearance is sometimes termed a ‘tube of flight’. Reference i assumed a pattern of traffic flying along rhumb lines, each flight having a starting position chosen at random in a region roughly the size of Europe. Flight was in a random direction and the flight path length was chosen at random from a plausible distribution.

Background: Open-label studies are not ideal for providing robust evidence for long-term maintenance of efficacy of medicines, especially where medicines provide symptom relief and where long-term use of a placebo may be problematic and not ethical. Objective: To evaluate the maintenance of efficacy of Sativex in subjects who have gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal. Methods: An enriched enrolment randomized withdrawal study design was used. Eligible subjects with ongoing benefit from Sativex for at least 12 weeks entered this 5-week placebo-controlled, parallel-group, randomized withdrawal study. Each subjects’ previous effective and tolerated dose was continued. Results: A total of 18 subjects per group were enrolled. Demographics showed a mean duration of MS of 16.4 years, spasticity 12.7 years, mean duration of Sativex use of 3.6 years (median 3.4 years) and a mean daily dose of 8.25 sprays. Primary outcome of time to treatment failure was significantly in favour of Sativex ( p = 0.013). Secondary endpoints showed significant changes in the Carer and Subject’s Global Impression of Change scales in favour of Sativex. Conclusions: Maintenance of Sativex efficacy in long-term symptomatic improvement of spasticity to a group of subjects with MS has been confirmed using this study design.

The purpose of this study was to examine two separate socioeconomic status (SES) indicators of obesity in Botswana, an African country that has experienced rapid economic development and where the prevalence of human immunodeficiency virus/acquired immune deficiency syndrome is high.We conducted a nationally representative, cross-sectional study of 707 adolescent secondary school students in Botswana. Measured height and weight were used to compute World Health Organization age- and sex-specific body mass index z-scores. SES was described by private vs. public school attendance and a survey of assets/facilities within the home.Overall, private school students and those with more assets had a higher prevalence of overweight and obesity than public school students (private: 27.1%, 95% confidence interval [CI]: 20.4-34.5; public: 13.1%, 95% CI: 9.8-16.8) and those with fewer assets (more assets: 20.0%, 95% CI: 16.0-24.4; fewer assets: 11.2%, 95% CI: 6.6-16.9).Public health interventions in developing countries may need to be targeted differently to low or high SES individuals in order to treat already high obesity rates in higher SES groups and to prevent the development of obesity in lower SES communities undergoing economic transition.

Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design. A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase. Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P=0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols. The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.

Muscle spasticity is common in multiple sclerosis (MS), occurring in more than 60% of patients.To compare Sativex with placebo in relieving symptoms of spasticity due to MS.A 15-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy.The primary endpoint was a spasticity 0-10 numeric rating scale (NRS). Intention-to-treat (ITT) analysis showed a non-significant improvement in NRS score, in favor of Sativex. The per protocol (PP) population (79% of subjects) change in NRS score and responder analyses (or =30% improvement from baseline) were both significantly superior for Sativex, compared with placebo: -1.3 versus -0.8 points (change from baseline, p=0.035); and 36% versus 24% (responders, p=0.040). These were supported by the time to response (ITT: p=0.068; PP: p=0.025) analyses, carer global impression of change assessment (p=0.013) and timed 10-meter walk (p=0.042). Among the subjects who achieved aor =30% response in spasticity with Sativex, 98, 94 and 73% reported improvements of 10, 20 and 30%, respectively, at least once during the first 4 weeks of treatment. Sativex was generally well tolerated, with most adverse events reported being mild-to-moderate in severity.The 0-10 NRS and responder PP analyses demonstrated that Sativex treatment resulted in a significant reduction in treatment-resistant spasticity, in subjects with advanced MS and severe spasticity. The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status.

This paper attempts to challenge some of the principles on which en-route airspace is presently allocated, whilst pointing out the practical difficulties of implementing any alternative strategy. The paper does not discuss airport capacity limitations and terminal area problems, although these also contribute to restrictions on traffic flow.

