Evidence-based curative health promotion : a systems biology-orientated treatment of seasonal allergic rhinitis with Citrus/Cydonia comp.

The prognosis of higher life expectancies of both men and women in the Netherlands, often related to chronic diseases and high healthcare costs, the changed role of patients into competent patients, and the increasing interest of patients in complementary medicine worldwide provides the scientific rationale to put more emphasis in healthcare on developing valid, effective, cost-effective and safe strategies that support and enable patients to actively contribute to their own health and disease status in order to promote their health in a preventive and/ or curative manner. Although much effort has been invested worldwide, a lot of scientific and practical work still has to be done to develop the health promotion approach into one that is evidenced-based and professional like the fighting disease approach. This thesis focuses on some of the conceptual, methodological and empirical issues of developing professional preventive and curative health promotion as a contribution to the further innovation of medicine and healthcare. Chapter 2 analyzed historic and current health concepts and developed and preliminarily validated the new concept of ‘health by self-regulation’ by means of analyzing its internal consistency, its accordance with other scientific concepts (e.g. the concepts of epigenetics, systems biology, and emergence) and its accordance with empirical facts. Finally, it demonstrated two examples of integration of the fighting disease and the health promotion approach and discussed the theoretical and practical implications of this new concept. In Chapter 3, the fundamental scientific discussion of holism versus reductionism was summarized. This chapter demonstrated that there are several arguments against the current reductionist point of view. This provides a scientific opening for a more holistic or systems biology-oriented concept of health and a more holistic or systems biology-oriented methodological approach. Chapter 4 described a new system’s biology-oriented methodological approach in developing immunological biomarkers for monitoring treatment effect in seasonal allergic rhinitis (hay fever) research. Using permuted stepwise regression, pattern variables that reflect immune system functioning on the systems level were computed and tested. Computation was based on a dataset (from a randomized controlled trial comparing two routes of administration) of allergen-specifically induced expression levels of cytokines (IL-1β, IL-5, IL-10, IL-12, IL-13, IL-17, IFN-γ and TNF-α) and symptom severity scores from 22 seasonal allergic rhinitis (SAR) patients measured before and after six weeks of treatment with medicinal products containing Citrus and Cydonia. Further computation and biomarker validation with larger datasets, including data from healthy persons and SAR patients, is indicated. In Chapter 5, the experiences of 39 Dutch general practitioners with anthroposophic SAR treatment were examined. The results of this survey provide the first practice-based evidence of positive treatment results of Citrus/Cydonia comp. for SAR. Chapter 6 examined, in two in vitro studies, the immunological pathways of the effects of Citrus/Cydonia comp. from a healthy and an allergic donor, respectively. Peripheral blood mononuclear cells (PBMCs) were isolated out of peripheral blood and analyzed in vitro after polyclonal stimulation of T-cells. The differentiation capacity and the influence regarding Th1 (IFN-γ) and Th2 (IL-5) cells were examined. Citrus/Cydonia comp. has a selective effect on the differentiation of Th-cells by producing relatively more IL-10 than IL-12. It also seems to have an effect on the induction of regulatory (IL-10 producing) T-cell subsets. It is in vitro capable of partly neutralizing the changes, characteristic to allergic rhinitis, regarding the maturation, differentiation, and activity of the immune system. Thus, it was concluded that Citrus/Cydonia comp. can potentially restore the disturbed immune state of rhinitis patients, which essentially could be sufficient to make allergic symptoms disappear permanently. Chapter 7 examined the effects of the combined product, Citrus e fructibus/Cydonia e fructibus (Citrus/Cydonia), and separate products of Citrus and Cydonia on the immuno-pathological pathways involved in seasonal allergic rhinitis (SAR). Peripheral blood mononuclear cells (PBMCs) from five healthy and five grass pollen-allergic donors were isolated and analyzed in vitro after polyclonal and allergen-specific stimulation of T-cells in the presence of the three extracts. The analyses demonstrated acceptable cell survival with no signs of toxicity. Citrus mainly had a selective effect on reducing allergen-specific chronic inflammatory (TNF-a) and Th2 (IL-5) pathway activity; whereas both Cydonia and Citrus/Cydonia mainly affected the induction of the allergen-specific Th1 (IFN-g) pathway. Citrus and Cydonia demonstrated differential working mechanisms in the treatment of SAR, and the combination product did not demonstrate larger effects than the separate preparations. Hence, it was concluded that further effectiveness and efficacy studies comparing the effects of the products on SAR in vivo are required. Chapter 8 studied a small group of 13 patients with a mean history of hay fever with grass pollen allergy of 9 years’ duration, who in previous years used conventional hay fever medication because of the severity of their symptoms during the pollen season. Gencydo injections were administered to 12 patients before the onset of and during the grass pollen season, and in one patient during the grass pollen season only. Nasal and non-nasal hay fever symptom severity, use of rescue medication (antihistamines or corticosteroids), and the subjective experiences of patients were used as outcome measures. It was concluded that there are clear indications that Gencydo treatment is effective in a large subgroup of the research population. Chapter 9 compared the efficacy and safety of two routes of administration (subcutaneous injections (SI) versus nasal spray (NS)) in a national, randomized, comparative clinical trial with two parallel groups.  A total of 23 patients fulfilled the study requirements. After a one- or two-week wash-out period, twenty-three patients were randomized to a six-week treatment period. The outcomes assessed were immunological and symptom severity changes and safety. Immunologic outcome assessments were blinded to group assignment.It was concluded that both routes of administration are safe and demonstrate immunological and clinical effects, with larger inflammatory and innate immunological effects of the NS route and larger allergen-specific clinical effects in the SI group. Chapter 10 reported a study that was aiming to update the safety status of anthroposophic and homeopathic solutions for injection through a systematic evaluation of the reported adverse drug reactions (ADRs). ADRs were extracted from the pharmacovigilance databases of eight German anthroposophic and homeopathic manufacturers covering the period of 2000-2009. These eight manufacturers represent, in total, more than 94 percent of the sales of anthroposophic and homeopathic solutions for injection in Germany. Analyzed ADRs included reports in humans only, reports from post-marketing surveillance, literature cases and clinical/safety trials, and spontaneous reports from healthcare professionals and patients. The results suggest an excellent safety profile of solutions for injection as therapeutically applied in anthroposophic medicine and homeopathy, where the overall incidence of ADRs are very rare. Chapter 11 presented the major findings of this thesis, studying the concept of health, the methodology to monitor (changes in) health states, the effects and safety of Citrus/ Cydonia comp. on seasonal allergic rhinitis as an example of curative health promotion, and the cost-effectiveness of integrative medicine in the Netherlands. The theoretical and practical implications of the results of this thesis were discussed and reflected on the scientific fundament of anthroposophic medicine. Future perspectives were also described for the implementation of new research lines, the further development of professional preventive and curative health promotion as a contribution to the further innovation of medicine and healthcare, and the investment in CAM/IM/AM research. In the Appendix, a cost-effectiveness study is presented in which the possible contribution of integrative medicine to the reduction of healthcare costs was studied. This study compared the performance of general practitioners who have completed certified additional training in CAM after obtaining their conventional medical degree (GP-CAMs) with general practitioners who have not (GPs). Patients whose GP has completed additional CAM training have 0–30 percent lower healthcare costs and mortality rates, depending on age group and the type of CAM. The lower costs result from fewer hospital stays and fewer prescription drugs. Since the differences are obtained while controlling for confounders, including neighborhood-specific fixed effects at a highly detailed level, the lower costs and longer lives are unlikely to be related to differences in socioeconomic status. Possible explanations include selection (e.g. people with low interest in medical interventions might be more likely to choose CAM) and better practices (e.g. less overtreatment, more focus on preventive and curative health promotion) by GPs with knowledge of complementary medicine. More controlled studies (replication studies, research based on more comprehensive data, cost-effectiveness studies on CAM for specific diagnostic categories) are required. These findings highlight the fact that the health-promoting methods that are considered CAM today could be effective and might have significant cost-saving potential. With the example of Citrus/Cydonia comp. in SAR treatment, this thesis demonstrates the safety, moderate efficacy and specific immunological working mechanism of this medicine, underscoring that CAM could be effective and might have a significant cost-saving potential, and collectively, the validity of the concept of preventive and curative health promotion. &nbsp

