From Melancholia to Depression: Disordered Mood in Nineteenth-Century Psychiatry.

My book From Melancholia to Depression: Disordered Mood in Nineteenth-Century Psychiatry charts how melancholia was reconceptualized in the nineteenth century as a modern mood disorder and a precursor to clinical depression. The book shows how this occurred chiefly in two ways. First, the idea of disordered mood as a medical concept was created through the appropriation of language from experimental physiology into the realm of psychopathology. Second, the interplay of statistical and diagnostic practices formed the basis for modern psychiatric classification and facilitated the standardization of melancholia as a psychiatric diagnosis. These developments were key to the reconceptualization of melancholia and the subsequent emergence of clinical depression, and were foundational to modern psychiatric theory and practice.

Disease-Modifying Effects of a Novel Cathepsin K Inhibitor in Osteoarthritis: A Randomized Controlled Trial.

Background: MIV-711 is a novel selective cathepsin K inhibitor with beneficial effects on bone and cartilage in preclinical osteoarthritis models. Objective: To evaluate the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographic knee osteoarthritis. Design: 26-week randomized, double-blind, placebo-controlled phase 2a study with a 26-week open-label safety extension substudy. (EudraCT: 2015-003230-26 and 2016-001096-73). Setting: Six European sites. Participants: 244 participants with primary knee osteoarthritis, Kellgren-Lawrence grade 2 or 3, and pain score of 4 to 10 on a numerical rating scale (NRS). Intervention: MIV-711, 100 (n = 82) or 200 (n = 81) mg daily, or matched placebo (n = 77). Participants (46 who initially received 200 mg/d and 4 who received placebo) received 200 mg of MIV-711 daily during the extension substudy. Measurements: The primary outcome was change in NRS pain score. The key secondary outcome was change in bone area on magnetic resonance imaging (MRI). Other secondary end points included cartilage thickness on quantitative MRI and type I and II collagen C-telopeptide biomarkers. Outcomes were assessed over 26 weeks. Results: Changes in NRS pain scores with MIV-711 were not statistically significant (placebo, -1.4; MIV-711, 100 mg/d, -1.7; MIV-711, 200 mg/d, -1.5). MIV-711 significantly reduced medial femoral bone area progression (P = 0.002 for 100 mg/d and 0.004 for 200 mg/d) and medial femoral cartilage thinning (P = 0.023 for 100 mg/d and 0.125 for 200 mg/d) versus placebo and substantially reduced bone and cartilage biomarker levels. Nine serious adverse events occurred in 6 participants (1 in the placebo group, 3 in the 100 mg group, and 2 in the 200 mg group); none were considered to be treatment-related. Limitation: The trial was relatively short. Conclusion: MIV-711 was not more effective than placebo for pain, but it significantly reduced bone and cartilage progression with a reassuring safety profile. This treatment may merit further evaluation as a disease-modifying osteoarthritis drug. Primary Funding Source: Medivir.

Reconnecting to the biosphere.

Humanity has emerged as a major force in the operation of the biosphere, with a significant imprint on the Earth System, challenging social-ecological resilience. This new situation calls for a fundamental shift in perspectives, world views, and institutions. Human development and progress must be reconnected to the capacity of the biosphere and essential ecosystem services to be sustained. Governance challenges include a highly interconnected and faster world, cascading social-ecological interactions and planetary boundaries that create vulnerabilities but also opportunities for social-ecological change and transformation. Tipping points and thresholds highlight the importance of understanding and managing resilience. New modes of flexible governance are emerging. A central challenge is to reconnect these efforts to the changing preconditions for societal development as active stewards of the Earth System. We suggest that the Millennium Development Goals need to be reframed in such a planetary stewardship context combined with a call for a new social contract on global sustainability. The ongoing mind shift in human relations with Earth and its boundaries provides exciting opportunities for societal development in collaboration with the biosphere--a global sustainability agenda for humanity.

A recombinant vaccine effectively induces c5a-specific neutralizing antibodies and prevents arthritis.

