Showing papers by "University of Bern published in 2012"

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Interactions between the microbiota and the immune system.

Abstract: The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity. Here, we review advances in our understanding of the interactions between resident microbes and the immune system and the implications of these findings for human health.

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Abstract: In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

The state and fate of Himalayan glaciers

Abstract: Himalayan glaciers are a focus of public and scientific debate. Prevailing uncertainties are of major concern because some projections of their future have serious implications for water resources. Most Himalayan glaciers are losing mass at rates similar to glaciers elsewhere, except for emerging indications of stability or mass gain in the Karakoram. A poor understanding of the processes affecting them, combined with the diversity of climatic conditions and the extremes of topographical relief within the region, makes projections speculative. Nevertheless, it is unlikely that dramatic changes in total runoff will occur soon, although continuing shrinkage outside the Karakoram will increase the seasonality of runoff, affect irrigation and hydropower, and alter hazards.

A global assessment of invasive plant impacts on resident species, communities and ecosystems: the interaction of impact measures, invading species' traits and environment

Abstract: With the growing body of literature assessing the impact of invasive alien plants on resident species and ecosystems, a comprehensive assessment of the relationship between invasive species traits and environmental settings of invasion on the characteristics of impacts is needed. Based on 287 publications with 1551 individual cases that addressed the impact of 167 invasive plant species belonging to 49 families, we present the first global overview of frequencies of significant and non-significant ecological impacts and their directions on 15 outcomes related to the responses of resident populations, species, communities and ecosystems. Species and community outcomes tend to decline following invasions, especially those for plants, but the abundance and richness of the soil biota, as well as concentrations of soil nutrients and water, more often increase than decrease following invasion. Data mining tools revealed that invasive plants exert consistent significant impacts on some outcomes (survival of resident biota, activity of resident animals, resident community productivity, mineral and nutrient content in plant tissues, and fire frequency and intensity), whereas for outcomes at the community level, such as species richness, diversity and soil resources, the significance of impacts is determined by interactions between species traits and the biome invaded. The latter outcomes are most likely to be impacted by annual grasses, and by wind pollinated trees invading mediterranean or tropical biomes. One of the clearest signals in this analysis is that invasive plants are far more likely to cause significant impacts on resident plant and animal richness on islands rather than mainland. This study shows that there is no universal measure of impact and the pattern observed depends on the ecological measure examined. Although impact is strongly context dependent, some species traits, especially life form, stature and pollination syndrome, may provide a means to predict impact, regardless of the particular habitat and geographical region invaded.

Enumeration of 166 Billion Organic Small Molecules in the Chemical Universe Database GDB-17

Abstract: Drug molecules consist of a few tens of atoms connected by covalent bonds. How many such molecules are possible in total and what is their structure? This question is of pressing interest in medicinal chemistry to help solve the problems of drug potency, selectivity, and toxicity and reduce attrition rates by pointing to new molecular series. To better define the unknown chemical space, we have enumerated 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens forming the chemical universe database GDB-17, covering a size range containing many drugs and typical for lead compounds. GDB-17 contains millions of isomers of known drugs, including analogs with high shape similarity to the parent drug. Compared to known molecules in PubChem, GDB-17 molecules are much richer in nonaromatic heterocycles, quaternary centers, and stereoisomers, densely populate the third dimension in shape space, and represent many more scaffold types.

PGDSpider: an automated data conversion tool for connecting population genetics and genomics programs.

Abstract: Summary: The analysis of genetic data often requires a combination of several approaches using different and sometimes incompatible programs. In order to facilitate data exchange and file conversions between population genetics programs, we introduce PGDSpider, a Java program that can read 27 different file formats and export data into 29, partially overlapping, other file formats. The PGDSpider package includes both an intuitive graphical user interface and a command-line version allowing its integration in complex data analysis pipelines. Availability: PGDSpider is freely available under the BSD 3-Clause license on http://cmpg.unibe.ch/software/PGDSpider/

Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials.

Abstract: Published evidence suggests that aspects of trial design lead to biased intervention effect estimates, but findings from different studies are inconsistent. This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials. Outcome measures were classified as "mortality," "other objective," "or subjective," and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity. Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear (vs. adequate) random-sequence generation (ratio of odds ratios, 0.89 [95% credible interval {CrI}, 0.82 to 0.96]) and with inadequate or unclear (vs. adequate) allocation concealment (ratio of odds ratios, 0.93 [CrI, 0.87 to 0.99]). Lack of or unclear double-blinding (vs. double-blinding) was associated with an average of 13% exaggeration of intervention effects (ratio of odds ratios, 0.87 [CrI, 0.79 to 0.96]), and between-trial heterogeneity was increased for such studies (SD increase in heterogeneity, 0.14 [CrI, 0.02 to 0.30]). For each characteristic, average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes, with little evidence of bias in trials with objective and mortality outcomes. This study is limited by incomplete trial reporting, and findings may be confounded by other study design characteristics. Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes.