Acceptance of Anxiety through Art Therapy: A Case Report Exploring How Anthroposophic Art Therapy Addresses Emotion Regulation and Executive Functioning

Anxiety is a major problem for many individuals, causing impairment in daily life. Art therapy is often deployed and although positive results are communicated in clinical practice, its effectiveness and working mechanisms have hardly been studied. Therefore, it is important to systematically describe the intervention process and to detect the working mechanisms to be able to evaluate them. Narrative case studies help to understand the intervention in more depth. A typical case file was selected for case reporting according to scientific (CARE & CARE-AAT) guidelines, with the aim to explore the therapeutic elements that contributed to the reduction of anxiety. The report describes the intervention process of a 54-year-old female, suffering from anxiety since childhood and diagnosed with panic disorder, agoraphobia, claustrophobia and hypochondria. After 14 sessions of anthroposophic art therapy, reduction of anxiety was shown, as well as improvements of emotion regulation and executive functioning. The client indicated that she became more tolerant and accepting towards her anxiety. She noted a softened attitude towards herself and her complaints, even one year after art therapy. The course of treatment suggests that aspects of emotion regulation and executive functioning were addressed through implicit learning processes in different art therapy assignments.Development Psychopathology in context: clinical setting

The Effectiveness of Art Therapy for Anxiety in Adult Women: A Randomized Controlled Trial

