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The St. Elias orogen and the Surveyor Fan in the adjacent Gulf of Alaska are a coupled source to sink system recording the interplay of tectonics and variable degrees of glaciation during the collision of the Yakutat terrane with the southern Alaska margin since the Miocene. The Miocene to Holocene sediments of the Surveyor Fan were drilled during IODP expedition 341. The recovered material is used to constrain information on changes in erosion centers during the last 10 Ma to study the impact of climatic and tectonic processes on orogen evolution. Point counting of sand- and silt-sized light framework components and geochemical single grain analysis of heavy mineral groups epidote and pyroxene is applied to analyze patterns of sedimentary provenance of two sites on the distal and proximal Surveyor Fan (Site U1417 and U1418, respectively). The studied sands and silts of Miocene to Pleistocene age are slightly enriched in feldspar (plag >> kf) at the proximal site, compositions at both sites do not show systematical changes with time of deposition. Framework component spectra uniformly reflect the expected active margin provenance. Epidote and pyroxene compositions are very consistent and show no change with time of deposition. Associations of epidote and pyroxene with albite, titanite and pumpellyite are in line with near-shore sources in the Chugach Metamorphic Complex and the metabasite belt at its southern border, and in units of recycled detritus exposed in the fold and thrust belt on the western Yakutat Terrane, respectively. Rock fragments indicate input from mainly metamorphic sources during the Miocene and Pliocene and an increase of input from low-grade metamorphic and sedimentary rocks in the Pleistocene, a finding also indicated by the abundance of epidote and pyroxene. This implies increasing erosion of the near-shore areas of the fold and thrust belt with advance of glaciers to the shore since the Miocene, being enhanced by the onset of the Northern Hemisphere glaciation at the beginning of the Pleistocene. Climate changes connected to the mid-Pleistocene transition did not result in appreciable changes in the petrographic compositions. Glaciers seem to have remained nested in their topographically predefined positions, continuously feeding material with uniform characteristics into the fan.

Olfaction has profoundly shaped human experience and behaviour from the deep past through to the present day. Advanced biomolecular and ‘omics’ sciences enable more direct insights into past scents, offering new options to explore critical aspects of ancient society and lifeways as well as the historical meanings of smell. Challenges of finding past smells Biomolecular reconstruction of scent Using smell to understand the past

The origins and dispersal of the chicken across the ancient world remains one of the most enigmatic questions regarding Eurasian domesticated animals1,2. The lack of agreement regarding the timing and center of origin is due, in large part, to issues with morphological identifications, a lack of direct dating, and poor preservation of thin bird bones. Historical sources attest to the prominence of chickens in southern Europe and southwest Asia by the last centuries BC3. Likewise, art historical depictions of chickens and anthropomorphic rooster-human chimeras are reoccurring motifs in Central Asian prehistoric and historic traditions4-6. However, when this ritually and economically significant bird spread along the trans-Eurasian exchange routes has remained a mystery. Here we show that chickens were widely raised by people at villages across southern Central Asia from the third century BC through medieval periods for their eggs and likely also meat. In this study, we present archaeological and molecular evidence for the cultivation of chickens for egg production from 12 different Central Asian archaeological sites spanning a millennium and a half. These eggshells were recovered in high abundance at all of these sites, suggesting that chickens were widely raised by people at villages across southern Central Asia from the third century BC through medieval periods and that they were an important part of the overall diet. Contrary to views that ancient peoples of Central Asia were primarily herding sheep, goat, and cattle, these data show that chicken was also important in the subsistence economy and that it was widely spread along the ancient Silk Road. Introduction - Rapid Dissemination across the Ancient World Results - Archaeological Eggshells - Peptide Mass Fingerprinting Discussion - Evidence for Non-Seasonal Egg Laying - The Rise in Symbolic and Economic Prominence of the Chicken in Central Asia Conclusions

