Inflammatory responses to platelet-activating factor in human skin

Since its discovery over 20 years ago, platelet- activating factor (PAF) has been the subject of intensive research. In particular, its role in pathophysiology has provoked as much controversy as research interest. The pharmacological profile and ubiquity of PAF have made it a candidate for involvement in a number of inflammatory processes. No clear evidence has been demonstrated however to establish a role in disease in man, although clinical caution about its potential toxic effects has limited the number of available experimental human models. One particular tissue which lends itself to examination of the effects of PAF is the skin. A series of studies has been undertaken to define accurately the characteristics of the acute responses to PAF in human skin and to study the role of histamine in these responses. By way of comparison, the acute responses to other inflammatory mediators (PGE2, substance P, and CGRP) has also been investigated. The effects of histamine antagonism, and depletion on the PAF responses have been examined together with evaluation of local histamine release from the skin after PAF treatment. Additionally, a comparison of the PAF-induced responses in atopic and non-atopic subjects has been undertaken. As a consequence of these studies, quantitative methods have been validated as sensitive and reproducible techniques for evaluating hyperalgesia and histamine-type flare and weal responses in the skin. Using the hyperalgesia model, intradermally injected PAF failed to cause hyperalgesia in the skin. Conversely intradermal PGE2 was shown to provoke dose- related hyperalgesia, which was associated with spreading erythema, lasting for 2-3 hours. Apart from at high doses where the effect was marginal when compared with PGE2, the neuropeptides substance P and CGRP also failed to produce hyperalgesia in the skin. Using the flare and weal model, PAF, substance P and PGE2 were associated with dose-related histamine-like weal and flare responses, although the PGE2 responses were considerably weaker. CGRP did not produce these responses and instead caused a local intense erythema, similar to the later effect of PGE2. Evaluation of the effects of H1-antagonism and histamine depletion, and the quantification of local histamine release have demonstrated that the PAF responses in the skin are largely mediated by histamine. Indomethacin was also found to have a small inhibitory effect on the PAF responses implicating secondary prostaglandin release. The acute inflammatory responses to intradermal PAF have been shown to be similar in atopic subjects compared with non-atopics using the techniques described above. Baseline plasma histamine, however, was found to be higher in atopic subjects

Association between relative age at school and persistence of attention-deficit hyperactivity disorder in prospective studies: an individual participant data meta-analysis

Background The youngest children in a school class are more likely than the oldest to be diagnosed with ADHD, but this relative age effect is less frequent in older than in younger school-grade children. However, no study has explored the association between relative age and the persistence of ADHD diagnosis at older ages. We aimed to quantify the association between relative age and persistence of ADHD at older ages. Methods For this meta-analysis, we searched MEDLINE, Embase, CINAHL, PsycINFO, and PubPsych up to April 1, 2022, with terms related to “cohort” and “ADHD” with no date, publication type, or language restrictions. We gathered individual participant data from prospective cohorts that included at least ten children identified with ADHD before age 10 years. ADHD was defined by either a clinical diagnosis or symptoms exceeding clinical cutoffs. Relative age was recorded as the month of birth in relation to the school-entry cutoff date. Study authors were invited to share raw data or to apply a script to analyse data locally and generate anonymised results. Our outcome was ADHD status at a diagnostic reassessment, conducted at least 4 years after the initial assessment and after age 10 years. No information on sex, gender, or ethnicity was collected. We did a two-stage random-effects individual participant data meta-analysis to assess the association of relative age with persistence of ADHD at follow-up. This study was registered with PROSPERO, CRD42020212650. Findings Of 33 119 studies generated by our search, we identified 130 eligible unique studies and were able to gather individual participant data from 57 prospective studies following up 6504 children with ADHD. After exclusion of 16 studies in regions with a flexible school entry system that did not allow confident linkage of birthdate to relative age, the primary analysis included 41 studies in 15 countries following up 4708 children for a period of 4 to 33 years. We found that younger relative age was not statistically significantly associated with ADHD persistence at follow-up (odds ratio 1·02, 95% CI 0·99–1·06; p=0·19). We observed statistically significant heterogeneity in our model (Q=75·82, p=0·0011, I2=45%). Participant-level sensitivity analyses showed similar results in cohorts with a robust relative age effect at baseline and when restricting to cohorts involving children with a clinical diagnosis of ADHD or with a follow-up duration of more than 10 years. Interpretation The diagnosis of ADHD in younger children in a class is no more likely to be disconfirmed over time than that of older children in the class. One interpretation is that the relative age effect decreases the likelihood of children of older relative age receiving a diagnosis of ADHD, and another is that assigning a diagnostic label of ADHD leads to unexplored carryover effects of the initial diagnosis that persist over time. Future studies should be conducted to explore these interpretations further

Association between relative age at school and persistence of attention-deficit hyperactivity disorder in prospective studies: an individual participant data meta-analysis

Background: the youngest children in a school class are more likely than the oldest to be diagnosed with ADHD, but this relative age effect is less frequent in older than in younger school-grade children. However, no study has explored the association between relative age and the persistence of ADHD diagnosis at older ages. We aimed to quantify the association between relative age and persistence of ADHD at older ages.Methods: for this meta-analysis, we searched MEDLINE, Embase, CINAHL, PsycINFO, and PubPsych up to April 1, 2022, with terms related to “cohort” and “ADHD” with no date, publication type, or language restrictions. We gathered individual participant data from prospective cohorts that included at least ten children identified with ADHD before age 10 years. ADHD was defined by either a clinical diagnosis or symptoms exceeding clinical cutoffs. Relative age was recorded as the month of birth in relation to the school-entry cutoff date. Study authors were invited to share raw data or to apply a script to analyse data locally and generate anonymised results. Our outcome was ADHD status at a diagnostic reassessment, conducted at least 4 years after the initial assessment and after age 10 years. No information on sex, gender, or ethnicity was collected. We did a two-stage random-effects individual participant data meta-analysis to assess the association of relative age with persistence of ADHD at follow-up. This study was registered with PROSPERO, CRD42020212650.Findings: of 33 119 studies generated by our search, we identified 130 eligible unique studies and were able to gather individual participant data from 57 prospective studies following up 6504 children with ADHD. After exclusion of 16 studies in regions with a flexible school entry system that did not allow confident linkage of birthdate to relative age, the primary analysis included 41 studies in 15 countries following up 4708 children for a period of 4 to 33 years. We found that younger relative age was not statistically significantly associated with ADHD persistence at follow-up (odds ratio 1·02, 95% CI 0·99–1·06; p=0·19). We observed statistically significant heterogeneity in our model (Q=75·82, p=0·0011, I2=45%). Participant-level sensitivity analyses showed similar results in cohorts with a robust relative age effect at baseline and when restricting to cohorts involving children with a clinical diagnosis of ADHD or with a follow-up duration of more than 10 years.Interpretation: the diagnosis of ADHD in younger children in a class is no more likely to be disconfirmed over time than that of older children in the class. One interpretation is that the relative age effect decreases the likelihood of children of older relative age receiving a diagnosis of ADHD, and another is that assigning a diagnostic label of ADHD leads to unexplored carryover effects of the initial diagnosis that persist over time. Future studies should be conducted to explore these interpretations further