Rapid and Sustained Long-Term Efficacy and Safety of Canakinumab in Patients With Cryopyrin-Associated Periodic Syndrome Ages Five Years and Younger.

To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS). CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy. Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age

Long-term land-cover/use change in a traditional farming landscape in Romania inferred from pollen data, historical maps and satellite images

Traditional farming landscapes in the temperate zone that have persisted for millennia can be exceptionally species-rich and are therefore key conservation targets. In contrast to Europe’s West, Eastern Europe harbours widespread traditional farming landscapes, but drastic socio-economic and political changes in the twentieth century are likely to have impacted these landscapes profoundly. We reconstructed long-term land-use/cover and biodiversity changes over the last 150 years in a traditional farming landscape of outstanding species diversity in Transylvania. We used the Regional Estimates of Vegetation Abundance from Large Sites model applied to a pollen record from the Transylvanian Plain and a suite of historical and satellite-based maps. We documented widespread changes in the extent and location of grassland and cropland, a loss of wood pastures as well as a gradual increase in forest extent. Land management in the socialist period (1947–1989) led to grassland expansion, but grassland diversity decreased due to intensive production. Land-use intensity has declined since the collapse of socialism in 1989, resulting in widespread cropland abandonment and conversion to grassland. However, these trends may be temporary due to both ongoing woody encroachment as well as grassland management intensification in productive areas. Remarkably, only 8% of all grasslands existed throughout the entire time period (1860–2010), highlighting the importance of land-use history when identifying target areas for conservation, given that old-growth grasslands are most valuable in terms of biodiversity. Combining datasets from different disciplines can yield important additional insights into dynamic landscape and biodiversity changes, informing conservation actions to maintain these species-rich landscapes in the longer term

Anti-EGFR Antibody Efficiently and Specifically Inhibits Human TSC2−/− Smooth Muscle Cell Proliferation. Possible Treatment Options for TSC and LAM

BACKGROUND: Tuberous sclerosis complex (TSC), a tumor syndrome caused by mutations in TSC1 or TSC2 genes, is characterized by the development of hamartomas. We previously isolated, from an angiomyolipoma of a TSC2 patient, a homogenous population of smooth muscle-like cells (TSC2(-/-) ASM cells) that have a mutation in the TSC2 gene as well as TSC2 loss of heterozygosity (LOH) and consequently, do not produce the TSC2 gene product, tuberin. TSC2(-/-) ASM cell proliferation is EGF-dependent. METHODS AND FINDINGS: Effects of EGF on proliferation of TSC2(-/-) ASM cells and TSC2(-/-) ASM cells transfected with TSC2 gene were determined. In contrast to TSC2(-/-) ASM cells, growth of TSC2-transfected cells was not dependent on EGF. Moreover, phosphorylation of Akt, PTEN, Erk and S6 was significantly decreased. EGF is a proliferative factor of TSC2(-/-) ASM cells. Exposure of TSC2(-/-) ASM cells to anti-EGFR antibodies significantly inhibited their proliferation, reverted reactivity to HMB45 antibody, a marker of TSC2(-/-) cell phenotype, and inhibited constitutive phosphorylation of S6 and ERK. Exposure of TSC2(-/-) ASM cells to rapamycin reduced the proliferation rate, but only when added at plating time. Although rapamycin efficiently inhibited S6 phosphorylation, it was less efficient than anti-EGFR antibody in reverting HMB45 reactivity and blocking ERK phosphorylation. In TSC2(-/-) ASM cells specific PI3K inhibitors (e.g. LY294002, wortmannin) and Akt1 siRNA had little effect on S6 and ERK phosphorylation. Following TSC2-gene transfection, Akt inhibitor sensitivity was observed. CONCLUSION: Our results show that an EGF independent pathway is more important than that involving IGF-I for growth and survival of TSC(-/-) ASM cells, and such EGF-dependency is the result of the lack of tuberin

International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor–Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome

