The treatment of spasticity with Delta9-tetrahydrocannabinol in persons with spinal cord injury

STUDY DESIGN: Open label study to determine drug dose for a randomized double-blind placebo-controlled parallel study. OBJECTIVES: To assess the efficacy and side effects of oral Delta(9)-tetrahydrocannabinol (THC) and rectal THC-hemisuccinate (THC-HS) in SCI patients. SETTING: REHAB Basel, Switzerland. METHOD: Twenty-five patients with SCI were included in this three-phase study with individual dose adjustment, each consisting of 6 weeks. Twenty-two participants received oral THC open label starting with a single dose of 10 mg (Phase 1, completed by 15 patients). Eight subjects received rectal THC-HS (Phase 2, completed by seven patients). In Phase 3, six patients were treated with oral THC and seven with placebo. Major outcome parameters were the spasticity sum score (SSS) using the Modified Ashworth Scale (MAS) and self-ratings of spasticity. RESULTS: Mean daily doses were 31 mg with THC and 43 mg with THC-HS. Mean SSS for THC decreased significantly from 16.72 (+/-7.60) at baseline to 8.92 (+/-7.14) on day 43. Similar improvement was seen with THC-HS. We observed a significant improvement of SSS with active drug (P=0.001) in the seven subjects who received oral THC in Phase 1 and placebo in Phase 3. Major reasons for drop out were increase of pain and psychological side effects. CONCLUSION: THC is an effective and safe drug in the treatment of spasticity. At least 15-20 mg per day were needed to achieve a therapeutic effect.

Natalizumab: targeting alpha4-integrins in multiple sclerosis

In 1992, it was shown that monoclonal antibodies blocking alpha(4)-integrins prevent the development of experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS). As alpha(4)beta(1)-integrin was demonstrated to mediate the attachment of immune-competent cells to inflamed brain endothelium in experimental autoimmune encephalomyelitis, the therapeutic effect was attributed to the inhibition of immune cell extravasation and inflammation in the central nervous system. This novel therapeutic approach was rapidly and successfully translated into the clinic. The humanized anti-alpha(4)-integrin antibody natalizumab demonstrated an unequivocal therapeutic effect in preventing relapses and slowing down the pace of neurological deterioration in patients with relapsing-remitting MS in phase II and phase III clinical trials. The occurrence of 3 cases of progressive multifocal leukoencephalopathy in patients treated with natalizumab led to the voluntary withdrawal of the drug from the market. After a thorough safety evaluation of all patients receiving this drug in past and ongoing studies for MS and Crohn's disease, natalizumab again obtained approval in the US and the European Community. A treatment targeting leukocyte trafficking in MS has now re-entered the clinic. Further thorough evaluation is necessary for a better understanding of the risk-benefit balance of this new treatment option for relapsing MS. In this review, we discuss the basic mechanism of action, key clinical results of clinical trials and the emerging indication of natalizumab in MS.

Different patterns of Siglec-9-mediated neutrophil death responses in septic shock

Sialic-acid-binding immunoglobulin-like lectin (Siglec) 9 mediates death signals in neutrophils. The objective of this study was to determine the heterogeneity of neutrophil death responses in septic shock patients and to analyze whether these ex vivo data are related to the severity and outcome of septic shock. In this prospective cohort study, blood samples of patients with septic shock (n = 26) in a medical-surgical intensive care unit (ICU) were taken within 24 h of starting the treatment of septic shock (phase A), after circulatory stabilization (phase B), and 10 days after admission or at ICU discharge if earlier (phase C). Neutrophil death was quantified in the presence and absence of an agonistic anti-Siglec-9 antibody after 24 h ex vivo. In phase A, two distinct patterns of Siglec-9-mediated neutrophil death were observed: resistance to neutrophil death (n = 14; Siglec-9 nonresponders) and increased neutrophil death (n = 12; Siglec-9 responders) after Siglec-9 ligation compared with neutrophils from normal donors. Experiments using a pharmacological pan-caspase-inhibitor provided evidence for caspase-independent neutrophil death in Siglec-9 responders upon Siglec-9 ligation. There were no differences between Siglec-9 responders and nonresponders in length of ICU or hospital stay of survivors or severity of organ dysfunction. Taken together, septic shock patients exhibit different ex vivo death responses of blood neutrophils after Siglec-9 ligation early in shock. Both the resistance and the increased susceptibility to Siglec-9-mediated neutrophil death tend to normalize within 72 h after shock. Further studies are required to understand the role of Siglec-9-mediated neutrophil death in septic shock.

