Transcutaneous electrical stimulation in obstructive sleep apnoea: current developments and concepts of the TESLA-home programme.

PURPOSE OF REVIEW: Obstructive sleep apnoea (OSA) is a highly prevalent condition affecting about 1 billion people worldwide. The first line therapy for most patients with OSA is continuous positive airway pressure (CPAP) therapy. However, there are significant limitations with long-term adherence to CPAP therapy, which may be as low as 30-60%. RECENT FINDING: Electrical stimulation of the hypoglossal nerve has been studied in recent years. It achieves upper airway patency by causing a contraction of the genioglossus muscle, the strongest dilator of the upper airway, and by maintaining its neuromuscular tone in the asleep patient with OSA. Electrical stimulation can be delivered invasively, hypoglossal nerve stimulation (HNS), and noninvasively, transcutaneous electrical stimulation in OSA (TESLA). However, randomised controlled trials, the STAR and the TESLA trial, have provided promising results on efficacy and safety of the methods. SUMMARY: Patient and public involvement underlines the interest in TESLA and HNS and highlights the need to provide non-CPAP therapeutic options to those who may find it difficult to cope with first line therapies. The relatively low costs and the favourable safety profile of the TESLA approach provide the chance to offer this treatment to patients with OSA following further development of the evidence.

Characterising the unity and diversity of executive functions in a within-subject fMRI study.

Behavioural studies investigating the relationship between Executive Functions (EFs) demonstrated evidence that different EFs are correlated with each other, but also that they are partially independent from each other. Neuroimaging studies investigating such an interrelationship with respect to the functional neuroanatomical correlates are sparse and have revealed inconsistent findings. To address this question, we created four tasks derived from the same basic paradigm, one each for updating, inhibition, switching, and dual-tasking. We assessed brain activity through functional magnetic resonance imaging (fMRI) in twenty-nine participants while they performed the four EF tasks plus control tasks. For the analysis, we first determined the neural correlates of each EF by subtracting the respective control tasks from the EF tasks. We tested for unity in EF tasks by calculating the conjunction across these four "EF-minus-control" contrasts. This identified common areas including left lateral frontal cortices [middle and superior frontal gyrus (BA 6)], medial frontal cortices (BA 8) as well as parietal cortices [inferior and superior parietal lobules (BA 39/7)]. We also observed areas activated by two or three EF tasks only, such as frontoparietal areas [e.g., SFG (BA8) right inferior parietal lobule (BA 40), left precuneus (BA 7)], and subcortical regions [bilateral thalamus (BA 50)]. Finally, we found areas uniquely activated for updating [bilateral MFG (BA 8) and left supramarginal gyrus (BA 39)], inhibition (left IFG BA 46), and dual-tasking [left postcentral gyrus (BA 40)]. These results demonstrate that the functional neuroanatomical correlates of the four investigated EFs show unity as well as diversity.

Smartphone mindfulness meditation training reduces Pro-inflammatory gene expression in stressed adults: A randomized controlled trial.

Mindfulness meditation training has been shown to be an effective stress reduction strategy, but less is known about its immunoregulatory impact. In a randomized controlled trial of stressed customer service workers, the present study tested whether a 30-day smartphone-based mindfulness meditation training program (compared to a problem-solving control program) would affect pro-inflammatory gene expression. Both interventions led to reductions in stress levels, but there was no difference in stress reduction between conditions. Consistent with predictions, mindfulness training reduced activity of the pro-inflammatory NF-κB transcription control pathway compared to the active control. These results suggest that mindfulness training may be a particularly effective method for improving immune cell gene expression in stressful work environments.

Three-year follow up of using combination therapy with fresh-frozen plasma and iron chelation in a patient with acaeruloplasminemia.

Acaeruloplasminemia is a rare autosomal recessive condition caused by inactivating mutations of the CP gene encoding caeruloplasmin (ferroxidase). Caeruloplasmin is a copper-containing plasma ferroxidase enzyme with a key role in facilitating cellular iron efflux. We describe a case of a patient with acaeruloplasminemia, confirmed by genetic analysis, treated with combination therapy of monthly fresh-frozen plasma (FFP) or Octaplas and iron chelation over a 3-year period. This 19-year-old male was diagnosed at the age of 14 after developing issues with social interaction at school prompting investigation. Prior to this, he had been well with a normal childhood. He was found to have an iron deficient picture with a paradoxically high ferritin, with low serum copper and undetectable caeruloplasmin. Genetic testing identified a homozygous splicing mutation, c.(1713 + delG);(c.1713 + delG), in intron 9 of the caeruloplasmin gene. Ferriscan showed a high liver iron concentration of 5.3 mg/g dry tissue (0.17-1.8). Brain and cardiac T2-weighted magnetic resonance (MR) imaging did not detect iron deposition of the brain or heart respectively. Treatment with monthly Octaplas infusion was commenced alongside deferasirox (540 mg o.d.) in an attempt to increase caeruloplasmin levels and reduce iron overload, respectively. After 3 years of treatment, there was biochemical improvement with a reduction in ferritin from 1084 (12-250) to 457 µg/L, ALT from 87 (<50) to 34 U/L together with improvement in his microcytic anaemia. No significant adverse events occurred. This case report adds further evidence of treatment efficacy and safety of combined FFP and iron chelation therapy in acaeruloplasminemia.