Objectives: Art therapy (AT) as a treatment option for anxiety is regularly employed in clinical practice, but scientific evidence for its effectiveness is lacking, since this intervention has hardly been studied. The aim was to study the effectiveness of AT on anxiety in adult women. The specific type of AT studied was anthroposophic AT.Methods: A RCT comparing AT versus a waiting list (WL) condition on anxiety symptom severity, quality of life, and emotion regulation. Factors influencing treatment outcome were additionally explored. Participants were women, aged 18–65 years, diagnosed with generalized anxiety disorder, social anxiety disorder or panic disorder, with moderate to severe anxiety symptoms. The trial was registered in the Dutch Trial Registration (NL6661).Results: Fifty-nine women were included, of which 47 completed the trial. Both per-protocol and intention-to treat analyses demonstrated effectiveness of AT compared to WL, showing a reduction in anxiety, an increase in subjective quality of life (both with large effects) and an improvement in accessibility of emotion regulation strategies (medium effect). Treatment effects remained after 3 months follow-up. Improved acceptance of emotions and improved goal-oriented action are aspects of emotion regulation that are associated with the decrease in anxiety level.Conclusion: AT is effective in reducing anxiety symptoms, improving quality of life and aspects of emotion regulation. Future RCTs should use active controls (treatment as usual) and study cost-effectiveness.Development Psychopathology in context: clinical setting

Protein polymer accumulation during grain development and relations to quality: Influences of cultivar and environment

OBJECTIVE: To assess the independent and combined impact of frailty, multi-morbidity, and activities of daily living (ADL) limitations on self-reported quality of life and healthcare costs in elderly people. DESIGN: Cross-sectional, descriptive study. METHOD: Data came from The Older Persons and Informal Caregivers Minimum DataSet (TOPICS-MDS), a pooled dataset with information from 41 projects across the Netherlands from the Dutch national care for the Elderly programme. Frailty, multi-morbidity and ADL limitations, and the interactions between these domains, were used as predictors in regression analyses with quality of life and healthcare costs as outcome measures. Analyses were stratified by living situation (independent or care home). Directionality and magnitude of associations were assessed using linear mixed models. RESULTS: A total of 11,093 elderly people were interviewed. A substantial proportion of elderly people living independently reported frailty, multi-morbidity, and/or ADL limitations (56.4%, 88.3% and 41.4%, respectively), as did elderly people living in a care home (88.7%, 89.2% and 77,3%, respectively). One-third of elderly people living at home (31.9%) reported all three conditions compared with two-thirds of elderly people living in a care home (68.3%). In the multivariable analysis, frailty had a strong impact on outcomes independently of multi-morbidity and ADL limitations. Elderly people experiencing problems across all three domains reported the poorest quality-of-life scores and the highest healthcare costs, irrespective of their living situation. CONCLUSION: Frailty, multi-morbidity and ADL limitations are complementary measurements, which together provide a more holistic understanding of health status in elderly people. A multi-dimensional approach is important in mapping the complex relationships between these measurements on the one hand and the quality of life and healthcare costs on the other

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity

Background: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. Methods: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. Results: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p Pathophysiology and treatment of rheumatic disease

Host-guest chemistry of dendritic molecules

In this chapter we will discuss the contribution of dendritic macromolecules to the field of supramolecular host-guest chemistry. Since the first publications on dendrimers more than two decades ago, their properties as molecular recognition compounds have been discussed many times. A brief introduction to the common host-guest interactions in the traditional supramolecular field is accompanied by a short overview of specific properties of these highly branched, three-dimensional macromolecules. Emphasis will be placed on the existence of internal voids in the dendritic interior. Subsequently, an overview will be given of the reported host-guest systems based on dendritic molecules. The host-guest systems discussed are arranged by type of interactions: from topological encapsulation to electrostatic, hydrophobic or hydrogen-bonding interactions. This review will emphasize contributions in which the pre-organized three-dimensional dendritic structure and the high local concentrations of sites display cooperative effects and which could be of interest towards future applications

Development of systems biology-oriented biomarkers by permuted stepwise regression for the monitoring of seasonal allergic rhinitis treatment effects

Background: The immune system, a complex set of integrated responses, often cannot be explained, predicted, or monitored by examining its separate components as biomarkers. Combining different components may therefore be a suitable approach to develop relevant biomarkers reflecting immune system functioning in an appropriate way. Methods: Here we compute and test pattern variables that should reflect immune system functioning on the systems level. Computation was based on a dataset (from a randomized controlled trial comparing two routes of administration) of allergen-specifically induced expression levels of cytokines IL-1 beta, IL-5, IL-10, IL-12, IL-17, IFN-gamma and TNF-alpha) and symptom severity scores from 22 seasonal allergic rhinitis (SAR) patients measured before and after six weeks of treatment with medicinal products containing Citrus and Cydonia. By means of stepwise regression analyses we explored and tested pattern variables of the immunological data using permuted stepwise regression (PStR) to distinguish optimally between (immunological) baseline and post-baseline data for the whole treatment group (22 patients) and the two separate treatment groups (11 patients in each group). The validity of the stepwise selection method for the computed pattern variables was tested by means of random permutation tests and evaluated with the cross-validated correct rate of classification (CV correct). Results: For the total group a pattern variable was computed with three variables: IL-10 (day 7), TNF-alpha (day 1) and IL-10 (day 1) (CV correct: 091;

Polystyrene-dendrimer amphiphilic block copolymers with a generation-dependent aggregation

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