Asthma and allergies: is the farming environment (still) protective in Poland? The GABRIEL Advanced Studies

BACKGROUND Evidence exists that a farming environment in childhood may provide protection against atopic respiratory disease. In the GABRIEL project based in Poland and Alpine regions of Germany, Austria and Switzerland, we aimed to assess whether a farming environment in childhood is protective against allergic diseases in Poland and whether specific exposures explain any protective effect. METHODS In rural Poland, 23 331 families of schoolchildren completed a questionnaire enquiring into farming practices and allergic diseases (Phase I). A subsample (n = 2586) participated in Phase II involving a more detailed questionnaire on specific farm exposures with objective measures of atopy. RESULTS Farming differed between Poland and the Alpine centres; in the latter, cattle farming was prevalent, whereas in Poland 18% of village farms kept ≥1 cow and 34% kept ≥1 pig. Polish children in villages had lower prevalences of asthma and hay fever than children from towns, and in the Phase II population, farm children had a reduced risk of atopy measured by IgE (aOR = 0.72, 95% CI 0.57, 0.91) and skin prick test (aOR = 0.65, 95% CI 0.50, 0.86). Early-life contact with grain was inversely related to the risk of atopy measured by IgE (aOR = 0.66, 95% CI 0.47, 0.92) and appeared to explain part of the farming effect. CONCLUSION While farming in Poland differed from that in the Alpine areas as did the exposure-response associations, we found in communities engaged in small-scale, mixed farming, there was a protective farming effect against objective measures of atopy potentially related to contact with grain or associated farm activities.

Summer temperature in the eastern part of southern South America: its variability in the twentieth century and a teleconnection with Oceania

The 1907–2001 summer-to-summer surface air temperature variability in the eastern part of southern South America (SSA, partly including Patagonia) is analysed. Based on records from instruments located next to the Atlantic Ocean (36°S–55°S), we define indices for the interannual and interdecadal timescales. The main interdecadal mode reflects the late-1970s cold-to-warm climate shift in the region and a warm-to-cold transition during early 1930s. Although it has been in phase with the Pacific Decadal Oscillation (PDO) index since the 1960s, they diverged in the preceding decades. The main interannual variability index exhibits high spectral power at ~3.4 years and is representative of temperature variability in a broad area in the southern half of the continent. Eleven-years running correlation coefficients between this index and December-to-February (DJF) Niño3.4 show significant decadal fluctuations, out-of-phase with the running correlation with a DJF index of the Southern Annular Mode. The main interannual variability index is associated with a barotropic wavetrain-like pattern extending over the South Pacific from Oceania to SSA. During warm (cold) summers in SSA, significant anticyclonic (cyclonic) anomalies tend to predominate over eastern Australia, to the north of the Ross Sea, and to the east of SSA, whereas anomalous cyclonic (anticyclonic) circulation is observed over New Zealand and west of SSA. This teleconnection links warm (cold) SSA anomalies with dry (wet) summers in eastern Australia. The covariability seems to be influenced by the characteristics of tropical forcing; indeed, a disruption has been observed since late 1970s, presumably due to the PDO warm phase.

S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents.