NREM parasomnias: a treatment approach based upon a retrospective case series of 512 patients.

BACKGROUND: Non-REM parasomnias are not uncommon conditions in the general population. Current treatment options are based on small case series and reports. In this study, we aimed to present the clinical experience from a large cohort of patients. PATIENTS: Five hundred and twelve patients with Non-REM parasomnia or parasomnia overlap disorder (POD), who had undergone a video polysomnography and were exposed to treatment, were retrospectively identified. Treatment outcome was assessed based on patients' reports, and treatment approach on a locally accepted hierarchy of interventions. RESULTS: Forty percent of patients were diagnosed with sleepwalking, 23.8% with mixed-phenotype and 10% with POD. Ultimately, 97.2% reported adequate control of their symptoms. Moreover, 60.1% were treated with pharmacotherapy and 32.0% without, consistent across all phenotypes (p = 0.09). Benzodiazepines were the most common drugs prescribed (47.1%, p < 0.05). In the end, 37.7% of our patients were receiving a benzodiazepine as part of their successful treatment, 11.7% an antidepressant, 9.2% a z-drug, and 10.7% melatonin. Finally, 13.2%, 12.1%, and 5.8% of our patients reported good control of their symptoms with sleep hygiene, management of sleep-disordered breathing, and psychological interventions (cognitive behavioral therapy [CBT] or mindfulness-based stress reduction [MBSR]), as monotherapy, respectively. CONCLUSION: The treatment approach to effective treatment of the patients with Non-REM parasomnias or POD offering first sleep hygiene advice, next treatment of concurrent sleep disorders and management of other priming factors like stress and anxiety, and lastly pharmacotherapy for Non-REM parasomnia is supported by our results. Non pharmacological interventions were effective in one third of our patients, and CBT/MBSR and melatonin appeared promising new treatments.

Nicotinamide's Ups and Downs: Consequences for Fertility, Development, Longevity and Diseases of Poverty and Affluence.

To further explore the role of dietary nicotinamide in both brain development and diseases, particularly those of ageing. Articles cover neurodegenerative disease and cancer. Also discussed are the effects of nicotinamide, contained in meat and supplements and derived from symbionts, on the major transitions of disease and fertility from ancient times up to the present day. A key role for the tryptophan - NAD 'de novo' and immune tolerance pathway are discussed at length in the context of fertility and longevity and the transitions from immune paresis to Treg-mediated immune tolerance and then finally to intolerance and their associated diseases. Abstract: Nicotinamide in human evolution increased cognitive power in a positive feedback loop originally involving hunting. As the precursor to metabolic master molecule NAD it is, as vitamin B3, vital for health. Paradoxically, a lower dose on a diverse plant then cereal-based diet fuelled population booms from the Mesolithic onwards, by upping immune tolerance of the foetus. Increased tolerance of risky symbionts, whether in the gut or TB, that excrete nicotinamide co-evolved as buffers for when diet was inadequate. High biological fertility, despite disease trade-offs, avoided the extinction of Homo sapiens and heralded the dawn of a conscious, creative, and pro-fertility culture. Nicotinamide equity now would stabilise populations and prevent NAD-based diseases of poverty and affluence.

Nicotinamide alone accelerates the conversion of mouse embryonic stem cells into mature neuronal populations.

