Sigurd Johnsen

The spectral composition of evening light and individual differences in the suppression of melatonin and delay of sleep in humans

Abstract:  The effect of light on circadian rhythms and sleep is mediated by a multi‐component photoreceptive system of rods, cones and melanopsin‐expressing intrinsically photosensitive retinal ganglion cells. The intensity and spectral sensitivity characteristics of this system are to be fully determined. Whether the intensity and spectral composition of light exposure at home in the evening is such that it delays circadian rhythms and sleep also remains to be established. We monitored light exposure at home during 6–8 wk and assessed light effects on sleep and circadian rhythms in the laboratory. Twenty‐two women and men (23.1 ± 4.7 yr) participated in a six‐way, cross‐over design using polychromatic light conditions relevant to the light exposure at home, but with reduced, intermediate or enhanced efficacy with respect to the photopic and melanopsin systems. The evening rise of melatonin, sleepiness and EEG‐assessed sleep onset varied significantly (P < 0.01) across the light conditions, and these effects appeared to be largely mediated by the melanopsin, rather than the photopic system. Moreover, there were individual differences in the sensitivity to the disruptive effect of light on melatonin, which were robust against experimental manipulations (intra‐class correlation = 0.44). The data show that light at home in the evening affects circadian physiology and imply that the spectral composition of artificial light can be modified to minimize this disruptive effect on sleep and circadian rhythms. These findings have implications for our understanding of the contribution of artificial light exposure to sleep and circadian rhythm disorders such as delayed sleep phase disorder.

Randomized, Placebo-Controlled Comparison of Amitriptyline, Duloxetine, and Pregabalin in Patients With Chronic Diabetic Peripheral Neuropathic Pain Impact on pain, polysomnographic sleep, daytime functioning, and quality of life

OBJECTIVE Chronic diabetic peripheral neuropathic pain (DPNP) is difficult to treat, with treatment regimens often inadequate at controlling pain and limited by side effects and drug tolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful DPNP management. The objectives of this study were to compare the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on polysomnographic sleep, daytime functioning, and quality of life in patients with DPNP. RESEARCH DESIGN AND METHODS This was a double-blind, randomized, parallel group investigation of type 1 and 2 diabetic subjects with DPNP. Each treatment group had a single-blind, 8-day, placebo run-in followed by 14 days of lower-dose and 14 days of higher-dose medication. At the end of each dose titration period, subjective pain, sleep, and daytime functioning were assessed during a 2-day residential period. RESULTS All medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group. CONCLUSIONS There was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin. However, there were significant differences in the secondary parameters, which may be of relevance when deciding the optimal treatment for DPNP.

Effect of selenium on markers of risk of pre-eclampsia in UK pregnant women: A randomised, controlled pilot trial

Pre-eclampsia is a serious hypertensive condition of pregnancy associated with high maternal and fetal morbidity and mortality. Se intake or status has been linked to the occurrence of pre-eclampsia by our own work and that of others. We hypothesised that a small increase in the Se intake of UK pregnant women of inadequate Se status would protect against the risk of pre-eclampsia, as assessed by biomarkers of pre-eclampsia. In a double-blind, placebo-controlled, pilot trial, we randomised 230 primiparous pregnant women to Se (60 μg/d, as Se-enriched yeast) or placebo treatment from 12 to 14 weeks of gestation until delivery. Whole-blood Se concentration was measured at baseline and 35 weeks, and plasma selenoprotein P (SEPP1) concentration at 35 weeks. The primary outcome measure of the present study was serum soluble vascular endothelial growth factor receptor-1 (sFlt-1), an anti-angiogenic factor linked with the risk of pre-eclampsia. Other serum/plasma components related to the risk of pre-eclampsia were also measured. Between 12 and 35 weeks, whole-blood Se concentration increased significantly in the Se-treated group but decreased significantly in the placebo group. At 35 weeks, significantly higher concentrations of whole-blood Se and plasma SEPP1 were observed in the Se-treated group than in the placebo group. In line with our hypothesis, the concentration of sFlt-1 was significantly lower at 35 weeks in the Se-treated group than in the placebo group in participants in the lowest quartile of Se status at baseline (P= 0·039). None of the secondary outcome measures was significantly affected by treatment. The present finding that Se supplementation has the potential to reduce the risk of pre-eclampsia in pregnant women of low Se status needs to be validated in an adequately powered trial.

