Nerve growth factor: a novel mediator in asthma

Nerve growth factor (NGF) is known for years for its properties to induce neurite outgrowth. Its role in inflammation has recently been discovered. In this thesis the role of NGF in allergic asthma is shown. In chapter 2 we showed that NGF can induce airway hyperresponsiveness in guinea pigs. Simply injecting 8-80 ng NGF intravenously resulted in an airway hyperresponsiveness within 1 hr after administration. Sensory nerves in the aiwarys signal to the central nervous system. A subtype of these neurons express tachykinins, e.g. substance P and neurokinin A. Tachykinins can induce airway hyperresponsiveness. It seems NGF acts by sensitizing the sensory neurons. A neurokinin-1 receptor antagonist can prevent the induction of airway hyperresponsiveness by NGF. The neurokinin-1 receptor is the preferred receptor for the ligand substance P. In chapter 3 we show that NGF can sensitize the sensory nerve endings, and this either results in the release of more substance P or sensitization of the neurokinin-1 receptor, but does not involve an increased synthesis of substance P. Furthermore, cannabinoids can prevent the NGF-induced hyperresponsiveness in isolated tracheal ring as well as in the guinea pig in vivo. Cannabinoids induce an inhibitory signal in sensory neurons and thereby proof again that sensory nerve endings are involved in the induction of airway hyperresponsiveness by NGF. In a model for allergic asthma, using ovalbumin as an allergen, antibodies against NGF can prevent the acutely induced bronchoconstriction by inhalation of ovalbumin (chapter 4). This model for allergic asthma shows airway hyperresponsiveness as well, and this coincides with an increased content of tachykinins in the sensory neuronal cell bodies. In chapter 5 we show that this coincides with an increase in NGF in the airways as well. When the signal transduction pathway of the high affinity receptor for NGF, trkA, is blocked, the airway hyperresponsiveness can be prevented. Furthermore, the increase in substance P in the airways and neurons is prevented as well. Neurons as well as immune cells can release NGF. One of these cells is the mast cell. It has been suggested sensory neurons and mast cells interact. In chapter 6 we co-cultured bone marrow derived mast cells and dorsal root ganglion neurons to study whether these cells would affect each others function. The cells specifically adhered to each other. They only affect each other's function, though this seems not to be of any significant physiological importance. Concluding, NGF affects airway function by affecting sensory nerve function. This thesis shows NGF is involved in the development of airway pathology in a model for allergic asthma. This could lead to the development of a new class of therapeutics against allergic asthma

Justice in climate policy:Distributing climate costs fairly

This open access book is looking into ways to achieve just climate policy within a country. The authors of this monograph share a unique, timely and original vision: continuous support for climate policy is more likely to emerge when citizens find that the distribution of the bill for climate costs is fair. But what is a fair distribution of climate costs? This is an important question because financial costs of mitigation (reducing greenhouse gases), adaptation (adapting to climate change) and damage (compensating or compensating after weather extremes) increase significantly in the coming decades. Drawing on philosophy and ethics, the authors propose ten principles for achieving just distributions of domestic climate costs. Examples of such principles are individual responsibility, the polluter pays, greatest utility and capacity to pay. Yet what a fair distribution is, depends on, for example, political preferences and the policy issue at hand. Empirical research on designing climate policies, however, shows that distributive principles are not part of the political, policy, and public discussions. The authors therefore argue that explicit attention to principles of just distribution at the start of a policy process contributes to support for climate policy. This book provides tools to professionals and students to achieve justice in climate policy

Cerebrospinal fluid cortisol levels are higher in patients with delirium versus controls