INTRODUCTION: Vitamin B3 has been shown to play an important role during embryogenesis. Specifically, there is growing evidence that nicotinamide, the biologically active form of vitamin B3, plays a critical role as a morphogen in the differentiation of stem cells to mature cell phenotypes, including those of the central nervous system (CNS). Detailed knowledge of the action of small molecules during neuronal differentiation is not only critical for uncovering mechanisms underlying lineage-specification, but also to establish more effective differentiation protocols to obtain clinically relevant cells for regenerative therapies for neurodegenerative conditions such as Huntington's disease (HD). Thus, this study aimed to investigate the potential of nicotinamide to promote the conversion of stem cells to mature CNS neurons. METHODS: Nicotinamide was applied to differentiating mouse embryonic stem cells (mESC; Sox1GFP knock-in 46C cell line) during their conversion towards a neural fate. Cells were assessed for changes in their proliferation, differentiation and maturation; using immunocytochemistry and morphometric analysis methods. RESULTS: Results presented indicate that 10 mM nicotinamide, when added at the initial stages of differentiation, promoted accelerated progression of ESCs to a neural lineage in adherent monolayer cultures. By 14 days in vitro (DIV), early exposure to nicotinamide was shown to increase the numbers of differentiated ßIII-tubulin-positive neurons. Nicotinamide decreased the proportion of pluripotent stem cells, concomitantly increasing numbers of neural progenitors at 4 DIV. These progenitors then underwent rapid conversion to neurons, observed by a reduction in Sox 1 expression and decreased numbers of neural progenitors in the cultures at 14 DIV. Furthermore, GABAergic neurons generated in the presence of nicotinamide showed increased maturity and complexity of neurites at 14 DIV. Therefore, addition of nicotinamide alone caused an accelerated passage of pluripotent cells through lineage specification and further to non-dividing mature neurons. CONCLUSIONS: Our results show that, within an optimal dose range, nicotinamide is able to singly and selectively direct the conversion of embryonic stem cells to mature neurons, and therefore may be a critical factor for normal brain development, thus supporting previous evidence of the fundamental role of vitamins and their metabolites during early CNS development. In addition, nicotinamide may offer a simple effective supplement to enhance the conversion of stem cells to clinically relevant neurons.

Preliminary fMRI findings concerning the influence of 5-HTP on food selection.

OBJECTIVE: This functional magnetic resonance imaging study was designed to observe how physiological brain states can alter food preferences. A primary goal was to observe food-sensitive regions and moreover examine whether 5-HTP intake would activate areas which have been associated with appetite suppression, anorexia, satiety, and weight loss. METHODS AND PROCEDURE: Fourteen healthy male and female participants took part in the study, of which half of them received the supplement 5-HTP and the rest vitamin C (control) on an empty stomach. During the scanning session, they passively observed food (high calories, proteins, carbohydrates) and nonfood movie stimuli. RESULTS: Within the 5-HTP group, a comparison of food and nonfood stimuli showed significant responses that included the limbic system, the basal ganglia, and the prefrontal, temporal, and parietal cortices. For the vitamin C group, activity was mainly located in temporal and occipital regions. Compared to the vitamin C group, the 5-HTP group in response to food showed increased activation on the VMPFC, the DLPFC, limbic, and temporal regions. For the 5-HTP group, activity in response to food high in protein content compared to food high in calories and carbohydrates was located in the limbic system and the right caudomedial OFC, whereas for the vitamin C group, activity was mainly located at the inferior parietal lobes, the anterior cingulate gyri, and the left ventrolateral OFC. Greater responses to carbohydrates and high calorie stimuli in the vitamin C group were located at the right temporal gyrus, the occipital gyrus, the right VLPFC, whereas for the 5-HTP group, activity was observed at the left VMPFC, the parahippocampal gyrus bilaterally, the occipital lobe, and middle temporal gyri. DISCUSSION: In line with the hypotheses, 5-HTP triggered cortical responses associated with healthy body weight as well as cerebral preferences for protein-rich stimuli. The brain's activity is altered by macronutrients rich or deprived in the body. By reading the organisms physiological states and combining them with memory experiences, it constructs behavioral strategies steering an individual toward or in opposition to a particular food.

Randomised sham-controlled trial of transcutaneous electrical stimulation in obstructive sleep apnoea.

INTRODUCTION: Obstructive sleep apnoea (OSA) is characterised by a loss of neuromuscular tone of the upper airway dilator muscles while asleep. This study investigated the effectiveness of transcutaneous electrical stimulation in patients with OSA. PATIENTS AND METHODS: This was a randomised, sham-controlled crossover trial using transcutaneous electrical stimulation of the upper airway dilator muscles in patients with confirmed OSA. Patients were randomly assigned to one night of sham stimulation and one night of active treatment. The primary outcome was the 4% oxygen desaturation index, responders were defined as patients with a reduction >25% in the oxygen desaturation index when compared with sham stimulation and/or with an index <5/hour in the active treatment night. RESULTS: In 36 patients (age mean 50.8 (SD 11.2) years, male/female 30/6, body mass index median 29.6 (IQR 26.9-34.9) kg/m(2), Epworth Sleepiness Scale 10.5 (4.6) points, oxygen desaturation index median 25.7 (16.0-49.1)/hour, apnoea-hypopnoea index median 28.1 (19.0-57.0)/hour) the primary outcome measure improved when comparing sham stimulation (median 26.9 (17.5-39.5)/hour) with active treatment (median 19.5 (11.6-40.0)/hour; p=0.026), a modest reduction of the mean by 4.1 (95% CI -0.6 to 8.9)/hour. Secondary outcome parameters of patients' perception indicated that stimulation was well tolerated. Responders (47.2%) were predominantly from the mild-to-moderate OSA category. In this subgroup, the oxygen desaturation index was reduced by 10.0 (95% CI 3.9 to 16.0)/hour (p<0.001) and the apnoea-hypopnoea index was reduced by 9.1 (95% CI 2.0 to 16.2)/hour (p=0.004). CONCLUSION: Transcutaneous electrical stimulation of the pharyngeal dilators during a single night in patients with OSA improves upper airway obstruction and is well tolerated. TRIAL REGISTRATION NUMBER: NCT01661712.

The man who mistook his neuropsychologist for a popstar: when configural processing fails in acquired prosopagnosia.

We report the case of an individual with acquired prosopagnosia who experiences extreme difficulties in recognizing familiar faces in everyday life despite excellent object recognition skills. Formal testing indicates that he is also severely impaired at remembering pre-experimentally unfamiliar faces and that he takes an extremely long time to identify famous faces and to match unfamiliar faces. Nevertheless, he performs as accurately and quickly as controls at identifying inverted familiar and unfamiliar faces and can recognize famous faces from their external features. He also performs as accurately as controls at recognizing famous faces when fracturing conceals the configural information in the face. He shows evidence of impaired global processing but normal local processing of Navon figures. This case appears to reflect the clearest example yet of an acquired prosopagnosic patient whose familiar face recognition deficit is caused by a severe configural processing deficit in the absence of any problems in featural processing. These preserved featural skills together with apparently intact visual imagery for faces allow him to identify a surprisingly large number of famous faces when unlimited time is available. The theoretical implications of this pattern of performance for understanding the nature of acquired prosopagnosia are discussed.

Effects of dietary protease on nitrogen emissions from broiler production: a holistic comparison using Life Cycle Assessment.

BACKGROUND: The aim of the study was to quantify the effects of the use of a protease Ronozyme® ProAct in broiler feed on the environmental impacts of broiler and broiler feed production chains. This was done by using a Life Cycle Assessment (LCA) modelling approach with data from trials using both standard soya-based broiler diets and reduced-protein diets with added protease. RESULTS: The results for the feed production chain showed that there was a reduction in all environmental impact categories when protease was used in the diets. The biggest reduction occurred in the category of Global Warming Potential, mainly as a result of decreased carbon dioxide emissions from land use changes related to soya production. In the results for the broiler production chain, there were relatively bigger reductions in Eutrophication Potential and especially in Acidification Potential, mainly as a result of reduced feed protein content and subsequent nitrogen emissions from housing and manure management. CONCLUSION: The use of protease in the broiler diets reduced the environmental impacts of both feed production and broiler production. The latter is mainly through reduced ammonia emissions, which has substantial benefit per se in the poultry industry.

Narcolepsy presenting as REM sleep behaviour disorder.

REM sleep behaviour disorder (RBD) is a neurological condition well known to be associated with the synucleinopathies in middle-aged patients. However, there is much less data concerning its development, evolution, and association with other disorders in younger patients. We report two patients aged less than 33 years who presented with clinical and polysomnographical features of RBD, both of whom proved to have previously undiagnosed narcolepsy. Whilst the association of narcolepsy with RBD has been previously recognised, this is the first report of narcoleptic patients presenting with RBD. Narcolepsy should be included in the differential diagnosis of young patients presenting with abnormal behaviour during sleep compatible with RBD.

The effect of treatment on diaphragm contractility in obstructive sleep apnea syndrome.

In untreated obstructive sleep apnea syndrome (OSAS) inspiratory efforts are made against an occluded airway and diaphragm fatigue might therefore complicate OSAS. To test this hypothesis we measured twitch transdiaphragmatic pressure (Tw Pdi) in response to bilateral cervical magnetic stimulation of the phrenic nerve roots in nine patients with OSAS before and one month after successful therapy with nasal continuous positive airways pressure (nCPAP). The mean Tw Pdi before therapy was 23.2cm H2O and after therapy was 22.8cm H2O (P = 0.59); the mean change after initiation of nCPAP was 0.4cm H2O with 95% confidence intervals of -1.3cm H2O and +2.1 cm H2O. We conclude that low frequency diaphragm fatigue does not complicate untreated OSAS.

A sleep disorders centre in the United Kingdom.

The demographic features of 296 patients who consulted a sleep disorders centre in the United Kingdom were reviewed. Diagnosis after a sleep study was mainly that of sleep-related breathing disorders; however, various other sleep disorders were also diagnosed. Considering that most sleep disorders are diagnosed only after sleep investigations, it should be emphasized that such a facility should be well prepared in undertaking not only polysomnography but also various sleep investigations, including multiple sleep latency testing and actigraphy. In addition, several treatment options, including sleep hygiene, light therapy, and behavioural therapy, should be available. Therefore, a sleep disorders centre needs to be operated by sleep specialists.