Excessive Muscle Activity Increases Over Time in Idiopathic REM Sleep Behavior Disorder

Study Objectives:

Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by excessive electromyographic (EMG) activity due to dysfunction of the brainstem structures modulating REM sleep atonia. Patients with idiopathic RBD often develop a neurodegenerative disease, such as Parkinson disease, over the years, suggesting progression of an underlying pathologic process in the brainstem. It is unknown if the excessive EMG activity in REM sleep changes over time in patients with idiopathic RBD.

Setting:

University hospital sleep disorders center.

Participants:

Eleven patients with idiopathic RBD who were studied at baseline and after a mean follow-up of 5 years.

Interventions:

NA.

Measurements and Results:

Eleven patients with idiopathic RBD underwent polysomnography (PSG) at the moment of the diagnosis of RBD (PSG1) and after a mean follow-up of 5 years (PSG2). Tonic EMG activity in PSG1 and PSG2 was blindly quantified and compared in the mentalis muscle during REM sleep. Phasic EMG activity in PSG1 and PSG2 was blindly quantified and compared in the mentalis muscle, both biceps brachii, and both anterior tibialis during REM sleep. Patients were 9 men and 2 women with a mean age of 73.2 ± 5.4 years and a mean RBD duration of 10.7 ± 5.3 years at PSG2. In each of the 5 muscles and combination of muscles evaluated, phasic EMG activity was significantly greater in PSG2 than in PSG1 (P < 0.022 in all muscles studied). Mentalis tonic EMG activity increased from 30% to 54% (P = 0.013). No correlation was found between age of the patients and quantity of EMG activity at PSG1 (tonic; P = 0.69, phasic P = 0.89) and at PSG2 (tonic; P = 0.16, phasic; P = 0.42).

Conclusion:

Excessive tonic and phasic EMG activity during REM sleep increases over time in subjects with idiopathic RBD. This finding suggests that, in subjects with idiopathic RBD, there is an underlying progressive pathologic process damaging the brainstem structures that modulate REM sleep.

Citation:

Iranzo A; Ratti PL; Casanova-Molla J; Serradell M; Vilaseca I; Santamaria J. Excessive muscle activity increases over time in idiopathic REM sleep behavior disorder. SLEEP 2009;32(9):1149-1153.     

Phasic muscle activity during REM sleep in infancy-normal maturation and contrastive abnormality in SIDS/ALTE and West syndrome

The generation of phasic muscle activity during REM sleep is regulated by the brainstem. We proposed two sleep indices for phasic muscle activity during REM sleep, and examine their usefulness in assessing normal brainstem maturation and functional brainstem impairment during infancy. One - the dissociation index (DI) - seems to reflect maturation of the tonic inhibitory system functioning during REM sleep, and the other - % body movements in REMs bursts (%BMs-R) - to reflect that of the phasic one. In normal infants, DI showed a gradual, linear and significant increase with age, whereas %BMs-R showed a gradual and significant decrease with age. In infants with sudden infant death syndrome (SIDS) and one who had experienced apparent life-threatening events (ALTE), the DI values were lower than those in controls, although %BMs-R values were identical in the controls. In contrast, DI was variable in infants with West syndrome (WS), while %BMs-R exceeded normal values. The tonic inhibitory system seemed to be specifically involved in SIDS and ALTE, but the phasic inhibitory one in WS. Anatomical differences between these inhibitory systems are also discussed.     

Auditory Evoked Potential in Stage 2 and REM Sleep During a 30-Day Exposure to Tone Pulses

Ten subjects were exposed to 3.5K Hz tone pulses of 660 msec duration, presented 24-hr-per-day for 30 days. The interstimulus interval was 22 sec. There were 10 days each at 80, 85, and 90 dB in that order. The average evoked potential (AEP) at C₃ referenced to linked mastoids was obtained from contiguous stage 2 and REM sleep segments on the first, second, and last recorded nights of tone-pulse exposure. The AEP was consistently larger in stage 2 than in REM sleep. In both stage 2 and REM sleep, AEP amplitude on the second recorded night bore no consistent relationship to first or last recorded night AEPs. Only the N2–P3 amplitude yielded consistent decreases, with 9 of 10 subjects in both stage 2 and REM sleep having smaller N2–P3 amplitudes on the last than on the first recorded night. There were no changes in latency of any component. During sleep there is little, if any, habituation of the auditory AEP during long-duration exposures to nonmeaningful stimuli, and certainly no extinction of the AEP under these conditions.     