BACKGROUND Intra-operative muscle relaxation is often required in orthopaedic surgery and the hand train-of-four (TOF) test is usually used for its quantification. However, even though full muscle relaxation is claimed by anaesthesiologists based on a TOF count of zero, surgeons observe residual muscle activity. OBJECTIVE The aim of the study was to assess if hand or foot TOF adequately represents intra-operative muscle relaxation compared with multiple motor evoked potentials. DESIGN Prospective observational study. SETTING A single-centre study performed between February 2016 and December 2018 at the Balgrist University Hospital, Zurich, Switzerland. PATIENTS Twenty patients scheduled for elective lumbar spinal fusion were prospectively enrolled in this study after giving written informed consent. INTERVENTIONS To assess neuromuscular blockade (NMB) with the intermediate duration nondepolarising neuromuscular blocking agent rocuronium, hand TOF (adductor pollicis) and foot TOF (flexor hallucis brevis) monitoring, and muscle motor evoked potentials (MMEPs) from the upper and lower extremities were assessed prior to surgery under general anaesthesia. Following baseline measurements, muscle relaxation was performed with rocuronium until the spinal surgeon observed sufficient relaxation for surgical intervention. At this timepoint, NMB was assessed by TOF and MMEP. MAIN OUTCOME MEASURES The primary outcome was to determine the different effect of rocuronium on muscle relaxation comparing hand and foot TOF with the paraspinal musculature assessed by MMEP. RESULTS Hand TOF was more resistant to NMB and had a shorter recovery time than foot TOF. When comparing MMEPs, muscle relaxation occurred first in the hip abductors, and the paraspinal and deltoid muscles. The most resistant muscle to NMB was the abductor digiti minimi. Direct comparison showed that repetitive MMEPs simultaneously recorded from various muscles at the upper and lower extremities and from paraspinal muscles reflect muscle relaxation similar to TOF testing. CONCLUSION Hand TOF is superior to foot TOF in assessing muscle relaxation during spinal surgery. Hand TOF adequately represents the degree of muscle relaxation not only for the paraspinal muscles but also for all orthopaedic surgical sites where NMB is crucial for good surgical conditions. TRIAL REGISTRATION clinicalTrials.gov (NCT03318718).

Aims Climate change is expected to markedly change site factors, tree species composition and finally ecosystem services provided by forests. Here, we describe the development of a framework for modelling how these changes may transform forest site types. Site types capture information on site conditions like climate, topography and soil, all factors with strong influence on tree species occurrence. Location Switzerland. Methods We elicited expert knowledge and followed a participatory modelling approach for quantifying upward shifts of altitudinal vegetation belts and the changes in the zonal distribution of main tree species, as a basis for assessing transformation pathways of forest site types for three climate projections. Results The model results show marked range shifts of altitudinal vegetation belts. The change in the vegetation belt and a rule base for forest site type transformations allow for assessing the location-specific and long-term transformation pathway from the current to a future forest site type. Conclusions The resulting maps enable forest managers to take climate change into account when selecting tree species. The presented method complements statistical distribution models as it considers more site information, integrates expert knowledge and is based on a forest site type classification which is already widely used by forest practitioners., Applied Vegetation Science, 24 (4), ISSN:1402-2001, ISSN:1654-109X

The history of exhumation and denudation of the Cenozoic St. Elias orogen is stored in the sediments of the Miocene to Holocene Surveyor Fan, Gulf of Alaska. The orogeny of the mountain bel...

The St. Elias orogen formed as a result of the northwestward drift of the Yakutat terrane along and final collision with the Alaska margin in the Miocene. Its exhumation coincided with changing glacial conditions that are considered to have strongly interacted with mountain building processes. A significant part of the record of these tectonic-climatic interactions is stored in sediments on the Gulf of Alaska abyssal plain including the Surveyor fan. Our study examines temporal provenance changes of Miocene through Pleistocene sediments of the Surveyor fan, Gulf of Alaska, to constrain the dynamics of exhumation and mass transfer from the evolving St. Elias orogen to the adjacent Surveyor deep sea fan. We present single grain geochemical data of amphibole and garnet and 40Ar/39Ar cooling ages of biotite and amphibole together with point counting data of heavy minerals from sands and silts from two sites in the distal and proximal fan, drilled by IODP expedition 341 in 2013 (sites U1417 and U1418, respectively). A shift in heavy mineral composition during the Miocene, predating the onset of glaciation, points to a tectonically-induced change in erosion centers and sediment transport, probably caused by the rise of the St. Elias Mountains. Garnet and amphibole data suggest the Chugach metamorphic complex is the main sediment source, implying input to the Surveyor fan from sources relatively far in the north during the Miocene. Changing provenance signals from the Miocene to Pliocene suggest rising input from the lower grade metamorphic areas at the southern flanks of the orogen, indicating the advance of glaciers to the tidewater line, providing material from this flanking region. Higher input from the Chugach metamorphic complex in all Pleistocene sediments suggests the Northern Hemisphere glaciation at the Plio-Pleistocene boundary caused erosion and sediment yield from the interior of the orogen. Climatic changes at the mid-Pleistocene transition did not cause significant changes in the provenance signal.