OBJECTIVES: To develop and validate a recombinant vaccine to attenuate inflammation in arthritis by sustained neutralization of the anaphylatoxin C5a. METHODS: We constructed and expressed fusion protein of C5a and maltose binding protein. Efficacy of specific C5a neutralization was tested using the fusion protein as vaccine in three different arthritis mouse models: collagen induced arthritis (CIA), chronic relapsing CIA and collagen antibody induced arthritis (CAIA). Levels of anti-C5a antibodies and anti-collagen type II were measured by ELISA. C5a neutralization assay was done using a rat basophilic leukemia cell-line transfected with the human C5aR. Complement activity was determined using a hemolytic assay and joint morphology was assessed by histology. RESULTS: Vaccination of mice with MBP-C5a led to significant reduction of arthritis incidence and severity but not anti-collagen antibody synthesis. Histology of the MBP-C5a and control (MBP or PBS) vaccinated mice paws confirmed the vaccination effect. Sera from the vaccinated mice developed C5a-specific neutralizing antibodies, however C5 activation and formation of the membrane attack complex by C5b were not significantly altered. CONCLUSIONS: Exploitation of host immune response to generate sustained C5a neutralizing antibodies without significantly compromising C5/C5b activity is a useful strategy for developing an effective vaccine for antibody mediated and C5a dependent inflammatory diseases. Further developing of such a therapeutic vaccine would be more optimal and cost effective to attenuate inflammation without affecting host immunity.

Accounting for ecosystem services as a way to understand the requirements for sustainable development.

Millennium Ecosystem Assessment documented the importance of ecosystem services. It is therefore important that these services are included in our economic accounts (Standard National Accounts), as long as we believe that these accounts should tell us something about our wellbeing. This requires measures of the ecosystem assets and their accounting prices. This article discusses how the concept of inclusive wealth can be exploited for creating such accounts.

Biosensor-based characterization of serum antibodies during development of an anti-IgE immunotherapeutic against allergy and asthma.

Antibody responses, induced in Cynomolgus monkey by recombinant IgE-derived immunotherapeutic protein against atopic allergies and asthma, were characterized using label-free, real-time protein interaction analysis. The effects of two different immunotherapeutic proteins were compared. Active concentrations of specific anti-IgE antibodies formed were determined in sera sampled at multiple time points, using conditions of total mass transport limitation that were proved to exist on the sensor surface. These concentrations varied from about 0.4 to 35 microg/ml among the monkeys and throughout the immunization period. Based on these concentrations, the rate and affinity constants for the binding of antibody populations to the antigen could be determined. The apparent equilibrium dissociation constant decreased during the immunization period, for all the monkeys, by a factor between 6 and 50, ending at values from approximately 2 x 10(-9) to approximately 2 x 10(-11) M among the animals. This affinity maturation was attributable to the changes in both rate constants, although the magnitude of the contribution of each constant depended partly on specimen, but primarily on the immunotherapeutic used. The immunotherapeutic proteins examined showed excellent immunogenic properties, providing the basis for a new and effective treatment for allergy and asthma.

Tradeoffs between environmental goals and urban development: the case of nitrogen load from the Stockholm County to the Baltic Sea.

Urban dwellers depend on the generation of ecosystem services for their welfare. The city of Stockholm is growing, and a 25% increase in population is projected by 2030. The effects of urban development were estimated through the quantification of nitrogen (N) leakage to the Baltic Sea under two urban development scenarios. We found that total net N load will increase by 6% or 8%, depending on which growth scenario is applied, and population increase by itself will contribute at least 15% of the point source N leakage. Technical improvements in sewage treatment could, according to our results, decrease total N load to the Baltic Sea by 4%. Based on our results, we conclude that proactive measures such as spatial urban planning can provide a constructive tool for sustainable urban development on regional as well as national and international scales, depending on geographical context as well as the ecosystem services' scale of operation.

High-performance liquid chromatographic method for the determination of quinine and 3-hydroxyquinine in blood samples dried on filter paper.

A simple high-performance liquid chromatographic method for the simultaneous analysis of quinine and 3-hydroxyquinine in blood samples dried on filter paper is described. Sample preparation involves liquid-liquid extraction with toluene-butanol 75:25 (v/v) followed by evaporation. A reversed-phase liquid chromatography system with fluorescence detection was used. The limit of determination was 10 nM for both quinine and 3-hydroxyquinine and the recovery varied between 78 and 109%. The within- and between-assay coefficients of variation varied between 2-5% and 4-10%, respectively. No loss of either analyte occurred after storage for 2 months at room temperature or at 37 degrees C. This method for sampling has advantages that make it of great value for clinical and pharmacokinetic studies especially in remote regions where storage and transportation is problematic.