Quantitative electroencephalography during rapid eye movement (REM) and non‐REM sleep in combat‐exposed veterans with and without post‐traumatic stress disorder

Sleep disturbances are a hallmark feature of post‐traumatic stress disorder (PTSD), and associated with poor clinical outcomes. Few studies have examined sleep quantitative electroencephalography (qEEG), a technique able to detect subtle differences that polysomnography does not capture. We hypothesized that greater high‐frequency qEEG would reflect ‘hyperarousal’ in combat veterans with PTSD (n = 16) compared to veterans without PTSD (n = 13). EEG power in traditional EEG frequency bands was computed for artifact‐free sleep epochs across an entire night. Correlations were performed between qEEG and ratings of PTSD symptoms and combat exposure. The groups did not differ significantly in whole‐night qEEG measures for either rapid eye movement (REM) or non‐REM (NREM) sleep. Non‐significant medium effect sizes suggest less REM beta (opposite to our hypothesis), less REM and NREM sigma and more NREM gamma in combat veterans with PTSD. Positive correlations were found between combat exposure and NREM beta (PTSD group only), and REM and NREM sigma (non‐PTSD group only). Results did not support global hyperarousal in PTSD as indexed by increased beta qEEG activity. The correlation of sigma activity with combat exposure in those without PTSD and the non‐significant trend towards less sigma activity during both REM and NREM sleep in combat veterans with PTSD suggests that differential information processing during sleep may characterize combat‐exposed military veterans with and without PTSD.     

Airway Dilator Muscle Activity and Lung Volume During Stable Breathing in Obstructive Sleep Apnea

Study Objectives:

Many patients with obstructive sleep apnea (OSA) have spontaneous periods of stable flow limited breathing during sleep without respiratory events or arousals. In addition, OSA is often more severe during REM than NREM and more severe during stage 2 than slow wave sleep (SWS). The physiological mechanisms for these observations are unknown. Thus we aimed to determine whether the activity of two upper airway dilator muscles (genioglossus and tensor palatini) or end-expiratory lung volume (EELV) differ between (1) spontaneously occurring stable and cyclical breathing and (2) different sleep stages in OSA.

Design:

Physiologic observation.

Setting:

Sleep physiology laboratory.

Study Participants:

15 OSA patients with documented periods of spontaneous stable breathing.

Intervention:

Subjects were instrumented with intramuscular electrodes for genioglossus and tensor palatini electromyograms (EMG_GG and EMG_TP), chest and abdominal magnetometers (EELV measurement), an epiglottic pressure catheter (respiratory effort), and a mask and pneumotachograph (airflow/ventilation). Patients slept supine overnight without CPAP.

Measurements and Results:

Peak and Tonic EMG_GG were significantly lower during cyclical (85.4 ± 2.7 and 94.6 ± 4.7 % total activity) than stable breathing (109.4 ± 0.4 and 103 ± 0.8 % total activity, respectively). During respiratory events in REM, tonic EMG_GG activity was lower than during respiratory events in stage 2 (71.9 ± 5.1 and 119.6 ± 5.6 % total activity). EMG_GG did not differ between stable stage 2 and stable SWS (98.9 ± 3.2 versus 109.7 ± 4.4 % total activity), nor did EMG_TP or EELV differ in any breathing condition/sleep stage.

Conclusions:

Increased genioglossus muscle tone is associated with spontaneous periods of stable flow limited breathing in the OSA subjects studied. Reductions in genioglossus activity during REM may explain the higher severity of OSA in that stage. Increased lung volume and tensor palatini activity do not appear to be major mechanisms enabling spontaneous stable flow limited breathing periods.