Neue Waldstandort-Hinweiskarte Graubündens zur Ermittlung sensitiver Standorte und Bestände Kenntnisse der Waldstandorttypen sind grundlegend, um den heutigen Zustand und die künftige Entwick-lung des Waldes zu verstehen. Insbesondere in Schutzwäldern ist entscheidend, wie widerstands- und anpassungsfähig die heutigen Bestände sind. Die komplett überarbeitete, flächendeckende Waldstandort- Hinweiskarte für den Kanton Graubünden ist ein wichtiges Planungsinstrument: Sie dient als Grundlage für die Bestimmung von Standorten und Beständen, die empfindlich auf den Klimawandel reagieren könnten. Darüber hinaus ermöglicht sie es, flächendeckende Baumartenempfehlungen für die Zukunft zu erstellen.

Modelling of the vegetation belts and the areas of beech and silver fir for Switzerland The vegetation belts and the distribution area of beech and silver fir in Switzerland are an essential basis for the classification of forest site types with ecograms and therefore for site-specific recommendations of tree species and for forestry. Their limits, which are to a large extend defined by climatic factors, were until now only defined on a qualitative basis. For the future usage of the ecograms for tree species recommendations the limits must be described quantitatively, so that they can be modelled for the future with climate scenarios. With maps in a high spatial resolution of the forest-relevant climate variables and with additional important site parameters, those parameters were selected, which were relevant for the actual limits of the vegetation belts as well as for the beech and silver fir areal. The altitudinal belts were modelled by means of a linear regression between the known position of a representative altitudinal limit and the respective climatic factors at that position. The areal limits were modelled with a fuzzy logic approach. The climatic variables for the time span 2070–2099 were calculated on the basis of the climate (emission) scenario A1B (regional models RegCM3 and CLM), so that the limits of the altitudinal belts and the areas could be modelled for the future. The results of the model approaches are ecologically plausible. This could be shown in a comparison with the forest site types on the sample points of the National Forest Inventory and in an expert evaluation. The developed vegetation and climate maps as well as the modelled projections of the altitudinal belts in the future are the basis for the inclusion of climate change in the recommendation of tree species. They serve as decision support for forest managers and authorities in the forestry planning which is confronted with many uncertainties.

Assessing the impacts of climatic changes on forests requires the analysis of actual climatology within the forested area. In mountainous areas, climatological indices vary markedly with the micro-relief, i.e., with altitude, slope, and aspect. Consequently, when modelling potential shifts of altitudinal belts in mountainous areas due to climatic changes, maps with a high spatial resolution of the underlying climatological indices are fundamental. Here we present a set of maps of climatological indices with a spatial resolution of 25 by 25 m. The presented dataset consists of maps of the following parameters: average daily temperature high and low in January, April, July, and October as well as of the year; seasonal and annual thermal continentality; first and last freezing day; frost-free vegetation period; relative air humidity; solar radiation; and foehn conditions. The parameters represented in the maps have been selected in a knowledge engineering approach. The maps show the climatology of the periods 1961–1990 and 1981–2010. The data can be used for statistical analyses of forest climatology, for developing tree distribution models, and for assessing the impacts of climatic changes on Swiss forests., Forests, 10 (8), ISSN:1999-4907