Effects of prehospital 12-lead ECG on processes of care and mortality in acute coronary syndrome: a linked cohort study from the Myocardial Ischaemia National Audit Project

Objective To describe patterns of prehospital ECG (PHECG) use and determine its association with processes and outcomes of care in patients with ST-elevation myocardial infarction (STEMI) and non-STEMI. Methods Population-based linked cohort study of a national myocardial infarction registry. Results 288 990 patients were admitted to hospitals via emergency medical services (EMS) between 1 January 2005 and 31 December 2009. PHECG use increased overall (51% vs 64%, adjusted OR (aOR) 2.17, 95% CI 2.12 to 2.22), and in STEMI (64% vs 79%, aOR 2.34, 95% CI 2.25 to 2.44). Patients who received PHECG were younger (71 years vs 74 years, P<0.0001); and less likely to be female (33.1% vs 40.3%, OR 0.87, 95% CI 0.86 to 0.89), or to have comorbidities than those who did not. For STEMI, reperfusion was more frequent in those having PHECG (83.5% vs 74.4%, p<0.0001). PHECG was associated with more primary percutaneous coronary intervention patients achieving call-to-balloon time <90 min (27.9% vs 21.4%, aOR 1.38, 95% CI 1.24 to 1.54) and more patients who received fibrinolytic therapy achieving door-to-needle time <30 min (90.6% vs 83.7%, aOR 2.13, 95% CI 1.91 to 2.38). Patients with PHECG exhibited significantly lower 30-day mortality rates than those who did not (7.4% vs 8.2%, aOR 0.94, 95% CI 0.91 to 0.96). Conclusions Findings from this national MI registry demonstrate a survival advantage in STEMI and non-STEMI patients when PHECG was used.

Insulin Detemir Reduces Weight Gain as a Result of Reduced Food Intake in Patients With Type 1 Diabetes

OBJECTIVE Insulin detemir lacks the usual propensity for insulin to cause weight gain. We investigated whether this effect was a result of reduced energy intake and/or increased energy expenditure. RESEARCH DESIGN AND METHODS A 32-week, randomized crossover design trial was undertaken in 23 patients with type 1 diabetes. Patients on a basal-bolus regimen (with insulin aspart as the bolus insulin) were randomly assigned to insulin detemir or NPH insulin as a basal insulin for 16 weeks, followed by the other basal insulin for 16 weeks. At the end of each 16-week period, total energy expenditure, resting energy expenditure, diet-induced thermogenesis, activity energy expenditure, energy intake, weight change, glycemic control, hypoglycemic episodes, and hormones that affect satiety and fuel partitioning were measured. RESULTS After 16 weeks, weight change was −0.69 ± 1.85 kg with insulin detemir and +1.7 ± 2.46 kg with NPH insulin (P < 0.001). Total energy intake was significantly less with insulin detemir (2,016 ± 501 kcal/day) than with NPH insulin (2,181 ± 559 kcal/day) (P = 0.026). There was no significant difference in any measure of energy expenditure, HbA1c percentage, or number of hypoglycemic episodes. Leptin was lower and resistin was higher with insulin detemir compared with NPH insulin (P = 0.039, P = 0.047). After the meal, ghrelin and pancreatic polypeptide levels (P = 0.002, P = 0.001) were higher with insulin detemir. CONCLUSIONS The reduced weight gain with insulin detemir compared with NPH insulin is attributed to reduced energy intake rather than increased energy expenditure. This may be mediated by a direct or indirect effect of insulin detemir on the hormones that control satiety.

Next‐day cognition, psychomotor function, and driving‐related skills following nighttime administration of eszopiclone

To evaluate next‐day driving ability, as assessed by brake reaction time (BRT), and cognitive/psychomotor function following nighttime administration of 3 mg eszopiclone.