Citation:

Jordan AS; White DP; Lo YL; Wellman A; Eckert DJ; Yim-Yeh S; Eikermann M; Smith SA; Stevenson KE; Malhotra A. Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. SLEEP 2009;32(3):361–368.     

Sleep architecture as correlate and predictor of symptoms and impairment in inter‐episode bipolar disorder: taking on the challenge of medication effects

This study was designed to clarify the association between inter‐episode bipolar disorder (BD) and sleep architecture. Participants completed a baseline symptom and sleep assessment and, 3 months later, an assessment of symptoms and impairment. The effects of psychiatric medications on sleep architecture were also considered. Participants included 22 adults with BD I or II (inter‐episode) and 22 non‐psychiatric controls. The sleep assessment was conducted at the Sleep and Psychological Disorders Laboratory at the University of California, Berkeley. Follow‐up assessments 3 months later were conducted over the phone. Results indicate that, at the sleep assessment, BD participants exhibited greater rapid eye movement sleep (REM) density than control participants with no other group differences in sleep architecture. Sleep architecture was not correlated with concurrent mood symptoms in either group. In the BD group, duration of the first REM period and slow‐wave sleep (SWS) amount were positively correlated with manic symptoms and impairment at 3 months, while REM density was positively correlated with depressive symptoms and impairment at 3 months. The amount of Stage 2 sleep was negatively correlated with manic symptoms and impairment at 3 months. In contrast, for the control group, REM density was negatively correlated with impairment at 3 months. SWS and Stage 2 sleep were not correlated with symptoms or impairment. Study findings suggest that inter‐episode REM sleep, SWS and Stage 2 sleep are correlated with future manic and depressive symptoms and impairment in BD. This is consistent with the proposition that sleep architecture may be a mechanism of illness maintenance in BD.     

Sleep deprivation has a neuroprotective role in a traumatic brain injury of the rat

During the process of a brain injury, responses to produce damage and cell death are activated, but self-protective responses that attempt to maintain the integrity and functionality of the brain are also activated. We have previously reported that the recovery from a traumatic brain injury (TBI) is better in rats if it occurs during the dark phase of the diurnal cycle when rats are in the waking period. This suggests that wakefulness causes a neuroprotective role in this type of injury. Here we report that 24 h of total sleep deprivation after a TBI reduces the morphological damage and enhances the recovery of the rats, as seen on a neurobiological scale.     

Altered intestinal microflora and barrier injury in severe acute pancreatitis can be changed by zinc

To investigate the effect of zinc (Zn) supplementation on intestinal microflora changes and bacterial translocation in rats with severe acute pancreatitis (SAP), the rats were divided into the sham surgery (SS), SAP, SS + Zn, and SAP + Zn groups. Saline (0.1 mL/100g) and 5% sodium taurocholate were injected into the pancreaticobiliary duct of the rats in the SS and SAP + Zn groups, respectively. Intraperitoneal injection of 5 mg/kg Zn was performed immediately after injecting saline or 5% sodium taurocholate into the rats in both groups. Serum amylase and Zn levels, plasma endogenous endotoxin, intestinal permeability, and the positive rate of intestinal bacterial translocation were detected, haematoxylin and eosin (H&E) staining was performed, and the pancreatic tissue scores were calculated for each group. In addition, immunohistochemical (IHC) staining was performed to evaluate the expression of IL-1β and TNF-α. Real-time fluorescence quantitative PCR was used to quantify the gene copy numbers of Escherichia, Bifidobacterium, and Lactobacillus in the cecum. The levels of amylase and plasma endotoxin in the SAP group were significantly higher than those in the SS and SS + Zn groups. Intestinal mucosal permeability and intestinal bacterial translocation in the liver, pancreas, and mesenteric lymph nodes were increased in the SAP group. However, the levels of amylase and plasma endotoxin were decreased as a result of zinc supplementation in the SAP group. The expression of IL-1β and TNF-α was also reduced to a greater degree in the SAP + Zn group than in the SAP group. Moreover, alleviated intestinal mucosal permeability and intestinal bacterial translocation in the liver, pancreas, and mesenteric lymph nodes were found in the SAP + Zn group. The results of real-time quantitative PCR showed that the gene copy number of Escherichia increased with time, and the gene copy numbers of Lactobacillus and Bifidobacterium decreased over time. Zn supplementation prevented the release of TNF-α and IL-1β, alleviated intestinal permeability and endotoxemia, reduced bacterial translocation, and inhibited changes in pathogenic intestinal flora in rats with SAP.     