Expansion and development of Green Alder stands in eastern Switzerland In many subalpine regions of Switzerland, the Green Alder (Alnus viridis) is expanding as summer pastures are abandoned. The Federal Office for the Environment has set up a research project to improve the understanding of the characteristics of Green Alder and the consequences of its expansion. This project is based on a literature search, interviews with experts and GIS-based analysis of the past and present occurrence of Green Alder in three areas of eastern Switzerland. The results show that Green Alder is present at all exposures in the research areas. It is not lime-intolerant, but is less present on well drained basic subsoils. It is much more widespread than hitherto believed. In the canton of Glarus as well as in the Surselva, the area of Green Alder stands has doubled in the past 75 years. Only a few have developed to high forest stands. Therefore Green Alder stands should be considered, at least in their optimum oceanic sites, as permanent association, and not pioneer forests. In many places a broad belt of Green Alder has developed at the upper treeline, which is preventing the establishment of other species (e.g. Spruce) which might be possible because of climate change. Without intervention, the Green Alder stands will in all likelihood continue to expand over the coming decades. The areas affected by this expansion should be identified as of now, and a decision taken as to whether or not to tolerate this expansion. It is important that planning measures (agriculture, forestry, regional development) be taken early enough.

Our previous studies indicated that LTβR activation mainly by T cell derived LTα1β2 is crucial for the control and down-regulation of intestinal inflammation. In order to dissect the cellular and molecular role of LTβR activation in the experimental model of DSS-induced intestinal inflammation, we have generated cell type-specific LTβR-deficient mice with specific ablation of LTβR expression on macrophages/neutrophils (LTβR(flox/flox) × LysM-Cre). These mice develop an exacerbated intestinal inflammation in our experimental model indicating that LTβR expression on macrophages/neutrophils is responsible for the control and down-regulation of the inflammatory reaction. These results were verified by adoptive transfer experiments of BMDM from wild-type and LTβR-deficient mice. Furthermore, transfer of activated CD4+ T cells derived from wild-type mice, but not from LTβR ligand-deficient mice attenuated the signs of intestinal inflammation. Finally, we demonstrate that LTβR activation on BMDM results in induction of TRIM30α, a negative regulator of NFκB activation. Concordantly, ablation of LTβR signaling results in the inability to induce TRIM30α expression concomitant with an increased expression of pro-inflammatory cytokines in our experimental model. Taken together, our data demonstrate that LTβR activation on macrophages by CD4+ T cell derived LTαβ controls the pro-inflammatory response by activation of a TRIM30α-dependent signaling pathway, crucial for the down-regulation of the inflammatory response in this experimental model.

β-defensins are known for their antimicrobial activity and belong to the molecular barrier of the innate immune system against invading pathogens. In addition, it has been shown that some members of the β-defensin superfamily have the capacity to promote local innate inflammatory and systemic adaptive immune responses, mediated in part by the interaction with CCR6. We found that mouse β-defensin 14 (mBD14, Defb14), a newly identified member of the mouse β-defensin superfamily, is expressed in mouse fibrosarcoma tumor tissue. Tumor cells overexpressing mBD14 demonstrated enhanced solid tumor growth in syngeneic C57BL/6 mice concomitant with increased vascularization of these tumors. Furthermore, mBD14-overexpressing tumors demonstrated increased expression of proangiogenic MIP-2 (CXCL2) ex vivo. In contrast, vascular endothelial growth factor expression was not affected. Cellular analysis of tumor-infiltrating leukocytes revealed a significant increase of CCR6+ B220+ lymphocytes in solid tumors derived from mBD14-overexpressing tumor cells. Enhanced tumor growth of mBD14-overexpressing fibrosarcomas was abolished in CCR6-deficient mice, which was paralleled by decreased infiltration of CCR6+ B220+ lymphocytes, indicating the requirement of CCR6 expression on host cells. Previously, the interaction of activated, LTαβ+, lymphocytes with lymphotoxin β-receptor–expressing fibrosarcoma tumor cells has been identified as a new CXCL2-dependent proangiogenic pathway. Coexpression of a soluble lymphotoxin β-receptor:Ig fusion protein, an inhibitor of CXCL2-dependent angiogenesis, in mBD14-overexpressing fibrosarcoma tumor cells abolished enhanced solid tumor growth. Thus, we conclude that mBD14 expression by tumor-infiltrating host cells results in the chemoattraction of CCR6+ B220+ lymphocytes, which in turn initiates a proangiogenic pathway leading to enhanced angiogenesis and organized tumor tissue development.