Coagulation proteases are involved in a highly orchestrated proteolytic cascade which is essential for haemostasis and blood clotting. In particular, the initiator of the coagulation cascade, Factor VIIa, binds to its cofactor, tissue factor, and its substrate, Factor X, via exosite interactions to form a ternary catalytic complex named extrinsic Xase. These exosite interactions have also been shown to allosterically induce the active conformation of the catalytic site of Factor VIIa. We have developed a direct continuous fluorescence polarization-based extrinsic Xase assay, which has been used to screen in excess of 1 million structurally diverse low-molecular-mass compounds as a potential starting point for the development of anticoagulants. The primary screen hits were categorized with deconvolution assays into either active-site or exosite inhibitors. The latter category of hits displayed both competitive and uncompetitive modalities of inhibition with respect to Factor X activation. An uncompetitive mechanism of action is of particular interest as it offers a hypothetical inhibitory advantage in the context of inhibiting a proteolytic cascade such as the blood coagulation pathway.

Symptoms relating to spasticity are common in multiple sclerosis (MS) and can be difficult to treat. We have investigated the efficacy, safety and tolerability of a standardized oromucosal whole plant cannabis-based medicine (CBM) containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), upon spasticity in MS. A total of 189 subjects with definite MS and spasticity were randomized to receive daily doses of active preparation (n = 124) or placebo (n = 65) in a double blind study over 6 weeks. The primary endpoint was the change in a daily subject-recorded Numerical Rating Scale of spasticity. Secondary endpoints included a measure of spasticity (Ashworth Score) and a subjective measure of spasm. The primary efficacy analysis on the intention to treat (ITT) population (n = 184) showed the active preparation to be significantly superior (P = 0.048). Secondary efficacy measures were all in favour of active preparation but did not achieve statistical significance. The responder analysis favoured active preparation, 40% of subjects achieved30% benefit (P = 0.014). Eight withdrawals were attributed to adverse events (AEs); six were on active preparation and two on placebo. We conclude that this CBM may represent a useful new agent for treatment of the symptomatic relief of spasticity in MS.

In a randomised double-blind, placebo-controlled study, the respiratory effects of intravenous tramadol (1 mg or 2 mg.kg-1) were compared with intravenous pethidine 1 mg.kg-1 under halothane anaesthesia. Children, ASA 1-2 between 2 and 10 years, presenting for inguinal surgery were studied. Once a steady state for halothane was reached, baseline recordings of end-tidal carbon dioxide, oxygen saturation, respiratory rate, tidal volume, minute volume, blood pressure and pulse rate were recorded. Intravenous tramadol 1 mg.kg-1 (T1) or 2 mg.kg-1 (T2) or pethidine 1 mg.kg-1 (PE) or placebo (PL) was then given according to a computer-generated randomisation. Further sets of recordings were taken at 5-min intervals for 20 min prior to commencement of surgery. The rate of recovery was assessed according to Aldrete scoring and the time and need for further analgesia were noted. The postoperative pain intensity was scored by means of a five-point verbal rating scale hourly for 6 h. Eighty-eight children, 22 per group, were studied. The mean age, weight and height were similar in each group. There was a statistically significant difference between the maximum decrease in respiratory rate and increase in end-tidal carbon dioxide between group PE and groups T1/T2 (p0.001). Thirteen episodes of apnoea occurred in the PE group, 11 requiring naloxone. The mean respiratory rate was lowest 5 min after injection in all groups. There was a slow increase in respiratory rate until incision in groups T1 and T2. Respiratory rate remained almost unchanged in PL until incision. The decreases in respiratory rate were reflected by increases in end-tidal carbon dioxide, the highest being recorded in the PE group. A lower intensity of pain in the first 2 h was noted in the three opioid groups. During the first 6 h, the proportion of patients requiring a further dose of analgesia was highest in PL and lowest in T2. Tramadol appears safe for use in children.