Measuring visual cortical oxygenation in diabetes using functional near-infrared spectroscopy

Aims: Diabetes mellitus affects about 6% of the world’s population, and the chronic complications of the disease may result in macro- and micro-vascular changes. The purpose of the current study was to shed light on visual cortical oxygenation in diabetic individuals. We then aimed to compare the haemodynamic response (HDR) to visual stimulation with glycaemic control, given the likelihood of diabetic individuals suffering from such macro- and micro-vascular insult. Methodology: Thirty participants took part in this explorative study, fifteen of whom had diabetes and fifteen of whom were non-diabetic controls. The HDR, measured as concentrations of oxyhaemoglobin [HbO] and deoxyhaemoglobin [HbR], to visual stimulation was recorded over the primary visual cortex (V1) using a dual-channel oximeter. The stimulus comprised a pattern-reversal checkerboard presented in a block design. Participants’ mean glycated haemoglobin (HbA1c) level (±SD) was 7.2±0.6% in the diabetic group and 5.5±0.4% in the non-diabetic group. Raw haemodynamic data were normalised to baseline, and the last 15 s of data from each ‘stimulus on’ and ‘stimulus off’ condition were averaged over seven duty cycles for each participant. Results: There were statistically significant differences in ∆[HbO] and ∆[HbR] to visual stimulation between diabetic and non-diabetic groups (p<0.05). In the diabetic group, individuals with type 1 diabetes displayed an increased [HbO] (p<0.01) and decreased [HbR] (p<0.05) compared to their type 2 counterparts. There was also a linear relationship between both ∆[HbO] and ∆[HbR] as a function of HbA1c level (p<0.0005). Conclusions: Our findings suggest that fNIRS can be used as a quantitative measure of cortical oxygenation in diabetes. Diabetic individuals have a larger HDR to visual stimulation compared to non-diabetic individuals. This increase in ∆[HbO] and decrease in ∆[HbR] appears to be correlated with HbA1c level

Effects of glaucoma and snoring on cerebral oxygenation in the visual cortex: a study using functional Near Infrared Spectroscopy (fNIRS)

Purpose: The purpose of this study was to investigate the effects of snoring and glaucoma on the visual Haemodynamic Response (HDR) using functional Near Infrared Spectroscopy (fNIRS). Methods: We recruited 8 glaucoma patients (aged 56-79), 6 habitual snorers (aged 26-61) and 10 healthy control participants (aged 21-78). Glaucoma patients were of varying subtypes and under care of ophthalmologists. Prior to testing visual acuity, blood pressure, heart rate and a medical history were taken. HDRs were recorded over the primary visual cortex (V1) using a reversing checkerboard paradigm. Results & Discussion: All participants showed the characteristic increase of Oxyhaemoglobin concentration ([HbO]) and decrease of Deoxyhaemoglobin concentration ([HbR]) during visual stimulation (p < 0.001, η2 = 0.78). Despite this, there were signifi cant group differences with a large effect size (η2 = 0.28). During visual stimulation normal participants had greater [HbO] compared to snorers and glaucoma patients (p < 0.01). Both glaucoma patients and snorers presented with comparable HDR for [HbO] and [HbR] in V1. Importantly, during visual stimulation, the increased [HbO] in glaucoma patients correlated well with their visual fi elds and self-reported activities of daily living (r = -0.98, r = -0.82, p < 0.05). Both glaucoma patients and snorers presented with an attenuated HDR in V1. Our results suggest a possible vascular link between these conditions

Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases

SynGAP is a Ras and Rap GTPase-activating protein (GAP) found in high concentration in the postsynaptic density (PSD) fraction from mammalian forebrain where it binds to PDZ domains of PSD-95. Phosphorylation of pure recombinant synGAP by Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII) shifts the balance of synGAP's GAP activity toward inactivation of Rap1; whereas phosphorylation by cyclin-dependent kinase 5 (CDK5) has the opposite effect, shifting the balance toward inactivation of HRas. These shifts in balance contribute to regulation of the numbers of surface AMPA receptors, which rise during synaptic potentiation (CaMKII) and fall during synaptic scaling (CDK5). Polo-like kinase 2 (Plk2/SNK), like CDK5, contributes to synaptic scaling. These two kinases act in concert to reduce the number of surface AMPA receptors following elevated neuronal activity by tagging spine-associated RapGAP protein (SPAR) for degradation, thus raising the level of activated Rap. Here we show that Plk2 also phosphorylates and regulates synGAP. Phosphorylation of synGAP by Plk2 stimulates its GAP activity toward HRas by 65%, and toward Rap1 by 16%. Simultaneous phosphorylation of synGAP by Plk2 and CDK5 at distinct sites produces an additive increase in GAP activity toward HRas (∼230%) and a smaller, non-additive increase in activity toward Rap1 (∼15%). Dual phosphorylation also produces an increase in GAP activity toward Rap2 (∼40–50%), an effect not produced by either kinase alone. As we previously observed for CDK5, addition of Ca^(2+)/CaM causes a substrate-directed doubling of the rate and stoichiometry of phosphorylation of synGAP by Plk2, targeting residues also phosphorylated by CaMKII. In summary, phosphorylation by Plk2, like CDK5, shifts the ratio of GAP activity of synGAP to produce a greater decrease in active Ras than in active Rap, which would produce a shift toward a decrease in the number of surface AMPA receptors in neuronal dendrites

Phosphorylation of Synaptic GTPase Activating Protein (synGAP) by Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward Ras and Rap GTPases

SynGAP is a neuron-specific Ras and Rap GTPase-activating protein (GAP) found in high concentration in the postsynaptic density (PSD) fraction from mammalian forebrain. We have previously shown that, in situ in the PSD fraction or in recombinant form in Sf9 cell membranes, synGAP is phosphorylated by Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), another prominent component of the PSD. Here we show that recombinant synGAP (r-synGAP), lacking 102 residues at the N-terminus, can be purified in soluble form and is phosphorylated by cyclin-dependent kinase 5 (CDK5) as well as by CaMKII. Phos-phorylation of r-synGAP by CaMKII increases its HRas GAP activity by 25% and its Rap1 GAP activity by 76%. Conversely, phosphorylation by CDK5 increases r-synGAPs HRas GAP activity by 98% and its Rap1 GAP activity by 20%. Thus, phosphorylation by both kinases increases synGAP activity, but CaMKII shifts the relative GAP activity toward inactivation of Rap1; whereas CDK5 shifts the relative activity toward inactivation of HRas. GAP activity toward Rap2 is not altered by phosphorylation by either kinase. CDK5 phosphorylates synGAP primarily at two sites, S773 and S802. Phosphorylation at S773 inhibits r-synGAP activity, whereas phosphorylation at S802 increases it. However, the net effect of concurrent phosphorylation of both sites, S773 and S802, is an increase in GAP activity. SynGAP is phosphorylated at S773 and S802 in the PSD fraction, and its phosphorylation by CDK5 and CaMKII is differentially regulated by activation of NMDA-type glutamate receptors in cultured neurons

Major epidemiological changes in sudden infant death syndrome : a 20-year population-based study in the UK

Background Results of case-control studies in the past 5 years suggest that the epidemiology of sudden infant death syndrome (SIDS) has changed since the 1991 UK Back to Sleep campaign. The campaign's advice that parents put babies on their back to sleep led to a fall in death rates. We used a longitudinal dataset to assess these potential changes. Methods Population-based data from home visits have been collected for 369 consecutive unexpected infant deaths (300 SIDS and 69 explained deaths) in Avon over 20 years (1984—2003). Data obtained between 1993 and 1996 from 1300 controls with a chosen “reference” sleep before interview have been used for comparison. Findings Over the past 20 years, the proportion of children who died from SIDS while co-sleeping with their parents, has risen from 12% to 50% (p<0·0001), but the actual number of SIDS deaths in the parental bed has halved (p=0·01). The proportion seems to have increased partly because the Back to Sleep campaign led to fewer deaths in infants sleeping alone—rather than because of a rise in deaths of infants who bed-shared, and partly because of an increase in the number of deaths in infants sleeping with their parents on a sofa. The proportion of deaths in families from deprived socioeconomic backgrounds has risen from 47% to 74% (p=0·003), the prevalence of maternal smoking during pregnancy from 57% to 86% (p=0·0004), and the proportion of pre-term infants from 12% to 34% (p=0·0001). Although many SIDS infants come from large families, first-born infants are now the largest group. The age of infants who bed-share is significantly smaller than that before the campaign, and fewer are breastfed. Interpretation Factors that contribute to SIDS have changed in their importance over the past 20 years. Although the reasons for the rise in deaths when a parent sleeps with their infant on a sofa are still unclear, we strongly recommend that parents avoid this sleeping environment. Most SIDS deaths now occur in deprived families. To better understand contributory factors and plan preventive measures we need control data from similarly deprived families, and particularly, infant sleep environments