Objective: This study sought to examine the stability of dissociative symptoms in patients with schizophrenia spectrum disorders as well as relationships between psychotic symptoms, childhood trauma, and dissociation. Method: One hundred forty-five patients with schizophrenia spectrum disorders (72% schizophrenia, 67% men) were examined at admission to inpatient treatment and 3 weeks later using the Positive and Negative Syndrome Scale, the Childhood Trauma Questionnaire, and the Dissociative Experiences Scale. Results: Dissociative symptoms significantly decreased over time (mean, 19.2 vs 14.1; P < .001). The best predictor of dissociative symptoms at admission was the Positive and Negative Syndrome Scale positive subscale (Finc 3,64 = 3.66, P = .017), whereas childhood sexual abuse best predicted dissociation when patients were stabilized (Finc 10,80 = 2.00, P = .044). Conclusion: Dissociative symptoms in patients with schizophrenia spectrum disorders are related to childhood trauma. Dissociation seems to be state dependent in this diagnostic group. Moreover, diagnostic interviews, in addition to the Dissociative Experiences Scale, should be considered to avoid measurement artifacts.

Background Hepatitis E virus (HEV) has been identified as an emerging cause of infectious hepatitis over the last years in developed countries. In contrast to travel associated hepatitis E, zoonotic sources of infection are suspected for autochthonous cases in Europe. Objective Since pigs are known reservoirs of HEV, we tested porcine livers sold as food in Southeastern Germany for the presence of hepatitis E virus RNA. Study design We purchased 200 porcine liver samples in 81 butcher shops and grocery stores in Regensburg, Germany. Nucleic acid preparations were tested for the presence of HEV RNA by quantitative real-time PCR (RT-qPCR). HEV isolates from positive samples were characterized by partial sequencing of ORF1 and ORF2 regions in the HEV genome and by phylogenetic analysis. Results Specimens from eight (4%) of 200 purchased pig livers had detectable HEV RNA amounts. Sequence determination and phylogenetic analysis allowed two novel isolates to be classified as HEV genotype 3, subgenotype 3a (swR437) and 3c (swR269), respectively. Both novel swine HEV isolates showed high sequence homology to isolates obtained from patients with acute HEV infection from the same geographic region. Conclusions These results support the suggested role of undercooked pig products in food as a source of zoonotic HEV infection for humans. It remains to be clarified if this mechanism of transmission is responsible for the surprisingly high anti-HEV IgG prevalence recently observed in some European countries and the USA.

A new botulinum toxin type A (BoNT-A) has been assessed in the United States for treatment of glabellar lines. In April 2009, the US FDA approved the Biologics License Application for a new US formulation of BoNT-A (Dysport [abobotulinum toxin A]; Medicis Aesthetics Inc., Scottsdale, AZ).To compare efficacy and safety of a single treatment of BoNT-A with placebo in subjects with moderate to severe glabellar lines.One hundred fifty-eight subjects with moderate to severe glabellar lines were randomized 2:1 to receive 50 U of BoNT-A (n=105) or placebo (n=53). Responders were defined as having no or mild glabellar lines at 30 days posttreatment according to investigator and subject assessments (co-primary endpoint) using the validated Glabellar Line Scale Score at maximum frown. Subject diaries were used to document onset of effect. When conducting the research, the authors conformed to the ethical guidelines of the 1975 Declaration of Helsinki.According to investigator assessment, the proportion of responders to BoNT-A at Day 30 was 89.5%, versus 7.5% for placebo (p.001); according to subject assessment, the proportion of responders was 75.7%, versus 9.8% for placebo (p.001).A single treatment with BoNT-A (50 U) was significantly superior to placebo in the correction of moderate to severe glabellar lines, with comparable tolerability.