Tumour necrosis factor gene polymorphisms and migraine in Greek children

Introduction

Migraine is considered to be a multifactorial, complex disease. Various genetic and environmental factors contribute to the manifestation of this disease. The aim of this study was to determine whether polymorphisms in the tumour necrosis factor (TNF) region are associated with the risk of migraine. We examined the association between 6 single nucleotide polymorphisms in the coding regions of TNF-α and TNF-β genes and migraine.

Material and methods

The study included two groups of children (group A and group B). Group A consisted of 103 unrelated children with typical migraine without aura 5–14 years of age. Group B (control group) consisted of 178 unrelated healthy children. The diagnosis of migraine was, in all patients, made according to the International Classification of Headache Disorders (ICHD II).

Results

According to our results positive family history was present in 62.2% of patients of group A. No significant differences were found in the frequencies of genotypes or alleles between patients and controls. The non-parametric analyses of variance showed no significant differences in the age at onset between genotype groups of the TNF-α and TNF-β gene polymorphisms. Comparison of genotype frequencies between boys and girls in affected patients and control individuals were not significantly different (p = 0.089, p =0.073 respectively). The distribution of TNF polymorphisms was not associated with the presence of family history of migraine in patients.

Conclusions

Our data indicate that TNF-α and TNF-β gene polymorphisms are not a significant risk factor for migraine without aura in Greek children.     

Cytokine TGF-β1, TNF-α, IFN-γ and IL‐6 Gene Polymorphisms and Localization of Premalignant Gastric Lesions in Immunohistochemically H. pylori-negative Patients

Background: Cytokines and their gene variants are proven to play a role in pathogenic gastritis and carcinogenesis. The study assesses associations of the cytokine gene polymorphisms with extension of atrophic gastritis/intestinal metaplasia (AGIM) in patients without Helicobacter pylori infection on immunohistochemistry study.Methods: 224 adult consecutive patients undergoing an upper digestive endoscopy were included and grouped according to localization of AGIM: 37 patients with antrum-limited AGIM, 21 corpus-limited AGIM, 15 extended-AGIM (antrum and corpus) and 151 patients had no AGIM. Medical records of the patients were checked and a structured direct interview was applied in order to collect clinical data, including digestive symptoms. In all cases, IFN-γ +874T>A, TGF-β1 +869T>C, TNF‐α-308G>A and -238G>A, and IL-6 -174C>G polymorphisms were genotyped.Results: The mean age was significantly higher in the AGIM group, while the comorbidies were similar among patients with different localization of lesions or in patients without AGIM. There were no significant differences in digestive symptoms, nor in the consumption of non-steroidal anti-inflammatory drugs or proton pump inhibitor with the different extensions of AGIM. There was a significant association between oral anticoagulant consumption and localization of AGIM (P = 0.042), frequency being higher among patients with corpus-limited AGIM than those with no AGIM (P = 0.007, adjusted P = 0.041). TGF-β1 +869T>C was less frequent among patients with corpus-limited AGIM (n=7, 33.3%) and extended AGIM (n=5, 33.3%) than in antrum-limited AGIM (n=25, 67.6%). There were no other significant differences regarding variant and wild genotype frequencies of IFN-γ +874T>A (86.5%, 81.0%, 86.7%, p=0.814), TNF‐α-308G>A (35.1%, 28.6%, 53.3%, p=0.48) and IL-6 -174C>G (70.3%. 61.9%, 73.3% p=0.656) among patients with antrum-limited, corpus-limited or extended AGIM. TGF-β1 +869T>C was associated with a decreased risk for corpus-affected AGIM (adjusted odds ratio: 0.42, 95% confidence interval: 0.19-0.93, P = 0.032). The dominant inheritance models no revealed significant association for IFN-γ +874T>A, TNF‐α-308G>A and IL-6 -174C>G gene polymorphism and the risk of localization of AGIM.Conclusion: TGF-β1 +869T>C gene polymorphism is associated with a decreased risk for corporeal localization of premalignant lesions, while IFN-γ +874T>A, TNF-α-308G>A and IL-6 -174C>G are not associated with the risk for AGIM in immunohistochemically H. pylori negative patients.     