The anatomical and cellular basis of immune surveillance in the central nervous system

Abstract: The central nervous system (CNS) comprises the brain, spinal cord, optic nerves and retina, and contains post-mitotic, delicate cells. As the rigid coverings of the CNS render swelling dangerous and destructive, inflammatory reactions must be carefully controlled in CNS tissues. Nevertheless, effector immune responses that protect the host during CNS infection still occur in the CNS. Here, we describe the anatomical and cellular basis of immune surveillance in the CNS, and explain how this shapes the unique immunology of these tissues. The Review focuses principally on insights gained from the study of autoimmune responses in the CNS and to a lesser extent on models of infectious disease. Furthermore, we propose a new model to explain how antigen-specific T cell responses occur in the CNS.

Systematic review of the survival rate and the incidence of biological, technical, and aesthetic complications of single crowns on implants reported in longitudinal studies with a mean follow-up of 5 years

Abstract: Objective To assess the 5-year survival of implant-supported single crowns (SCs) and to describe the incidence of biological, technical, and aesthetic complications. The focused question was: What is the survival rate of implants supporting single crowns and implant-supported crowns with a mean follow-up of 5 years and to which extent do biological, technical, and aesthetic complications occur? Methods A Medline search (2006–2011) was performed for clinical studies focusing on implant-supported SCs with a mean follow-up of at least 5 years. The search was complemented by an additional hand search and the inclusion of 24 studies from a previous systematic review (Jung et al. 2008a). Survival and complication rates were analyzed using random-effects Poisson's regression models to obtain summary estimates of 5- and 10-year proportions. Results Forty-six studies derived from an initial search count of 1083 titles and the complementary publications from the previous systematic review (Jung et al. 2008a) were selected and the data were extracted. Based on the meta-analysis, survival of implants supporting SCs at 5 years amounted to 97.2% (95% CI: 96.3–97.9%), and at 10 years amounted to 95.2% (95% CI: 91.8–97.2%). The survival of implant-supported SCs was 96.3% (95% CI: 94.2–97.6%) after 5 years and 89.4% (95% CI: 82.8–93.6%) after 10 years. For biological complications, a 5-year cumulative soft tissue complication rate of 7.1% (95% CI: 4.4–11.3%) and a cumulative complication rate for implants with bone loss >2 mm of 5.2% (95% CI: 3.1–8.6%) were calculated. Technical complications reached a cumulative incidence of 8.8% (95% CI: 5.1–15.0%) for screw-loosening, 4.1% (95% CI: 2.2–7.5%) for loss of retention, and 3.5% (95% CI: 2.4–5.2%) for fracture of the veneering material after 5 years. The cumulative 5-year aesthetic complication rate amounted to 7.1% (95% CI: 3.6–13.6%). Conclusions The outcomes of the meta-analysis demonstrated high implant survival rates for both the single tooth implants and the respective single crowns after 5 and 10 years. However, technical, biological, and aesthetic complications were frequent.

Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.

Abstract: Context Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort. Objective To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care. Design, setting, and patients Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251). Interventions Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials. Main outcome measures For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223). Results Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P Conclusions Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine. Trial registration clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.

The Path from β-Carotene to Carlactone, a Strigolactone-Like Plant Hormone

Abstract: Germination of parasitic witchweeds depends on strigolactones, which also regulate plant branching and signal in the context of mycorrhizal symbioses. The biosynthetic pathways that lead to strigolactones are founded in carotenoid biosynthesis, but further steps have been obscure. Alder et al. (p. [1348][1]) have now identified a biochemical pathway that generates a strigolactone-like compound, carlactone, which shows biological actions similar to those of strigolactone. [1]: /lookup/doi/10.1126/science.1218094

Climate change impacts on glaciers and runoff in Tien Shan (Central Asia)

Abstract: Climate-driven changes in glacier-fed streamflow regimes have direct implications on freshwater supply, irrigation and hydropower potential. Reliable information about current and future glaciation and runoff is crucial for water allocation, a complex task in Central Asia, where the collapse of the Soviet Union has transformed previously interdependent republics into autonomous upstream and downstream countries. Although the impacts of climate change on glaciation and runoff have been addressed in previous work undertaken in the Tien Shan (known as the ‘water tower of Central Asia’), a coherent, regional perspective of these findings has not been presented until now. Here we show that glacier shrinkage is most pronounced in peripheral, lower-elevation ranges near the densely populated forelands, where summers are dry and where snow and glacial meltwater is essential for water availability. Shifts of seasonal runoff maxima have already been observed in some rivers, and it is suggested that summer runoff will further decrease in these rivers if precipitation and discharge from thawing permafrost bodies do not compensate sufficiently for water shortfalls.