<p>Abstract</p> <p>Background</p> <p>High plasma cortisol levels can cause acute cognitive and neuropsychiatric dysfunction, and have been linked with delirium. CSF cortisol levels more closely reflect brain exposure to cortisol, but there are no studies of CSF cortisol levels in delirium. In this pilot study we acquired CSF specimens at the onset of spinal anaesthesia in patients undergoing hip fracture surgery, and compared CSF and plasma cortisol levels in delirium cases versus controls.</p> <p>Findings</p> <p>Delirium assessments were performed the evening before or on the morning of operation with a standard battery comprising cognitive tests, mental status assessments and the Confusion Assessment Method. CSF and plasma samples were obtained at the onset of the operation and cortisol levels measured. Twenty patients (15 female, 5 male) aged 62 - 93 years were studied. Seven patients were diagnosed with delirium. The mean ages of cases (81.4 (SD 7.2)) and controls (80.5 (SD 8.7)) were not significantly different (p = 0.88). The median (interquartile range) CSF cortisol levels were significantly higher in cases (63.9 (40.4-102.1) nmol/L) than controls (31.4 (21.7-43.3) nmol/L; Mann-Whitney U, p = 0.029). The median (interquartile range) of plasma cortisol was also significantly higher in cases (968.8 (886.2-1394.4) nmol/L, than controls (809.4 (544.0-986.4) nmol/L; Mann Whitney U, p = 0.036).</p> <p>Conclusions</p> <p>These findings support an association between higher CSF cortisol levels and delirium. This extends previous findings linking higher plasma cortisol and delirium, and suggests that more definitive studies of the relationship between cortisol levels and delirium are now required.</p

Rechtvaardigheid in klimaatbeleid:Over de verdeling van klimaatkosten

We zijn op een nieuw punt aanbeland in het debat over klimaatbeleid. Ooit ging het over de vraag of de aarde daadwerkelijk opwarmt door menselijk toedoen. Vervolgens ging het over de vraag wat daaraan te doen valt. Nu gaat het steeds vaker over de vraag wie de kosten van klimaatmaatregelen en van klimaatschademoet betalen. De protesten van de ‘gele hesjes’ in Frankrijk hebben laten zien hoe belangrijk het is dat de verdeling van zulke klimaatkosten als rechtvaardig gezien wordt. Als dat niet het geval is, dan kan het draagvlak voor klimaatbeleid afkalven. Hoe kunnen rechtvaardige verdelingen eruit zien? Dat analyseert de Wetenschappelijke Raad voor het Regeringsbeleid (wrr) in dit rapport. De hoofdboodschap van dit rapport is dat er in klimaatbeleid stelselmatige aandacht moet zijn voor de rechtvaardigheid van verdelingen. Maatregelen dienen niet alleen beoordeeld te worden vanuit het perspectief van doelmatigheid en rechtmatigheid, maar ook vanuit het perspectief van rechtvaardigheid. Onze belangrijkste boodschap is daarom dat de mogelijke verdelingen van klimaatkosten al vooraf expliciet op tafel komen en worden doordacht. Dat helptbeleidsmakers om meer oog te krijgen voor mogelijke onbedoelde en ongewensteneveneffecten. Het leidt ook tot een meer afgewogen en transparanter politiek debat. En het zorgt ervoor dat het draagvlak voor klimaatbeleid op peil blijft. De wrr doet drie aanbevelingen hoe de overheid rechtvaardige verdelingen in het klimaatbeleid tot stand kan brengen: zorg voor (1) inhoudelijke verbreding, (2) procedurele verankering en (3) institutionele borging

Prenatal Programming of Metabolic Syndrome in the Common Marmoset Is Associated With Increased Expression of 11β-Hydroxysteroid Dehydrogenase Type 1

OBJECTIVE: Recent studies in humans and animal models of obesity have shown increased adipose tissue activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which amplifies local tissue glucocorticoid concentrations. The reasons for this 11beta-HSD1 dysregulation are unknown. Here, we tested whether 11beta-HSD1 expression, like the metabolic syndrome, is "programmed" by prenatal environmental events in a nonhuman primate model, the common marmoset monkey. RESEARCH DESIGN AND METHODS: We used a "fetal programming" paradigm where brief antenatal exposure to glucocorticoids leads to the metabolic syndrome in the offspring. Pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for 1 week in either early or late gestation, or they were given vehicle. Tissue 11beta-HSD1 and glucocorticoid receptor mRNA expression were examined in the offspring at 4 and 24 months of age. RESULTS: Prenatal dexamethasone administration, selectively during late gestation, resulted in early and persistent elevations in 11beta-HSD1 mRNA expression and activity in the liver, pancreas, and subcutaneous-but not visceral-fat. The increase in 11beta-HSD1 occurred before animals developed obesity or overt features of the metabolic syndrome. In contrast to rodents, in utero dexamethasone exposure did not alter glucocorticoid receptor expression in metabolic tissues in marmosets. CONCLUSIONS: These data suggest that long-term upregulation of 11beta-HSD1 in metabolically active tissues may follow prenatal "stress" hormone exposure and indicates a novel mechanism for fetal origins of adult obesity and the metabolic syndrome