Functional strength training versus movement performance therapy for upper limb motor recovery early after stroke: a RCT

BACKGROUND: Not all stroke survivors respond to the same form of physical therapy in the same way early after stroke. The response is variable and a detailed understanding of the interaction between specific physical therapies and neural structure and function is needed. OBJECTIVES: To determine if upper limb recovery is enhanced more by functional strength training (FST) than by movement performance therapy (MPT), to identify the differences in the neural correlates of response to (1) FST and (2) MPT and to determine whether or not pretreatment neural characteristics can predict recovery in response to (1) FST and (2) MPT. DESIGN: Randomised, controlled, observer-blind, multicentre trial with embedded explanatory investigations. An independent facility used computer-generated randomisation for participants’ group allocation. SETTING: In-patient rehabilitation, participants’ homes, university movement analysis facilities and NHS or university neuroimaging departments in the UK. PARTICIPANTS: People who were between 2 and 60 days after stroke in the territory of the anterior cerebral circulation, with some voluntary muscle contraction in the more affected upper limb but not full function. INTERVENTIONS: Routine rehabilitation [conventional physical therapy (CPT)] plus either MPT or FST in equal doses during a 6-week intervention phase. FST was progressive resistive exercise provided during training of functional tasks. MPT was therapist ‘hands-on’ sensory input and guidance for production of smooth and accurate movement. MAIN OUTCOMES: Action Research Arm Test (ARAT) score for clinical efficacy. Neural measures were made of corticocortical [fractional anisotropy (FA) from corpus callosum midline], corticospinal connectivity (asymmetry of corticospinal tracts FA) and resting motor threshold of paretic biceps brachii (pBB) and extensor carpi radialis muscles (derived from transcranial magnetic stimulation). ANALYSIS: Change in ARAT scores were analysed using analysis of covariance models adjusted for baseline variables and randomisation strata. Correlation coefficients were calculated between change in neural measures and change in ARAT score per group and for the whole sample. An interaction term was calculated for each baseline neural measure and ARAT score change from baseline to outcome. RESULTS: A total of 288 participants were randomised [mean age 72.2 (standard deviation 12.5) years; mean ARAT score of 25.5 (18.2); n = 283]. For the 240 participants with ARAT measurements at baseline and outcome, the mean change scores were FST + CPT = 9.70 (11.72) and MPT + CPT = 7.90 (9.18). The group difference did not reach statistical significance (least squares mean difference 1.35, 95% confidence interval –1.20 to 3.90; p = 0.298). Correlations between ARAT change scores and baseline neural values ranged from –0.147 (p = 0.385) for whole-sample corticospinal connectivity (n = 37) to 0.199 (p = 0.320) for MPT + CPT resting motor threshold pBB (n = 27). No statistically significant interaction effects were found between baseline neural variables and change in ARAT score. There were no differences between groups in adverse events. LIMITATIONS: The number of participants in the embedded explanatory investigation was lower than expected. CONCLUSIONS: The small difference in upper limb improvement in response to FST and MPT did not reach statistical significance. Baseline neural measures neither correlated with upper limb recovery nor predicted therapy response. FUTURE WORK: Needs to continue investigation of the variability of response to specific physical therapies in people early after stroke. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19090862 and National Research Ethics Service reference number 11/EE/0524. FUNDING: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership

Identification of five fundamental implicit theories underlying cognitive distortions in child abusers : a preliminary study