Acute sleep deprivation: the effects of the AMPAKINE compound CX717 on human cognitive performance, alertness and recovery sleep

AMPA receptor modulation is a potential novel approach to enhance cognitive performance. CX717 is a positive allosteric modulator of the AMPA receptor that has shown efficacy in rodent and primate cognition models. CX717 (100 mg, 300 mg and 1000 mg) and placebo were studied in 16 healthy male volunteers (18–45 years) in a randomized, crossover study. Cognitive function, arousal and recovery sleep (by polysomnography) were assessed during the extended wakefulness protocol. Placebo condition was associated with significant decrements in cognition, particularly at the circadian nadir (between 03:00 and 05:00). Pre-specified primary and secondary analyses (general linear mixed modelling, GLMM) at each separate time point did not reveal consistent improvements in performance or objective alertness with any dose of CX717. Exploratory repeated measures analysis, a method used to take into account the influence of individual differences, demonstrated an improvement in attention-based task performance following the 1000 mg dose. Analysis of the recovery sleep showed that CX717 1000 mg significantly reduced stage 4 and slow-wave sleep (p ≤ 0.05) with evidence of reduced electroencephalogram (EEG) slow-wave and spindle activity. The study suggests that CX717 only at the 1000 mg dose may counteract effects of sleep deprivation on attention-based tasks and that it may interfere with subsequent recovery sleep.

Benzodiazepine-induced reduction in activity mirrors decrements in cognitive and psychomotor performance.

To assess whether actigraphy is sensitive to benzodiazepine‐induced changes in cognitive and psychomotor performance and sleep.

Suppression of the histamine-induced wheal and flare response by fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily and placebo in healthy Japanese volunteers

Summary Background: The effects of the selective H1-receptor antagonist fexofenadine have been widely demonstrated in Western populations; however, to date, limited data comparing the effects of fexofenadine with other antihistamines have been reported in Japanese subjects. Objective: To investigate the effect of fexofenadine and loratadine on the histamine-induced cutaneous wheal and flare response in healthy Japanese volunteers. Methods: Eighteen healthy male and female Japanese volunteers aged 20-53 years were randomized to receive fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily or placebo in a 1-day, three-period, double-blind, crossover study. For each treatment, the wheal and flare response to 100 mg/mL histamine was assessed at baseline and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, 12 and 24 hours post-dose. Blood samples were taken for pharmacokinetic analysis. Results: Fexofenadine produced significantly greater percentage suppression of the overall wheal response compared with placebo and loratadine (43.1% versus 10.0% and 15.2%, respectively; p < 0.001). Similarly, fexofenadine significantly suppressed the overall flare response compared with placebo and loratadine (43.0% versus 3.5% and -8.9%, respectively; p < 0.01). Loratadine was statistically no different from placebo in terms of both overall wheal and flare suppression. Area under the curve analysis for wheal and flare reduction (0-12 hours post-dose) confirmed these findings. For wheal inhibition, fexofenadine had a significantly faster onset of action (defined as time to ≥ 35% inhibition) compared with placebo (p < 0.001) and loratadine (p < 0.01); for flare, fexofenadine had a significantly faster onset of action than loratadine (p < 0.01). Mean maximum inhibition (the mean of the greatest inhibition achieved from baseline for each treatment) for wheal was achieved significantly faster with fexofenadine than loratadine (p < 0.01), and fexofenadine had a significantly longer duration of effect on suppressing wheal and flare compared with placebo and loratadine (p < 0.05 for all). The antihistamine effects of fexofenadine correlated significantly with its Cmax, while loratadine activity did not correlate significantly with its plasma levels. Conclusions: Fexofenadine is a potent suppressor of the histamine-induced wheal and flare response in healthy Japanese volunteers. These results support findings in Caucasian subjects, and confirm that fexofenadine has greater antihistaminergic activity than loratadine in this human model

Prediction of the rate of decline in cognitive function in Alzheimer's disease: a model based on simple demographic data and widely used rating scales.

Dementia represents a significant burden on the resources of both the National Health Service and Social Services as well as a great strain on the caregivers. The ability to predict, at diagnosis, those dementia patients that will deteriorate rapidly would allow a more effective allocation of resources as well as enabling the families and caregivers to make appropriate preparations. We performed discriminant analysis on a placebo data set of over 5,000 patients with Alzheimer’s disease in order to create a model that predicts the rate of cognitive decline in Alzheimer’s disease from simple demographic data and the baseline score on the cognitive subscale of the Alzheimer’s Disease Assessment Scale or the Mini Mental State Examination. This model has 96–97% sensitivity and 92–93% specificity. The potential benefits of this model argue for its validation in a prospective study.