Plasma elafin,cathelicidin, and α-defensins are increased in paediatric inflammatory Crohn’s disease and reflect disease location

IntroductionThe aim of our study was to assess antimicrobial peptides in children with Crohn’s disease (CD).MethodsPlasma elafin, cathelicidin, and α- and β-defensins were assessed in 35 children with CD using immunoassays. Phenotype and location of CD were assessed based on the results of endoscopic and radiological studies.ResultsWe found increased elafin, cathelicidin, and α-defensins in children with inflammatory phenotype as compared to stricturing and penetrating phenotypes of CD. Additionally, we found increased elafin and cathelicidin in colonic location and α-defensins in ileal CD locations.ConclusionsAssessing antimicrobial peptides may be helpful in estimating of phenotype and location of CD lesions.     

Influence of interleukin-1 beta gene polymorphisms on the risk of myocardial infarction and ischemic stroke at young age in vivo and in vitro

In this study, by using vivo and vitro model, we assessed whether interleukin (IL)-1beta gene polymorphisms influence on the risk of myocardial infarction and ischemic stroke at young age. 147 patients (age < 45 years) with a first episode of MI and 56 patients (age < 45 years) with first-ever cerebral ischemia consecutively were admitted to this study from the Department of Chinese PLA General Hospital. Meanwhile, 91 normal volunteers without MI or stroke were deeded as control group and greed to give blood samples for DNA analysis and biochemical measurements by written informed consent. IL-1β-511 wild type (WT, CC) and SNP (TT) were established and transfected into Rat myocardial H9c2 cell and Mouse brain endothelial bEND.3 cells. In Young Age MI or stroke patients, the IL-1β levels of patients with 511CC are higher than that of patients with 511TT. In our study, NF-κB miRNA, iNOS activity, NF-κB, iNOS and Bax protein expressions of MI-induced H9c2 cell or stroke-induced bEND.3 cells in IL-1β-511TT group were lower than those of IL-1β-511CC. Additionally, the protein expression of MMP-2 of MI-induced H9c2 cell or stroke-induced bEND.3 cells in IL-1β-511TT group were higher than that of IL-1β 511CC group. In conclusion, our data indicate that IL-1β-511TT/CC influence on the risk of myocardial infarction and ischemic stroke at young age through NF-κB, iNOS, MMP-2 and Bax.     

IL‐1β/IL‐1R1 signaling induced by intranasal lipopolysaccharide infusion regulates alpha‐Synuclein pathology in the olfactory bulb,substantia nigra and striatum