Quantifying the Effect of Methotrexate on Adalimumab Response in Psoriasis by Pharmacokinetic–Pharmacodynamic Modeling:When the rhetoric of sharing can backfire

Previously, we showed that the combination of methotrexate and adalimumab treatment leads to less antidrug antibody development. In this study, we quantify the pharmacokinetics/pharmacodynamics (PK/PD) of adalimumab and evaluate the influence of methotrexate cotreatment. A population PK–PD model was developed using prospective data from 59 patients with psoriasis (baseline PASI = 12.6) receiving adalimumab over 49 weeks. Typical PK and PD parameters and their corresponding interpatient variability were estimated. We performed a covariate analysis to assess whether interpatient variability could be explained by addition of methotrexate and other covariates. In total, 330 PASIs, 252 adalimumab serum concentrations, and 247 antidrug antibody titers were available. Presence of antidrug antibodies (adalimumab group = 46.7%, adalimumab + methotrexate group = 38.7%; P = .031) was correlated with increased adalimumab apparent clearance (P &lt; .001). In the PD model, the use of concomitant methotrexate was borderline to significantly correlated with a decreased half-maximal inhibitory concentration (adalimumab concentration for which clinical response score is reduced by half; P &lt; .10). On the basis of our PK–PD model, concomitant use of methotrexate indirectly increases adalimumab concentration, partially through less antidrug antibodies formation, which may result in better efficacy.</p

Using Real-World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic-Pharmacodynamic Study.

Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real-world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first-line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti-drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one-compartment model. A maximum effect (Emax ) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half-maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring "dashboard" to individualize dosing and improve treatment outcomes

The detection of a strong episignature for Chung–Jansen syndrome, partially overlapping with Börjeson–Forssman–Lehmann and White–Kernohan syndromes

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung–Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung–Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White–Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson–Forssman–Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung–Jansen, Börjeson–Forssman–Lehmann and White–Kernohan syndromes.</p

Cerebrospinal fluid markers of neuroinflammation in delirium:A role for interleukin-1β in delirium after hip fracture

AbstractObjectiveExaggerated central nervous system (CNS) inflammatory responses to peripheral stressors may be implicated in delirium. This study hypothesised that the IL-1β family is involved in delirium, predicting increased levels of interleukin-1β (IL-1β) and decreased IL-1 receptor antagonist (IL-1ra) in the cerebrospinal fluid (CSF) of elderly patients with acute hip fracture. We also hypothesised that Glial Fibrillary Acidic Protein (GFAP) and interferon-γ (IFN-γ) would be increased, and insulin-like growth factor 1 (IGF-1) would be decreased.MethodsParticipants with acute hip fracture aged >60 (N=43) were assessed for delirium before and 3–4 days after surgery. CSF samples were taken at induction of spinal anaesthesia. Enzyme-linked immunosorbent assays (ELISA) were used for protein concentrations.ResultsPrevalent delirium was diagnosed in eight patients and incident delirium in 17 patients. CSF IL-1β was higher in patients with incident delirium compared to never delirium (incident delirium 1.74pg/ml (1.02–1.74) vs. prevalent 0.84pg/ml (0.49–1.57) vs. never 0.66pg/ml (0–1.02), Kruskal–Wallis p=0.03). CSF:serum IL-1β ratios were higher in delirious than non-delirious patients. CSF IL-1ra was higher in prevalent delirium compared to incident delirium (prevalent delirium 70.75pg/ml (65.63–73.01) vs. incident 31.06pg/ml (28.12–35.15) vs. never 33.98pg/ml (28.71–43.28), Kruskal–Wallis p=0.04). GFAP was not increased in delirium. IFN-γ and IGF-1 were below the detection limit in CSF.ConclusionThis study provides novel evidence of CNS inflammation involving the IL-1β family in delirium and suggests a rise in CSF IL-1β early in delirium pathogenesis. Future larger CSF studies should examine the role of CNS inflammation in delirium and its sequelae