OBJECTIVE To determine the potency ratio between S-ketamine and racemic ketamine as inductive agents for achieving tracheal intubation in dogs. STUDY DESIGN Prospective, randomized, 'blinded', clinical trial conducted in two consecutive phases. ANIMALS 112 client-owned dogs (ASA I or II). METHODS All animals were premedicated with intramuscular acepromazine (0.02 mg kg(-1) ) and methadone (0.2 mg kg(-1) ). In phase 1, midazolam (0.2 mg kg(-1) ) with either 3 mg kg(-1) of racemic ketamine (group K) or 1.5 mg kg(-1) of S-ketamine (group S) was administered IV, for induction of anaesthesia and intubation. Up to two additional doses of racemic (1.5 mg kg(-1) ) or S-ketamine (0.75 mg kg(-1) ) were administered if required. In phase 2, midazolam (0.2 mg kg(-1) ) with 1 mg kg(-1) of either racemic ketamine (group K) or S-ketamine (group S) was injected and followed by a continuous infusion (1 mg kg minute(-1) ) of each respective drug. Differences between groups were statistically analyzed via t-test, Fisher exact test and ANOVA for repeated measures. RESULTS Demographics and quality and duration of premedication, induction and intubation were comparable among groups. During phase 1 it was possible to achieve tracheal intubation after a single dose in more dogs in group K (n = 25) than in group S (n = 16) (p = 0.046). A dose of 3 mg kg(-1) S-ketamine allowed tracheal intubation in the same number of dogs as 4.5 mg kg(-1) of racemic ketamine. The estimated potency ratio was 1.5:1. During phase 2, the total dose (mean ± SD) of S-ketamine (4.02 ±1.56 mg kg(-1) ) and racemic ketamine (4.01 ± 1.42) required for tracheal intubation was similar. CONCLUSION AND CLINICAL RELEVANCE Racemic and S-ketamine provide a similar quality of anaesthetic induction and intubation. S-ketamine is not twice as potent as racemic ketamine and, if infused, the potency ratio is 1:1.

Multimodal treatment for high-risk prostate cancer with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel and long-term androgen deprivation therapy: results of a prospective phase II trial.

BACKGROUND The optimal management of high-risk prostate cancer remains uncertain. In this study we assessed the safety and efficacy of a novel multimodal treatment paradigm for high-risk prostate cancer. METHODS This was a prospective phase II trial including 35 patients with newly diagnosed high-risk localized or locally advanced prostate cancer treated with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel-based chemotherapy and long-term androgen deprivation therapy. Primary endpoint was acute and late toxicity evaluated with the Common Terminology Criteria for Adverse Events version 3.0. Secondary endpoint was biochemical and clinical recurrence-free survival explored with the Kaplan-Meier method. RESULTS Acute gastro-intestinal and genito-urinary toxicity was grade 2 in 23% and 20% of patients, and grade 3 in 9% and 3% of patients, respectively. Acute blood/bone marrow toxicity was grade 2 in 20% of patients. No acute grade ≥ 4 toxicity was observed. Late gastro-intestinal and genito-urinary toxicity was grade 2 in 9% of patients each. No late grade ≥ 3 toxicity was observed. Median follow-up was 63 months (interquartile range 31-79). Actuarial 5-year biochemical and clinical recurrence-free survival rate was 55% (95% confidence interval, 35-75%) and 70% (95% confidence interval, 52-88%), respectively. CONCLUSIONS In our phase II trial testing a novel multimodal treatment paradigm for high-risk prostate cancer, toxicity was acceptably low and mid-term oncological outcome was good. This treatment paradigm, thus, may warrant further evaluation in phase III randomized trials.

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.

Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial

IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN54371254.

Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at √s=8 TeV with ATLAS

Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of √s = 8TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4 (stat.) +3.2 −2.9 (syst.) ±1.2 (lumi) fb for a Higgs boson of mass 125.4 GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations.