Olfactory dysfunction is one of the early symptoms seen in Parkinson’s disease (PD). However, the mechanisms underlying olfactory pathology that impacts PD disease progression and post‐mortem appearance of alpha‐Synuclein (α‐Syn) inclusions in and beyond olfactory bulb in PD remain unclear. It has been suggested that environmental toxins inhaled through the nose can induce inflammation in the olfactory bulb (OB), where Lewy body (LB) is the first to be found, and then, spread to related brain regions. We hypothesize that OB inflammation triggers local α‐Syn pathology and promotes its spreading to cause PD. In this study, we evaluated this hypothesis by intranasal infusion of lipopolysaccharides (LPS) to induce OB inflammation in mice and examined cytokines expression and PD‐like pathology. We found intranasal LPS‐induced microglia activation, inflammatory cytokine expression and α‐Syn overexpression and aggregation in the OB via interleukin‐1β (IL‐1β)/IL‐1 receptor type I (IL‐1R1) dependent signaling. In addition, an aberrant form of α‐Syn, the phosphorylated serine 129 α‐Syn (pS129 α‐Syn), was found in the OB, substantia nigra (SN) and striatum 6 weeks after the LPS treatment. Moreover, 6 weeks after the LPS treatment, mice showed reduced SN tyrosine hydroxylase, decreased striatal dopaminergic metabolites and PD‐like behaviors. These changes were blunted in IL‐1R1 deficient mice. Further studies found the LPS treatment inhibited IL‐1R1‐dependent autophagy in the OB. These results suggest that IL‐1β/IL‐1R1 signaling in OB play a vital role in the induction and propagation of aberrant α‐Syn, which may ultimately trigger PD pathology.     

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent α-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.     

α,β-Amyrin prevents steatosis and insulin resistance in a high-fat diet-induced mouse model of NAFLD via the AMPK-mTORC1-SREBP1 signaling mechanism

Nonalcoholic fatty liver disease (NAFLD), characterized by hepatosteatosis and steatohepatitis, is intrinsically related to obesity. Our previous study reported on the anti-obese activity of α,β-amyrin (AMY), a pentacyclic triterpene isolated from Protium heptaphyllum. This study investigated its ability to prevent fatty liver and the underlying mechanism using the mouse model of NAFLD. NAFLD was induced in male Swiss mice fed a high fat diet (HFD) for 15 weeks. The controls were fed a normal chow diet (ND). The mice were simultaneously treated with AMY at 10 and 20 mg/kg or fenofibrate at 50 mg/kg. Lipid levels along with metabolic and inflammatory parameters were assessed in liver and serum. The liver sections were histologically examined using H&E staining. RT-qPCR and western blotting assays were performed to analyze signaling mechanisms. Mice fed HFD developed severe hepatic steatosis with elevated triglycerides and lipid droplets compared with ND controls. This was associated with a decrease in AMP-activated protein kinase (AMPK) activity, an increase of mechanistic target of rapamycin complex 1 (mTORC1) signaling, and enhanced sterol regulatory element binding protein 1 (SREBP1) expression, which have roles in lipogenesis, inhibition of lipolysis, and inflammatory response. AMY treatment reversed these signaling activities and decreased the severity of hepatic steatosis and inflammatory response, evidenced by serum and liver parameters as well as histological findings. AMY-induced reduction in hepatic steatosis seemed to involve AMPK-mTORC1-SREBP1 signaling pathways, which supported its beneficial role in the prevention and treatment of NAFLD.     

Caveolin-1 promotes tumor cell proliferation and vasculogenic mimicry formation in human glioma

Vasculogenic mimicry (VM) plays an important role in human glioma progression and resistance to antiangiogenic therapy as a compensatory neovascularization mechanism in malignant tumors. Caveolin-1 (Cav-1) has been found to contribute to VM formation. However, it remains largely unknown whether Cav-1 expression correlates with VM in glioma. In this study, we examined CAV-1 expression levels and VM in human glioma cell lines and in 94 human gliomas with different grades of malignancy, and present Cox proportional hazards regression. The molecular role of Cav-1 in glioma cells was investigated using quantitative polymerase chain reaction (qRT-PCR) assays, western blotting, CCK-8 assays, and tubule formation assays. Cav-1 expression and VM formation were positively correlated with each other and both were closely associated with glioma development and progression as evidenced by the presence of cystic tumor, shortened survival time, and advanced-stage glioma in glioma patients with Cav-1 overexpression/increased VM formation. Cav-1 promoted U251 glioma cell proliferation and VM formation in a Matrigel-based 3D culture model. VM-associated factors including hypoxia-inducible factor 1α (HIF-1α) and p-Akt was significantly elevated by Cav-1 overexpression but suppressed by siCav-1 in U251 cells. Collectively, our study identified Cav-1 as an important regulator of glioma cell proliferation and VM formation, contributing to glioma development and progression.     

