Development of Methodologies and Tools—The HKKH Partnership Project

High mountains have sensitive social-ecological systems (SESs) characterized by fragility, complexity, and marginality. The local economies of these environments mainly rely on primary production, tourism, and leisure activities; thus human-ecosystem interactions are intricately linked. Many authors stress that this strict relationship must be assisted with a participatory approach involving interested stakeholders in the conceptualization, specification, and synthesis of knowledge and experience into useable information for the express purpose of addressing a problem complex. This paper presents experience garnered with a participatory modeling framework combining hard and soft methodology in 2 case studies: the Sagarmatha National Park and Buffer Zone (Nepal) and the Central Karakoram National Park (Pakistan). The modeling framework was developed based on local stakeholders' demands and needs; it consists of 5 modules, briefly presented here along with their conceptual background. In developing the framework, particular emphasis was given to considering the needs of decision-makers at the local level, rather than simply providing technical solutions to abstract problems. From the development of this modeling process, a need emerged to structure a management-oriented research module in order to generate management knowledge that is both stakeholderrelevant and evidence-based. The application of the framework in the 2 cases studies showed that the modeling can trigger valuable discussion among stakeholders as well as guidance for management-oriented research and feedback loops ensuring validation of knowledge. In addition, the resulting scenarios can help decision-makers in defining pathways for sustainable development in mountain areas, where people's livelihoods are closely dependent on ecosystems. The framework was developed in such a way that it can be replicated in other mountain areas with similar challenges

Epithelial ovarian cancer is infiltrated by activated effector T cells co-expressing CD39, PD-1, TIM-3, CD137 and interacting with cancer cells and myeloid cells

IntroductionDespite predicted efficacy, immunotherapy in epithelial ovarian cancer (EOC) has limited clinical benefit and the prognosis of patients remains poor. There is thus a strong need for better identifying local immune dynamics and immune-suppressive pathways limiting T-cell mediated anti-tumor immunity.MethodsIn this observational study we analyzed by immunohistochemistry, gene expression profiling and flow cytometry the antigenic landscape and immune composition of 48 EOC specimens, with a focus on tumor-infiltrating lymphocytes (TILs).ResultsActivated T cells showing features of partial exhaustion with a CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ surface profile were exclusively present in EOC specimens but not in corresponding peripheral blood or ascitic fluid, indicating that the tumor microenvironment might sustain this peculiar phenotype. Interestingly, while neoplastic cells expressed several tumor-associated antigens possibly able to stimulate tumor-specific TILs, macrophages provided both co-stimulatory and inhibitory signals and were more abundant in TILs-enriched specimens harboring the CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ signature.ConclusionThese data demonstrate that EOC is enriched in CD137+CD39+PD-1+TIM-3+CD45RA-CD62L-CD95+ T lymphocytes, a phenotype possibly modulated by antigen recognition on neoplastic cells and by a combination of inhibitory and co-stimulatory signals largely provided by infiltrating myeloid cells. Furthermore, we have identified immunosuppressive pathways potentially hampering local immunity which might be targeted by immunotherapeutic approaches

Experience With a Hard and Soft Participatory Modeling Framework for Social-ecological System Management in Mount Everest (Nepal) and K2 (Pakistan) Protected Areas