Objective: Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor–associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). Methods: PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de‐identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. Results: A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute‐phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8‐year delay in FMF patients. An equal proportion of TRAPS patients first received anti–interleukin‐1 (anti‐IL‐1) and anti–tumor necrosis factor (anti‐TNF) biologic agents, whereas IL‐1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti‐TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts. Conclusion: Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real‐world treatment assessment supports the need for further refinement of treatment practices

Partitioning the effects of habitat loss hunting and climate change on the endangered Chacoan peccary

Aim: Land-use change and overexploitation are major threats to biodiversity, and cli mate change will exert additional pressure in the 21st century. Although there are strong interactions between these threats, our understanding of the synergistic and compensatory effects on threatened species' range geography remains limited. Our aim was to disentangle the impact of habitat loss, hunting and climate change on spe cies, using the example of the endangered Chacoan peccary (Catagonus wagneri). Location: Gran Chaco ecoregion in South America. Methods: Using a large occurrence database, we integrated a time-calibrated species distribution model with a hunting pressure model to reconstruct changes in the distri bution of suitable peccary habitat between 1985 and 2015. We then used partitioning analysis to attribute the relative contribution of habitat change to land-use conver sion, climate change and varying hunting pressure. Results: Our results reveal widespread habitat deterioration, with only 11% of the habitat found in 2015 considered suitable and safe. Hunting pressure was the strong est single threat, yet most habitat deterioration (58%) was due to the combined, rather than individual, effects of the three drivers we assessed. Climate change would have led to a compensatory effect, increasing suitable habitat area, yet this effect was ne gated by the strongly negative and interacting threats of land-use change and hunting. Main Conclusions: Our study reveals the central role of overexploitation, which is often neglected in biogeographic assessments, and suggests that addressing overex ploitation has huge potential for increasing species' adaptive capacity in the face of climate and land-use change. More generally, we highlight the importance of jointly assessing extinction drivers to understand how species might fare in the 21st century. Here, we provide a simple and transferable framework to determine the separate and joint effects of three main drivers of biodiversity loss.Fil: Torres, Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Diversidad y Ecología Animal ; Argentina.Fil: Kuemmerle, Tobias. Humboldt-University Berlin. Integrative Research Institute for Transformations in Human Environment Systems. Geography Department; AlemaniaFil: Baumann, Matthias. Humboldt-University. Geography Department; Alemania.Fil: Romero Muñoz, Alfredo. Humboldt University. Geography Departament; Alemania. University of British Columbia. Institute for Resources, Environment and Sustainability (IRES); Canada. Helmholtz Centre for Environmental Research. Department Computational Landscape Ecology; Alemania. Transformations of Human-Environment Systems (IRI THESys). Integrative Research Institute; AlemaniaFil: Altrichter, Mariana. IUCN SSC Peccary Specialist Group; Suiza. Prescott College. Environmental Studies; Estados UnidosFil: Boaglio, Gabriel Ivan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; ArgentinaFil: Cabral, Hugo. Universidade Estadual Paulista. Programa de Pós-Graduação em Biologia Animal; Brasil. Instituto de Investigación Biológica del Paraguay; ParaguayFil: Camino, Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Ecología del Litoral. Laboratorio de Biología de la Conservación; ArgentinaFil: Campos Kraver, Juan M. University of Florida. College of Veterinary Medicine & Department of Wildlife Ecology and Conservation. Department of Large Animal Clinical Sciences; Estados UnidosFil: Giordano, Anthony. Society for the Preservation of Endangered Carnivores and their International Ecological Study (S.P.E.C.I.E.S); Estados Unidos. University of Los Angeles. Institute of the Environment and Sustainability. Center for Tropical Research; Estados UnidosFil: Cartes, José L. Guyra Paraguay, Parque del Río; ParaguayFil: Cuéllar, Rosa L. Fundación para la Conservación del Bosque Chiquitano; BoliviaFil: Decarre, Julieta. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Biológicos; ArgentinaFil: Gallegos, Marcelo. Provincia de Salta. Secretaría de Ambiente; ArgentinaFil: Lizárraga, Leónidas. Administración De Parques Nacionales. Dirección Regional Noroeste. Salta; Argentina.Fil: Maffei, Leonardo. Biósfera Consultores Ambientales, Lima, Perú.Fil: Neris, Nora N. Secretaria del Ambiente; ParaguayFil: Quiroga, Verónica. Universidad Nacional de Córdoba. Inst. de Diversidad y Ecología Animal (IDEA – CONICET), Centro de Zoología Aplicada; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Saldivar, Silvia. ITAIPU Binacional. Dirección de Coordinación. División de Áreas Protegidas; ParaguayFil: Tamburini, Daniela Maria. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Centro de Ecología y Recursos Naturales Renovables; Argentin