The role of seasonality of mineral dust concentration and size on glacial/interglacial dust changes in the EPICA Dronning Maud Land ice core

We present a record of particulate dust concentration and size distribution in subannual resolution measured on the European Project for Ice Coring in Antarctica (EPICA) Dronning Maud Land (EDML) ice core drilled in the Atlantic sector of the East Antarctic plateau. The record reaches from present day back to the penultimate glacial until 145,000 years B.P. with subannual resolution from 60,000 years B.P. to the present. Mean dust concentrations are a factor of 46 higher during the glacial (~850–4600 ng/mL) compared to the Holocene (~16–112 ng/mL) with slightly smaller dust particles during the glacial comparedto the Holocene and with an absolute minimum in the dust size at 16,000 years B.P. The changes in dust concentration are mainly attributed to changes in source conditions in southern South America. An increase in the modal value of the dust size suggests that at 16,000 years B.P. a major change in atmospheric circulation apparently allowed more direct transport of dust particles to the EDML drill site. We find a clear in-phase relation of the seasonal variation in dust mass concentration and dust size during the glacial (r(conc,size) = 0.8) but no clear phase relationship during the Holocene (0

Interobserver variations of target volume delineation in multicatheter partial breast brachytherapy after open cavity surgery

PURPOSE To investigate interobserver variations of target volume delineations in accelerated partial breast irradiation with multicatheter brachytherapy (BT) and to assess the impact of guidelines on consistency of contouring. METHODS AND MATERIALS A contouring study with two phases in interstitial accelerated partial breast irradiation after open cavity surgery was conducted by the Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology Breast Cancer Working Group. Contours of cavity and planning target volume (PTV) on preimplant and postimplant CT images were delineated. In Phase 1, nine radiation oncologists defined the target volumes of 5 patients, whereas in Phase 2, four observers draw the contours of 4 patients applying guidelines. In Phase 1, experience in breast BT after open cavity surgery was assessed. The delineations were compared between Phase 1 and Phase 2, the impact of guidelines was assessed, and cavity visualization score was related to consistency of delineations. RESULTS Significant interobserver variability in delineations of lumpectomy cavity and PTV was observed among the participants. Observers with BT experience after open cavity surgery outlined the cavity and PTV more consistently (conformity indexgen: 0.52 vs. 0.48 and 0.59 vs. 0.55 for preimplant and postimplant cavities). For all volumes, the mean Vmax/Vmin was 2.2 vs. 2.8. Having used guidelines all conformity indices increased significantly. For cavity, the increase was 14% and 11%, whereas for the PTV, 28% and 17% on the preimplant and postimplant CT images, respectively. A strong correlation was found between consistency of contours and cavity visualization score. CONCLUSIONS Simple guidelines on defining the lumpectomy cavity significantly increased the consistency of contouring. Reliable consistency of target volume definition can be expected only for good cavity visibility.

Effectiveness of Fluorescence-based Methods in Monitoring Progression of Noncavitated Caries-like Lesions on Smooth Surfaces

Although there has been a significant decrease in caries prevalence in developed countries, the slower progression of dental caries requires methods capable of detecting and quantifying lesions at an early stage. The aim of this study was to evaluate the effectiveness of fluorescence-based methods (DIAGNOdent 2095 laser fluorescence device [LF], DIAGNOdent 2190 pen [LFpen], and VistaProof fluorescence camera [FC]) in monitoring the progression of noncavitated caries-like lesions on smooth surfaces. Caries-like lesions were developed in 60 blocks of bovine enamel using a bacterial model of Streptococcus mutans and Lactobacillus acidophilus . Enamel blocks were evaluated by two independent examiners at baseline (phase I), after the first cariogenic challenge (eight days) (phase II), and after the second cariogenic challenge (a further eight days) (phase III) by two independent examiners using the LF, LFpen, and FC. Blocks were submitted to surface microhardness (SMH) and cross-sectional microhardness analyses. The intraclass correlation coefficient for intra- and interexaminer reproducibility ranged from 0.49 (FC) to 0.94 (LF/LFpen). SMH values decreased and fluorescence values increased significantly among the three phases. Higher values for sensitivity, specificity, and area under the receiver operating characteristic curve were observed for FC (phase II) and LFpen (phase III). A significant correlation was found between fluorescence values and SMH in all phases and integrated loss of surface hardness (ΔKHN) in phase III. In conclusion, fluorescence-based methods were effective in monitoring noncavitated caries-like lesions on smooth surfaces, with moderate correlation with SMH, allowing differentiation between sound and demineralized enamel.

