A systematic review of physiological reactivity to stimuli in autism

Objective: The prevalence of abnormal behavioural responses to a variety of stimuli among individuals with autism has led researchers to examine whether physiological reactivity (PR) is typical in this population. This article reviewed studies assessing PR to sensory, social and emotional, and stressor stimuli in individuals with autism. Methods: Systematic searches of electronic databases identified 57 studies that met our inclusion criteria. Studies were analysed to determine: (a) participant characteristics; (b) physiological measures used; (c) PR to sensory, social and emotional or stressor stimuli; (d) the relation between PR and behavioural or psychological variables and (e) baseline physiological activity. A novel measure of methodological quality suitable for use with non-randomized, non-interventional, psychophysiological studies was also developed and applied. Results: Individuals with autism were found to respond differently than typically developing controls in 78.6%, 66.7% and 71.4% of sensory, social and emotional, and stressor stimulus classes, respectively. However, this extant literature is characterized by variable and inconsistent findings, which do not appear to be accounted for by varying methodological quality, making it difficult to determine what specific factors differentiate individuals with autism who present with atypical PR from those who do not. Conclusions: Despite this uncertainty, individual differences in PR are clearly present in autism, suggesting additional research is needed to determine the variables relating to PR among those with ASD and to examine the possible existence of physiological subtype responders in the population.     

New methods for modelling EQ‐5D‐5L value sets: An application to English data

Value sets for the EQ‐5D‐5L are required to facilitate its use in estimating quality‐adjusted life years. An international protocol has been developed to guide the collection of stated preference data for this purpose and has been used to generate EQ‐5D‐5L valuation data for England. The aim of this paper is report the innovative methods used for modelling those data to obtain a value set. Nine hundred and ninety‐six members of the English general public completed time trade‐off (TTO) and discrete choice experiment (DCE) tasks. We estimate models, with and without interactions, using DCE data only, TTO data only, and TTO/DCE data combined. TTO data are interpreted as both left and right censored. Heteroskedasticity and preference heterogeneity between individuals are accounted for. We use Bayesian methods in the econometric analysis. The final model is chosen based on the deviance information criterion (DIC). Censoring and taking account of heteroskedasticity have important effects on parameter estimation. For DCE data only, TTO data only, and DCE/TTO data combined, models with parameters for all dimensions and levels perform best, as judged by the DIC. Taking account of heterogeneity improves fit, and the multinomial model reports the lowest DIC. This paper presents approaches that suit observed characteristics of EQ‐5D‐5L valuation data and recognise respondents' preference heterogeneity. The methods described are potentially relevant to other value set studies.     

Valuation of EuroQol Five-Dimensional Questionnaire,Youth Version (EQ-5D-Y) and EuroQol Five-Dimensional Questionnaire,Three-Level Version (EQ-5D-3L) Health States: The Impact of Wording and Perspective

Background

Valuations of health states were affected by the wording of the two instruments (EQ-5D-3L and EQ-5D-Y) and by the perspective taken (child or adult).

Comparative sensitivity of stopwatch methodology and conventional pain assessment measures for detecting early response to triptans in migraine: results of a randomized, open-label pilot study

BACKGROUND: The standard measure of efficacy used in migraine trials is a 4-point patient-rated headache pain intensity (HPI) scale. However, it has been suggested that using a stopwatch to measure the time to meaningful pain relief can provide a more precise measurement of treatment response. OBJECTIVE: This study evaluated the sensitivity of a stopwatch method for detecting meaningful relief of headache pain and the correlation of this method with the HPI scale and a 5-point pain relief scale. METHODS: In this open-label, parallel-group pilot study, patients were randomized to receive oral eletriptan 40 mg, eletriptan 80 mg, or rizatriptan 10 mg for the treatment of a single acute migraine attack. The effect of study treatment on migraine pain was assessed immediately before dosing and at 0.5, 1, 1.5, 2, 3, and 4 hours after dosing. At each time point, patients recorded the 3 types of pain assessment in a patient diary. HPI was rated using the standard 4-point International Headache Society pain intensity scale (from 0 = no pain to 3 = severe pain). Pain relief was rated on a 5-point pain relief scale (from 4 = no relief to 0 = complete relief). The time to the onset of meaningful pain relief was measured using a stopwatch. At 4 hours after dosing, patients provided a global rating of the overall efficacy of study medication on a 5-point scale (from 0 = poor to 4 = excellent). RESULTS: Seventy-nine patients participated in the trial (78.5% female; mean [SD] age, 37.7 [9.8] years; 58.2% white). The median times to meaningful pain relief measured by stopwatch were 84, 72, and 93 minutes for eletriptan 40 mg, eletriptan 80 mg, and rizatriptan 10 mg, respectively (log-rank P = 0.029, eletriptan 80 mg vs rizatriptan 10 mg). At 90 minutes (approximating the median time to meaningful pain relief on the stopwatch), headache response rates using HPI scoring (mild to no pain) were 65%, 68%, and 52% in the respective treatment groups, with no significant difference between groups. On the pain relief scale, the corresponding mean (SD) scores at 90 minutes were 1.6 (1.2), 1.4 (1.3), and 2.0 (1.4) (P = NS). The pain relief-defined response (> or = 75% pain relief) at 90 minutes did not differ significantly between the 3 treatment groups (62%, 56%, and 48%). Detection of early improvement (0.5 and 1 hour) was similar with the HPI and pain relief scales. CONCLUSION: The results of this open-label pilot study suggest the convergent validity of 3 pain-assessment methods in migraine, but indicate that the use of a stopwatch may be a more sensitive method for detecting between-group differences.     