Cancer classification using the Immunoscore: a worldwide task force

Abstract: Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres

Abstract: methods: A prospective, multi-centre, questionnaire-based survey measured costs and quality of life in ambulatory care and in 12 tertiary care centres in 10 countries. The study enrolled women with a diagnosis of endometriosis and with at least one centre-specific contact related to endometriosis-associated symptoms in 2008. The main outcome measures were health care costs, costs of productivity loss, total costs and quality-adjusted life years. Predictors of costs were identified using regression analysis. results: Data analysis of 909 women demonstrated that the average annual total cost per woman was E9579 (95% confidence interval E8559–E10 599). Costs of productivity loss of E6298 per woman were double the health care costs of E3113 per woman. Health care costs were mainly due to surgery (29%), monitoring tests (19%) and hospitalization (18%) and physician visits (16%). Endometriosis-associated symptoms generated 0.809 quality-adjusted life years per woman. Decreased quality of life was the most important predictor of direct health care and total costs. Costs were greater with increasing severity of endometriosis, presence of pelvic pain, presence of infertility and a higher number of years since diagnosis. conclusions: Our study invited women to report resource use based on endometriosis-associated symptoms only, rather than drawing on a control population of women without endometriosis. Our study showed that the economic burden associated with endometriosis treated in referral centres is high and is similar to other chronic diseases (diabetes, Crohn’s disease, rheumatoid arthritis). It arises predominantly from productivity loss, and is predicted by decreased quality of life.

A systematic review of the survival and complication rates of implant-supported fixed dental prostheses (FDPs) after a mean observation period of at least 5 years.

Abstract: Objectives The objective of this systematic review was to assess the 5- and 10-year survival of implant-supported fixed dental prostheses (FDPs) and to describe the incidence of biological and technical complications. Methods An electronic Medline search complemented by manual searching was conducted to identify prospective and retrospective cohort studies and case series on FDPs with a mean follow-up time of at least 5 years. Patients had to have been examined clinically at the follow-up visit. Failure and complication rates were analyzed using standard and random-effects Poisson regression models to obtain summary estimates of 5-year and 10-year survival and complication rates. Results The updated search provided 979 titles and 257 abstracts. Full-text analysis was performed for 90 articles resulting in a total 32 studies that met the inclusion criteria. Meta-analysis of these studies indicated an estimated survival of implants supporting FDPs of 95.6% after 5 years and 93.1% after 10 years. When machined surface implants were excluded from the analysis and only rough surface implants included, the survival rate increased to 97.2% after 5 years. The survival rate of implant-supported FDPs was 95.4% after 5 years and 80.1% after 10 years of function. When the analysis was done exclusively for metal–ceramic FDPs, hence the old gold–acrylic FDPs were excluded, the survival rate increased significantly. The survival rate of metal–ceramic implant-supported FDPs was 96.4% after 5 years and 93.9% after 10 years. Only 66.4% of the patients were free of any complications after 5 years. The most frequent complications over the 5-year observation period were fractures of the veneering material (13.5%), peri-implantitis and soft tissue complications (8.5%), loss of access hole restoration (5.4%), abutment or screw loosening (5.3%), and loss of retention of cemented FDPs (4.7%). Conclusion It may be concluded that implant-supported fixed dental prostheses (FDPs) are a safe and predictable treatment method with high survival rates. However, biological and technical complications were frequent (33.6%). To minimize the incidence of complications, dental professionals should make great effort in choosing reliable components and materials for implant-supported FDPs and the patients should be placed in well-structured maintenance system after treatment.

Reconstructing Native American population history

Abstract: The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.

Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis

Abstract: Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis.

How Many Cancer Patients Use Complementary and Alternative Medicine: A Systematic Review and Metaanalysis

Abstract: Background. No comprehensive systematic review has been published since 1998 about the frequency with which cancer patients use complementary and alternative medicine (CAM). Methods. MEDLINE, AMED, and Embase databases were searched for surveys published until January 2009. Surveys conducted in Australia, Canada, Europe, New Zealand, and the United States with at least 100 adult cancer patients were included. Detailed information on methods and results was independently extracted by 2 reviewers. Methodological quality was assessed using a criteria list developed according to the STROBE guideline. Exploratory random effects metaanalysis and metaregression were applied. Results. Studies from 18 countries (152; >65 000 cancer patients) were included. Heterogeneity of CAM use was high and to some extent explained by differences in survey methods. The combined prevalence for “current use” of CAM across all studies was 40%. The highest was in the United States and the lowest in Italy and the Netherlands. Metaanalysis suggested an increase in CAM use from an estimated 25% in the 1970s and 1980s to more than 32% in the 1990s and to 49% after 2000. Conclusions. The overall prevalence of CAM use found was lower than often claimed. However, there was some evidence that the use has increased considerably over the past years. Therefore, the health care systems ought to implement clear strategies of how to deal with this. To improve the validity and reporting of future surveys, the authors suggest criteria for methodological quality that should be fulfilled and reporting standards that should be required.

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Abstract: Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

The Effect of 3 Versus 6 Years of Zoledronic Acid Treatment of Osteoporosis: A Randomized Extension to the HORIZON-Pivotal Fracture Trial (PFT)

Abstract: Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.

Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes.

Abstract: Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.