Characteristics and drivers of forest cover change in the post-socialist era in Croatia: evidence from a mixed-methods approach

© 2016, Springer-Verlag Berlin Heidelberg.Extensive forests in Croatia represent an important biological and economic resource in Europe. They are characterised by heterogeneity in forest management practices dating back to the socialist planned economy of the pre-1991 era. In this study we investigated the difference in rates of deforestation and reforestation in private- and state-owned forests during the post-socialist period and the causal drivers of change. The selected region of Northern Croatia is characterised by a high percentage of privately owned forests with minimal national monitoring and control. We used a mixed-methods approach which combines remote sensing, statistical modelling and a household-based questionnaire survey to assess the rates of forest cover change and factors influencing those changes. The results show that predominantly privately owned forests in Northern Croatia have recorded a net forest loss of 1.8 % during the 1991–2011 period, while Croatia overall is characterised by a 10 % forest cover increase in predominantly state-owned forests. Main factors influencing forest cover changes in private forests are slope, altitude, education structure, population age and population density. The results also show that the deforestation in private forests is weakening overall, mostly due to the continuation of the de-agrarisation and de-ruralisation processes which began during socialism

How do MNC R&amp;D laboratory roles affect employee international assignments?

Research and development (R&#38;D) employees are important human resources for multinational corporations (MNCs) as they are the driving force behind the advancement of innovative ideas and products. International assignments of these employees can be a unique way to upgrade their expertise; allowing them to effectively recombine their unique human resources to progress existing knowledge and advance new ones. This study aims to investigate the effect of the roles of R&#38;D laboratories in which these employees work on the international assignments they undertake. We categorise R&#38;D laboratory roles into those of the support laboratory, the locally integrated laboratory and the internationally interdependent laboratory. Based on the theory of resource recombinations, we hypothesise that R&#38;D employees in support laboratories are not likely to assume international assignments, whereas those in locally integrated and internationally interdependent laboratories are likely to assume international assignments. The empirical evidence, which draws from research conducted on 559 professionals in 66 MNC subsidiaries based in Greece, provides support to our hypotheses. The resource recombinations theory that extends the resource based view can effectively illuminate the international assignment field. Also, research may provide more emphasis on the close work context of R&#38;D scientists rather than analyse their demographic characteristics, the latter being the focus of scholarly practice hitherto

The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist

BACKGROUND: The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes. OBJECTIVE: To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management. METHODS: A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. RESULTS: The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. CONCLUSION: The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes

Остеоартроз, артериальная гипертензия и ожирение: проблема коморбидности

Представлены данные современных исследований отечественных и зарубежных ученых, касающиеся распространенности сочетанной патологии − остеоартроза с артериальной гипертензией и ожирением.Наведено дані сучасних досліджень вітчизняних і зарубіжних вчених щодо поширеності поєднаної патології − остеоартрозу з артеріальною гіпертензією та ожирінням.The data of contemporary investigations of Ukrainian and foreign scientists about the prevalence of combined pathology (osteoarthrosis with arterial hypertension and obesity) are presented