C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK)—endogenous negative regulators of Src-family protein kinases

C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are endogenous inhibitors of the Src-family protein tyrosine kinases (SFKs). Since constitutive activation of SFKs contributes to cancer formation and progression, to prevent excessive activation of SFKs, their activity in normal cells is kept at the basal level by CSK and CHK. CSK and CHK inactivate SFKs by specifically phosphorylating a consensus tyrosine (called Y_T) near their C-termini. Upon phosphorylation, the phospho-Y_T engages in intramolecular interactions that lock the SFK molecule in an inactive conformation. SFKs are anchored to the plasma membrane, while CSK and CHK are localized predominantly in the cytosol. To inhibit SFKs, CSK and CHK need to translocate to the plasma membrane. Recruitment of CSK and CHK to the plasma membrane is mediated by the binding of their SH2, SH3 and/or kinase domains to specific transmembrane proteins, G-proteins and adaptor proteins located near the plasma membrane. For CSK, membrane recruitment often accompanies activation. CSK and CHK employ two types of direct interactions with SFKs to achieve efficient Y_T phosphorylation: (i) short-range interactions involving binding of the active sites of CSK and CHK to specific residues near Y_T, (ii) long-range non-catalytic interactions involving binding of SFKs to motifs located distally from the active sites of CSK and CHK. The interactions between CSK and SFKs are transient in nature. Unlike CSK, CHK binds tightly to SFKs to form stable protein complexes. The binding is non-catalytic as it is independent of Y_T. More importantly, the tight binding alone is sufficient to completely inhibit SFKs. This non-catalytic inhibitory binding represents a novel mechanism employed by CHK to inhibit SFKs. Given that SFKs are implicated in cancer development, compounds mimicking the non-catalytic inhibitory mechanism of CHK are potential anti-cancer therapeutics.     

Patterns of intellectual development among survivors of pediatric medulloblastoma: a longitudinal analysis.

PURPOSE: To examine two competing hypotheses relating to intellectual loss among children treated for medulloblastoma (MB): Children with MB either: (1) lose previously learned skills and information; or (2) acquire new skills and information but at a rate slower than expected compared with healthy same-age peers. PATIENTS AND METHODS: Forty-four pediatric MB patients were evaluated who were treated with postoperative radiation therapy (XRT) with or without chemotherapy. After completion of XRT, a total of 150 examinations were conducted by use of the child version of the Wechsler Intelligence SCALES: These evaluations provided a measure of intellectual functioning called the estimated full-scale intelligence quotient (FSIQ). Changes in patient performance corrected for age (scaled scores) as well as the uncorrected performance (raw scores) were analyzed. RESULTS: At the time of the most recent examination, the obtained mean estimated FSIQ of 83.57 was more than one SD below expected population norms. A significant decline in cognitive performance during the time since XRT was demonstrated, with a mean loss of 2.55 estimated FSIQ points per year (P =.0001). An analysis for the basis of the intelligence quotient (IQ) loss revealed that subtest raw score values increased significantly over time since XRT, but the rate of increase was less than normally expected, which resulted in decreased IQ scores. CONCLUSION: These results support the hypothesis that MB patients demonstrate a decline in IQ values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, as opposed to a loss of previously acquired information and skills.     

Cytoplasmic membrane potential of mouse lymphocytes is decreased by cyclosporins

Membrane potential of mouse lymphocytes was investigated in the presence and absence of cyclosporin A (CsA) and cyclosporin G (CsG) by flow cytometry and fluorescence spectroscopy. A carbocyanine dye, dihexyloxacarbocyanine iodide [DIOC6(3)], was applied as a membrane potential probe. A dose-dependent decrease in the membrane potential of T and B lymphocytes was observed in the presence of CsA and CsG. However, pretreatment of lymphocytes with insulin reduced the effect of the cyclosporins. Mobile ionophores, such as valinomycin, ionomycin and A23187 were less effective in changing the membrane potential of lymphocytes in the presence of CsA. The channel forming ionophore, gramicidin or high extra-cellular potassium concentration (160 mM) strongly reduced the membrane potential regardless of the absence or presence the CsA. These observations suggest incorporation of CsA into the cytoplasmic membrane causing changes in ion fluxes. Other reported biochemical effects of CsA may be secondary to the observed membrane potential changes. The membrane potential change induced by CsA may have selective biological consequences in a certain subpopulation of lymphocytes.