Zusammenfassung Nach drei Veranstaltungen fur und mit christlich-muslimischen Paaren und Familien und in den nachfolgenden Einzelgesprachen zeigte sich hoher seelsorglicher Beratungs- und vereinzelt auch Begleitungsbedarf. Da die Moglichkeiten kirchenrechtlicher Anerkennung dieser Verbindungen sowohl unter Seelsorgern wie auch Betroffenen selten bekanntsind, scheuen sich viele, danach zu fragen, und ziehen die Anonymitat vor.

Not many data are available on long-term immunity against hepatitis B (HB) for children vaccinated under real-life conditions.Two hundred and thirty-two children and adolescents vaccinated 6-14 years earlier in pediatric practices were examined for conditions of vaccination and markers of protection as anti-HBs, anamnestic response to a booster dose and cell-mediated immunity.Fifty-six percent of the participants were vaccinated according to the German vaccination recommendations (group 1). In 44.0% (group 2), these recommendations were not followed. Anti-HBs concentrations of ≥10 IU/L were found in 53.1% of group 1 and 45.1% of group 2 participants. A booster dose resulted in 91 of 99 participants in having an anamnestic response, in 3 (5.9%) of group 1 and 5 (10.4%) of group 2 anti-HBs remained below 10 IU/L. In group 1, postbooster anti-HBs concentration was inversely correlated with time since the last vaccination. Cellular immune responses were seen in only 5% of revaccinated individuals before the booster, increasing to 30% thereafter.Under real-life conditions about half of vaccinees have lost protecting antibodies 6-14 years after vaccination in infancy, but in approximately 90% of them, immune memory was demonstrated. However, as memory may wane, revaccination at a time when boostability is still present might be considered.

Outlines the extent and nature of white‐collar crime in Germany, and examines the attitudes towards sanctions against this type of offence in the work of the special tribunals in Germany and other countries. Describes how specialisation works on both prosecution and judicial levels, including the position of the court, its substantive jurisdiction, the composition of the court, special training for judges, court caseloads, sentencing practice, guilty pleas and the practice of deals. Includes shorter descriptions of the systems in other European countries: France, Austria, Italy and Spain.

Lymphotoxin beta-receptor (LTβR) is involved in the formation and maintenance of secondary lymphoid structures, as well as in the regulation of inflammatory responses. Because LTβR lymphoid structure formation continues to develop in infants, we compared two different chimera models: one using adult mice and the other using a transplantation model of neonatal mice. To elucidate the function of LTβR on lymphoid and non-lymphoid cells, we generated bone marrow chimeras on the wild type C57Bl/6 and the LTβR-deficient (LTβR−/−) background, and reconstituted the mice with bone marrow cells reciprocally. These chimeric mice were analyzed in the experimental model of acute dextran sulfate sodium-induced colitis. Interestingly, both models revealed not only equal reconstitution levels but also similar immunological responses: LTβR expression on stromal cells is essential for lymph node formation, whereas LTBR on hematopoietic cells is crucial for a decrease in inflammation. In addition, mice lacking LTβR on hematopoietic cells revealed (a) an increase of immature granulocytic cells in the spleen and (b) a reduced proportion of myeloid cells in peripheral blood and spleen expressing CD11b+Ly6C+Ly6G− (myeloid-derived suppressor cells expression profile). In conclusion, LTβR expression on hematopoietic cells seems to be involved in the down-regulation of acute inflammatory reactions paralleled by the appearance of immature myeloid cells.

Our previous studies indicated that lymphotoxin β receptor (LTβR) activation controls and downregulates inflammatory reactions. In this study, we report that LTβR activation on primary mouse macrophages results in induction of tripartite motif containing (TRIM) 30α, which negatively regulates NF-κB activation induced by TLR signaling. LTβR activation results in a downregulation of proinflammatory cytokine and mediator expression upon TLR restimulation, demonstrating that LTβR signaling is involved in the induction of TLR cross-tolerance. Specific knockdown experiments using TRIM30α-specific small interfering RNA abolished the LTβR-dependent induction of TRIM30α and LTβR-mediated TLR cross-tolerance. Concordantly, LTβR activation on bone marrow-derived macrophages induced cross-tolerance to TLR4 and TLR9 ligands in vitro. Furthermore, we have generated cell type-specific LTβR-deficient mice with ablation of LTβR expression on macrophages/neutrophils (LTβRflox/flox × LysM-Cre). In bone marrow-derived macrophages derived from these mice LTβR-induced cross-tolerance to TLR4 and TLR9 ligands was impaired. Additionally, mice with a conditional ablation of LTβR expression on macrophages (LTβRflox/flox × LysM-Cre) are resistant to LTβR-induced TLR4 tolerance in vivo. Collectively, our data indicate that LTβR activation on macrophages by T cell-derived lymphotoxin α1β2 controls proinflammatory responses by activation of a TRIM30α-controlled, counterregulatory signaling pathway to protect against exacerbating inflammatory reactions.