Human–climate interactions in the central Mediterranean region during the last millennia: The laminated record of Lake Butrint (Albania)

Lake Butrint (39°47 N, 20°1 E) is a ca. 21 m deep, coastal lagoon located in SW Albania where finely-laminated sediments have been continuously deposited during the last millennia. The multi-proxy analysis (sedimentology, high-resolution elemental geochemistry and pollen) of a 12 m long sediment core, supported by seven AMS radiocarbon dates and 137Cs dating, enable a precise reconstruction of the environmental change that occurred in the central Mediterranean region during the last ∼4.5 cal kyrs BP. Sediments consist of triplets of authigenic carbonates, organic matter and clayey laminae. Fluctuations in the thickness and/or presence of these different types of seasonal laminae indicate variations in water salinity, organic productivity and runoff in the lake's catchment, as a result of the complex interplay of tectonics, anthropogenic forcing and climate variability. The progradation of the Pavllo river delta, favoured by variable human activity from the nearby ancient city of Butrint, led to the progressive isolation of this hydrological system from the Ionian Sea. The system evolved from an open bay to a restricted lagoon, which is consistent with archaeological data. An abrupt increase in mass-wasting activity between 1515 and 1450 BC, likely caused by nearby seismic activity, led to the accumulation of 24 homogenites, up to 17 cm thick. They have been deposited during the onset of finely laminated sedimentation, which indicates restricted, anoxic bottom water conditions and higher salinity. Periods of maximum water salinity, biological productivity, and carbonate precipitation coincide with warmer intervals, such as the early Roman Warm Period (RWP) (500 BC–0 AD), the Medieval Climate Anomaly (MCA) (800–1400 AD) and recent times (after 1800 AD). Conversely, lower salinity and more oxic conditions, with higher clastic input were recorded during 1400–500 BC, the Late Roman and the Early Medieval periods (0–800 AD) and during the Little Ice Age (1400–1800 AD). Hydrological fluctuations recorded in Butrint are in phase with most central and western Mediterranean records and correlate with NAO variability. In contrast, opposite hydrological patterns have been recorded in the Eastern Balkans and the Levant during the last millennium, emphasizing a complex spatial variability in the region. Phases of maximum settlement intensity in Butrint (Roman-Late Antique) coincide with warmer and/or stable climate periods (0–800 AD and MCA, respectively), indicating a long-term influence of climatic conditions on human activities. The Late Holocene sedimentary record of Lake Butrint demonstrates the complex interplay of climate variability, tectonics and human impact in the recent evolution of coastal Mediterranean regions.

Intraoperative image-guided navigation system: development and applicability in 65 patients undergoing liver surgery

Background Image-guided systems have recently been introduced for their application in liver surgery.We aimed to identify and propose suitable indications for image-guided navigation systems in the domain of open oncologic liver surgery and,more specifically, in the setting of liver resection with and without microwave ablation. Method Retrospective analysis was conducted in patients undergoing liver resection with and without microwave ablation using an intraoperative image-guided stereotactic system during three stages of technological development (accuracy: 8.4 ± 4.4 mm in phase I and 8.4 ± 6.5 mm in phase II versus 4.5 ± 3.6 mm in phase III). It was evaluated, in which indications image-guided surgery was used according to the different stages of technical development. Results Between 2009 and 2013, 65 patients underwent image-guided surgical treatment, resection alone (n=38), ablation alone (n =11), or a combination thereof (n =16). With increasing accuracy of the system, image guidance was progressively used for atypical resections and combined microwave ablation and resection instead of formal liver resection (p<0.0001). Conclusion Clinical application of image guidance is feasible, while its efficacy is subject to accuracy. The concept of image guidance has been shown to be increasingly efficient for selected indications in liver surgery. While accuracy of available technology is increasing pertaining to technological advancements, more and more previously untreatable scenarios such as multiple small, bilobar lesions and so-called vanishing lesions come within reach.