High mountains have sensitive social-ecological systems (SESs) characterized by fragility, complexity, and marginality. The local economies of these environments mainly rely on primary production, tourism, and leisure activities; thus human-ecosystem interactions are intricately linked. Many authors stress that this strict relationship must be assisted with a participatory approach involving interested stakeholders in the conceptualization, specification, and synthesis of knowledge and experience into useable information for the express purpose of addressing a problem complex. This paper presents experience garnered with a participatory modeling framework combining hard and soft methodology in 2 case studies: the Sagarmatha National Park and Buffer Zone (Nepal) and the Central Karakoram National Park (Pakistan). The modeling framework was developed based on local stakeholders' demands and needs; it consists of 5 modules, briefly presented here along with their conceptual background. In developing the framework, particular emphasis was given to considering the needs of decision-makers at the local level, rather than simply providing technical solutions to abstract problems. From the development of this modeling process, a need emerged to structure a management-oriented research module in order to generate management knowledge that is both stakeholder-relevant and evidence-based. The application of the framework in the 2 cases studies showed that the modeling can trigger valuable discussion among stakeholders as well as guidance for management-oriented research and feedback loops ensuring validation of knowledge. In addition, the resulting scenarios can help decision-makers in defining pathways for sustainable development in mountain areas, where people's livelihoods are closely dependent on ecosystems. The framework was developed in such a way that it can be replicated in other mountain areas with similar challenges

Neurodevelopment in Schizophrenia: The Role of the Wnt Pathways

Objectives. To review the role of Wnt pathways in the neurodevelopment of schizophrenia. Methods: Systematic PubMed search, using as keywords all the terms related to the Wnt pathways and crossing them with each of the following areas: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. Results: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. Conclusions: The study of the involvement of Wnt pathway abnormalities in schizophrenia may help in understanding this multifaceted clinical entity; the development of Wnt-related pharmacological targets must await the collection of more data.OBJECTIVES: To review the role of Wnt pathways in the neurodevelopment of schizophrenia. METHODS: SYSTEMATIC PUBMED SEARCH, USING AS KEYWORDS ALL THE TERMS RELATED TO THE WNT PATHWAYS AND CROSSING THEM WITH EACH OF THE FOLLOWING AREAS: normal neurodevelopment and physiology, neurodevelopmental theory of schizophrenia, schizophrenia, and antipsychotic drug action. RESULTS: Neurodevelopmental, behavioural, genetic, and psychopharmacological data point to the possible involvement of Wnt systems, especially the canonical pathway, in the pathophysiology of schizophrenia and in the mechanism of antipsychotic drug action. The molecules most consistently found to be associated with abnormalities or in antipsychotic drug action are Akt1, glycogen synthase kinase3beta, and beta-catenin. However, the extent to which they contribute to the pathophysiology of schizophrenia or to antipsychotic action remains to be established. CONCLUSIONS: The study of the involvement of Wnt pathway abnormaliti

Low-dose acetazolamide in the treatment of premenstrual dysphoric disorder: a case series.

The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms.The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms

Solid Waste and Water Quality Management Models for Sagarmatha National Park and Buffer Zone, Nepal.

The problem of supporting decision- and policy-makers in managing issues related to solid waste and water quality was addressed within the context of a participatory modeling framework in the Sagarmatha National Park and Buffer Zone in Nepal. We present the main findings of management-oriented research projects conducted within this framework, thus providing an overview of the current situation in the park regarding solid waste and water quality issues. We found that most of the solid waste generated in the park is composed of organic matter, paper, and minor reused waste that is mainly reused for cattle feeding and manure, while disposal of other nondegradable categories of collected waste (glass, metal, and plastic) is not properly managed. Particularly, burning or disposal in open dumps poses a great hazard to environmental, human, and animal health, as most dump sites situated close to water courses are prone to regular flooding during the rainy season, thereby directly contaminating river water. Pollutants and microbiological contamination in water bodies were found and anthropogenic activities and hazardous practices such as solid waste dump sites, open defecation, and poor conditions of existing septic tanks are suggested as possibly affecting water quality. Collection of these data on solid waste and water quality and compilation of management information on the targeted social-ecological system allowed us to develop consensus-building models to be used as management supporting tools. By implementing such models, we were able to simulate scenarios identifying and evaluating possible management solutions and interventions in the park. This work reveals insights into general dynamics that can support the quest for solutions to waste and water quality management problems in other protected areas and mountain landscapes where traditional livelihood and land use patterns are changing under the influence of a growing population, changing consumption patterns, and international tourism