Background: In April, the U.S. Food and Drug Administration approved a new U.S. formulation of botulinum neurotoxin type A (Dysport; Medicis Aesthetics, Inc., Scottsdale, Ariz.). This formulation has demonstrated inhibition of glabellar lines at a 50-unit dose. Standard clinical practice is to adjust the dose based on muscle mass. Methods: Patients stratified by race/ethnicity were randomized to receive a single treatment of Dysport administered in various doses or placebo. Dysport was administered in a total volume of 0.4 to 0.6 ml for women (50, 60, or 70 units) and 0.5 to 0.7 ml for men (60, 70, or 80 units), based on procerus/ corrugator muscle mass. Efficacy was assessed by a blinded evaluator and patient self-evaluation on days 14, 30, 60, 90, 120, and 150 after treatment. Results: At day 30, 85 percent and 87 percent of Dysport-treated patients were responders as assessed by blinded evaluator and patient self-evaluation, respectively, compared with 3 percent and 5 percent of placebo-treated patients, respectively (p < 0.001). Median duration of effect was 109 days for Dysport versus 0 days for placebo (blinded evaluator) and 107 days for Dysport versus 0 days for placebo (patient self evaluation). Response and duration of action were slightly higher in African American patients. The majority of treatment-emergent adverse events were mild or moderate in severity. Conclusion: A single treatment with Dysport, with the dose based on gender and muscle mass, is well tolerated and provides a greater and longer-lasting improvement in glabellar lines compared with placebo.

Objective To evaluate the long-term safety of repeated administrations of a new botulinum toxin type A (Reloxin; Medicis Pharmaceutical Corp, Scottsdale, Arizona) in the treatment of moderate to severe glabellar lines. Methods Open-label assessment of 1200 patients receiving as many as 5 treatments of Reloxin over a 13-month period. The product was diluted in 2.5-mL sterile physiologic saline solution, 0.9%, without preservative to a concentration of 50 U of Reloxin per 0.25 mL of solution. Investigators injected 0.05 mL of the solution (10 U each) into each of 5 injection sites in the glabellar area on day 0 of each treatment cycle. There was a minimum 85-day gap between treatments. Postinjection clinical evaluation was performed on days 14 and 30 and monthly thereafter until retreatment, study completion, or early termination. The patients were telephoned on day 7 to check for adverse events (AEs) and concomitant medications, and patient diaries were used to document the onset of treatment effect. Results The majority (72%) of treatment-emergent AEs were considered unlikely or not related to study treatment. Probably or possibly related treatment-emergent AEs occurred in 36% of patients. The most frequently occurring related AEs were injection site disorders (18%), nervous system disorders (14% and 12% headache), and eye disorders (9%). Related AEs around the injection site or eyes were usually reported by day 7 and then resolved. Reported ptosis does not differentiate between brow ptosis and eyelid ptosis. A total of 45 patients had a total of 55 instances of ptosis across all cycles, with most episodes lasting less than 3 weeks. The rates of ptosis decreased during successive cycles from 2.4% in cycle 1 to 0.6% in cycle 5. The proportion of patients reporting an onset of response by day 7 ranged from 93% to 95%. By investigator assessment, the response rate (patients reporting none or mild glabellar line severity scale scores on day 30) ranged from 80% to 91% during cycles 1 to 5. Conclusions There was no evidence of cumulative AEs or tachyphylaxis with multiple Reloxin treatments over a period of 13 months. The treatments were well tolerated. The rates of ptosis decreased over successive cycles, and the proportion of responders by day 7 ranged from 93% to 95%.