Sleep and neurocognitive functioning in children with eczema

Sleep disruption in childhood is associated with clearly defined deficits in neurocognition and behaviour. Childhood eczema is also a potent cause of sleep disruption though it is unknown whether it too results in neurocognitive deficits. To test this hypothesis, neurocognitive (WISC-IV), parental-reported sleep quality (Sleep Disturbance Scale of Children (SDSC)) and overnight polysomnographic (PSG) data were collected in 21 children with eczema and 20 healthy controls (age range 6–16 years). Children with eczema had worse sleep quality on both PSG (notably increased nocturnal wakefulness, a higher number of stage shifts and a longer latency to REM onset) and parental report. In addition, they demonstrated significant neurocognitive deficits (especially verbal comprehension, perceptual reasoning and to a lesser extent working memory) with a composite Full Scale IQ 16 points lower than controls. Parental reported sleep problems but not PSG parameters were correlated with reduced neurocognitive performance. However, hierarchical regression analyses revealed that eczema status was predictive while sleep fragmentation (parental or PSG) was not predictive of neurocognitive performance. As this is the first study to systematically examine neurocognitive functioning in children with eczema and given the finding of significant deficits it merits replication especially given the prevalence of the condition. The unanswered question is whether these cognitive deficits normalise with effective eczema treatment and if this is mediated by improvements in sleep architecture.     

Neurosteroid Biosynthetic Pathway Changes in Substantia Nigra and Caudate Nucleus in Parkinson's Disease

There is emerging evidence from animal studies for a neuroprotective role of sex steroids in neurodegenerative diseases, but studies in human brain are lacking. We have carried out an extensive study of the neurosteroid biosynthetic pathways in substantia nigra (SN), caudate nucleus (CN) and putamen (PU) of 7 Parkinson''s disease (PD) patients and 7 matched controls. The mRNA levels of 37 genes including neurosteroid biosynthetic enzymes, hormone receptors and the neurosteroid‐modulated γ‐amino‐butyric acid ‐A (GABA‐A) receptor subunits were analyzed by quantitative PCR (qPCR). In the SN, we found downregulation of 5α‐reductase type 1 (5α‐R1), sulfotransferase 2B1 (SULT2B1) and some GABA‐A receptor subunits (α4, β1) while in the CN, upregulation of 3α‐hydroxysteroid dehydrogenase type 3 (3α‐HSD3) and α4 GABA‐A receptor subunit (22‐fold) was observed. No significant differences were found in the PU. These data imply an involvement of pregnane steroids and changes in GABAergic neurotransmission in the neurodegenerative process and suggest that neurosteroids may deserve further investigation as potential therapeutic agents in PD.     

The kinase p38α functions in dendritic cells to regulate Th2-cell differentiation and allergic inflammation

Dendritic cells (DCs) play a critical role in controlling T helper 2 (Th2) cell-dependent diseases, but the signaling mechanism that triggers this function is not fully understood. We showed that p38α activity in DCs was decreased upon HDM stimulation and dynamically regulated by both extrinsic signals and Th2-instructive cytokines. p38α-specific deletion in cDC1s but not in cDC2s or macrophages promoted Th2 responses under HDM stimulation. Further study showed that p38α in cDC1s regulated Th2-cell differentiation by modulating the MK2−c-FOS−IL-12 axis. Importantly, crosstalk between p38α-dependent DCs and Th2 cells occurred during the sensitization phase, not the effector phase, and was conserved between mice and humans. Our results identify p38α signaling as a central pathway in DCs that integrates allergic and parasitic instructive signals with Th2-instructive cytokines from the microenvironment to regulate Th2-cell differentiation and function, and this finding may offer a novel strategy for the treatment of allergic diseases and parasitic infection.