Qualitative analysis of interviews with 22 child abusers found strong evidence for Ward and Keenan\u27s (1999) proposal that there are five implicit theories in child abusers that account for the majority of their cognitive distortions/thinking errors. These implicit theories are: Child as a sexual being where children are perceived as being able to and wanting to engage in sexual activity with adults and also are not be harmed by such sexual contact; Nature of harm where the offender perceives that sexual activity does not cause harm (and may in fact be beneficial) to the child; Entitlement where the child abuser perceives that he is superior and more important than others: and hence is able to have sex with whoever, and whenever, he wants; Dangerous world where the offender perceives that that others are abusive and rejecting and he must fight to regain control; and Uncontrollable where the offender perceives the world as uncontrollable and hence he believes that circumstances are outside of his control. There was no evidence for any other type of implicit theory. Results of the study also indicated that there was a significant difference in terms of the endorsement of the Dangerous world implicit theory between participants reporting a history of child sexual abuse and those who did not. Offenders against male victims were significantly more likely to endorse the Child as a sexual being and Dangerous world implicit theories compared to men who had offended against female children

Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity

Peer reviewe

Functional strength training versus movement performance therapy for upper limb motor recovery early after stroke: a RCT

Background: Not all stroke survivors respond to the same form of physical therapy in the same way early after stroke. The response is variable and a detailed understanding of the interaction between specific physical therapies and neural structure and function is needed. Objectives: To determine if upper limb recovery is enhanced more by functional strength training (FST) than by movement performance therapy (MPT), to identify the differences in the neural correlates of response to (1) FST and (2) MPT and to determine whether or not pretreatment neural characteristics can predict recovery in response to (1) FST and (2) MPT. Design: Randomised, controlled, observer-blind, multicentre trial with embedded explanatory investigations. An independent facility used computer-generated randomisation for participants’ group allocation. Setting: In-patient rehabilitation, participants’ homes, university movement analysis facilities and NHS or university neuroimaging departments in the UK. Participants: People who were between 2 and 60 days after stroke in the territory of the anterior cerebral circulation, with some voluntary muscle contraction in the more affected upper limb but not full function. Interventions: Routine rehabilitation [conventional physical therapy (CPT)] plus either MPT or FST in equal doses during a 6-week intervention phase. FST was progressive resistive exercise provided during training of functional tasks. MPT was therapist ‘hands-on’ sensory input and guidance for production of smooth and accurate movement. Main outcomes: Action Research Arm Test (ARAT) score for clinical efficacy. Neural measures were made of corticocortical [fractional anisotropy (FA) from corpus callosum midline], corticospinal connectivity (asymmetry of corticospinal tracts FA) and resting motor threshold of paretic biceps brachii (pBB) and extensor carpi radialis muscles (derived from transcranial magnetic stimulation). Analysis: Change in ARAT scores were analysed using analysis of covariance models adjusted for baseline variables and randomisation strata. Correlation coefficients were calculated between change in neural measures and change in ARAT score per group and for the whole sample. An interaction term was calculated for each baseline neural measure and ARAT score change from baseline to outcome. Results: A total of 288 participants were randomised [mean age 72.2 (standard deviation 12.5) years; mean ARAT score of 25.5 (18.2); n = 283]. For the 240 participants with ARAT measurements at baseline and outcome, the mean change scores were FST + CPT = 9.70 (11.72) and MPT + CPT = 7.90 (9.18). The group difference did not reach statistical significance (least squares mean difference 1.35, 95% confidence interval –1.20 to 3.90; p = 0.298). Correlations between ARAT change scores and baseline neural values ranged from –0.147 (p = 0.385) for whole-sample corticospinal connectivity (n = 37) to 0.199 (p = 0.320) for MPT + CPT resting motor threshold pBB (n = 27). No statistically significant interaction effects were found between baseline neural variables and change in ARAT score. There were no differences between groups in adverse events. Limitations: The number of participants in the embedded explanatory investigation was lower than expected. Conclusions: The small difference in upper limb improvement in response to FST and MPT did not reach statistical significance. Baseline neural measures neither correlated with upper limb recovery nor predicted therapy response. Future work: Needs to continue investigation of the variability of response to specific physical therapies in people early after stroke. Trial registration: Current Controlled Trials ISRCTN19090862 and National Research Ethics Service reference number 11/EE/0524. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership