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

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

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

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

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock