Drosophila Homolog of the Human Carpenter Syndrome Linked Gene, MEGF8, Is Required for Synapse Development and Function.

Drosophila multiple epidermal growth factor-like domains 8 (dMegf8) is a homolog of human MEGF8 MEGF8 encodes a multidomain transmembrane protein which is highly conserved across species. In humans, MEGF8 mutations cause a rare genetic disorder called Carpenter syndrome, which is frequently associated with abnormal left-right patterning, cardiac defects, and learning disabilities. MEGF8 is also associated with psychiatric disorders. Despite its clinical relevance, MEGF8 remains poorly characterized; and although it is highly conserved, studies on animal models of Megf8 are also very limited. The presence of intellectual disabilities in Carpenter syndrome patients and association of MEGF8 with psychiatric disorders indicate that mutations in MEGF8 cause underlying defects in synaptic structure and functions. In this study, we investigated the role of Drosophila dMegf8 in glutamatergic synapses of the larval neuromuscular junctions (NMJ) in both males and females. We show that dMegf8 localizes to NMJ synapses and is required for proper synaptic growth. dMegf8 mutant larvae and adults show severe motor coordination deficits. At the NMJ, dMegf8 mutants show altered localization of presynaptic and postsynaptic proteins, defects in synaptic ultrastructure, and neurotransmission. Interestingly, dMegf8 mutants have reduced levels of the Type II BMP receptor Wishful thinking (Wit). dMegf8 displays genetic interactions with neurexin-1 (dnrx) and wit, and in association with Dnrx and Wit plays an essential role in synapse organization. Our studies provide insights into human MEGF8 functions and potentially into mechanisms that may underlie intellectual disabilities observed in Carpenter syndrome as well as MEGF8-related synaptic structural and/or functional deficits in psychiatric disorders.SIGNIFICANCE STATEMENT Carpenter syndrome, known for over a century now, is a genetic disorder linked to mutations in Multiple Epidermal Growth Factor-like Domains 8 (MEGF8) gene and associated with intellectual disabilities among other symptoms. MEGF8 is also associated with psychiatric disorders. Despite the high genetic conservation and clinical relevance, the functions of MEGF8 remain largely uncharacterized. Patients with intellectual disabilities and psychiatric diseases often have an underlying defect in synaptic structure and function. This work defines the role of the fly homolog of human MEGF8, dMegf8, in glutamatergic synapse growth, organization, and function and provide insights into potential functions of MEGF8 in human central synapses and synaptic mechanisms that may underlie psychiatric disorders and intellectual disabilities seen in Carpenter syndrome.

Human Pluripotent Stem Cells-Based Therapies for Neurodegenerative Diseases: Current Status and Challenges.

Neurodegenerative diseases are characterized by irreversible cell damage, loss of neuronal cells and limited regeneration potential of the adult nervous system. Pluripotent stem cells are capable of differentiating into the multitude of cell types that compose the central and peripheral nervous systems and so have become the major focus of cell replacement therapies for the treatment of neurological disorders. Human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC)-derived cells have both been extensively studied as cell therapies in a wide range of neurodegenerative disease models in rodents and non-human primates, including Parkinson's disease, stroke, epilepsy, spinal cord injury, Alzheimer's disease, multiple sclerosis and pain. In this review, we discuss the latest progress made with stem cell therapies targeting these pathologies. We also evaluate the challenges in clinical application of human pluripotent stem cell (hPSC)-based therapies including risk of oncogenesis and tumor formation, immune rejection and difficulty in regeneration of the heterogeneous cell types composing the central nervous system.

Easily Applicable Methods for Measuring the Mental Load on Tractor Operators.

Agriculture technology is moving toward automation, placing operators in a supervisory role. This change in operator workload may lead to increased stress and higher mental load, resulting in reduced attention and hence greater risk of illness or injury to humans and damage to equipment. This study investigated the use of easily applicable equipment to measure mental load. Three methods were used to measure the mental load on machine operators: heart rate monitoring, two types of electroencephalograph (EEG) evaluation, and an assessment protocol. Three driving exercises (general driving, slalom driving, and loading) and a counting exercise were used in a driving simulator to create different levels of mental load. Due to the number of exercises, a single-scale assessment protocol was used to save time. We found that only the assessment protocol gave clear results and would work well as an evaluation tool. The heart rate and EEG measurements did not provide clear data for mental load assessment.

Examining the Role of Spatial Changes in Bimodal and Uni-Modal To-Be-Ignored Stimuli and How They Affect Short-Term Memory Processes.

This study examines the potential vulnerability of short-term memory processes to distraction by spatial changes within to-be-ignored bimodal, vibratory, and auditory stimuli. Participants were asked to recall sequences of serially presented digits or locations of dots while being exposed to to-be-ignored stimuli. On unexpected occasions, the bimodal to-be-ignored sequence, vibratory to-be-ignored sequence, or auditory to-be-ignored sequence changed their spatial origin from one side of the body (e.g., ear and arm, arm only, ear only) to the other. It was expected that the bimodal stimuli would make the spatial change more salient compared to that of the uni-modal stimuli and that this, in turn, would yield an increase in distraction of serial short-term memory in both the verbal and spatial domains. Our results support this assumption as a disruptive effect of the spatial deviant was only observed when presented within the bimodal to-be-ignored sequence: uni-modal to-be-ignored sequences, whether vibratory: or auditory, had no impact on either verbal or spatial short-term memory. Implications for models of attention capture and the potential special attention capturing role of bimodal stimuli are discussed.

The impact of spoken action words on performance in a cross-modal oddball task.

In this study a cross-modal oddball task was employed to study the effect that words spoken either non-urgently or urgently would have on a digit categorization task and if women would exhibit greater behavioral inhibitory control. The words were unrelated to the task itself, but related to the action required to complete the task. Forty participants (21 women) conducted a computerized categorization task while exposed to a sinewave tone as a standard stimulus (75% of the trials) or a to-be ignored word (press, stop) spoken either non-urgently or urgently as unexpected auditory deviant stimulus (6.25% trials for each category). Urgent words had sharp intonation and an average fundamental frequency (F0) ranging from 191.9 (stop) to 204.6 (press) Hz. Non-urgent words had low intonation with average F0 ranging from 103.9.9 (stop) to 120.3 (press) Hz. As expected, deviant distraction and longer response times were found by exposure to the word stop, but deviant distraction was not found to be significant with the word press or due to intonation. While the results showed that women had in general longer reaction times, there were no gender differences found related to the deviant distraction caused by word or intonation. The present results do not support the hypothesis that women have greater behavioral inhibitory control, but there was evidence that the meaning of the word could influence response times.

Investigating Deviance Distraction and the Impact of the Modality of the To-Be-Ignored Stimuli.

It has been suggested that deviance distraction is caused by unexpected sensory events in the to-be-ignored stimuli violating the cognitive system's predictions of incoming stimuli. The majority of research has used methods where the to-be-ignored expected (standards) and the unexpected (deviants) stimuli are presented within the same modality. Less is known about the behavioral impact of deviance distraction when the to-be-ignored stimuli are presented in different modalities (e.g., standard and deviants presented in different modalities). In three experiments using cross-modal oddball tasks with mixed-modality to-be-ignored stimuli, we examined the distractive role of unexpected auditory deviants presented in a continuous stream of expected standard vibrations. The results showed that deviance distraction seems to be dependent upon the to-be-ignored stimuli being presented within the same modality, and that the simplest omission of something expected; in this case, a standard vibration may be enough to capture attention and distract performance.

Double-Sided Mechanical Shocks Provoke Larger Seated Postural Reactions Compared With Single-Sided Mechanical Shocks.

STUDY DESIGN: Human volunteers were exposed experimentally to single-sided mechanical shocks (SSMS) and double-sided mechanical shocks (DSMS) while seated. OBJECTIVE: The aim of this study was to describe and contrast seated postural reactions due to SSMS or DSMS in healthy male adults. SUMMARY OF BACKGROUND DATA: Mechanical shocks to the body, caused when driving on irregular terrain, are suggested to be hazardous to the spine and may be associated with the reported musculoskeletal pain of the back and neck among professional drivers. However, very little is known about the characteristics of seated postural reactions and the biomechanical effects caused by mechanical shocks. METHODS: Twenty healthy male subjects (18-43 years old) were exposed while seated to 5 SSMS and 15 DSMS in lateral directions. The second acceleration in the DSMS was in the opposite direction to the first acceleration and was fast, medium, or slow depending on the speed of direction change. Surface electromyography (EMG) was recorded in muscles of the upper neck, trapezius, erector spinae, and external oblique, while kinematics were recorded with inertial sensors placed at the neck, trunk, and pelvis. Muscle activity was normalized to maximum voluntary contractions (MVCs). RESULTS: The EMG amplitudes were significantly higher (0.6-1%; P < 0.001) for the fast DSMS than all other shocks. Range of motion (ROM) of the neck and trunk was greater during the DSMS than the SSMS. Evoked muscle activity was less than 2% MVC in the trapezius, less than 10% MVC in the erector spinae and upper neck, while the activity exceeded 10% MVC in the external oblique muscles. CONCLUSION: Fast DSMS in lateral directions appear more demanding than SSMS, demonstrating augmented seated postural reactions. However, the present mechanical shocks employed did not seem to induce postural reactions with regard to ROM or muscle activity of a magnitude likely to cause musculoskeletal overload. LEVEL OF EVIDENCE: 4.

Behavioral activation versus physical activity via the internet: A randomized controlled trial.

BACKGROUND: A major problem today is that only about fifty percent of those affected by depression seeks help. One way to reach more sufferers would be by offering easily accessible internet based treatments. The purpose of this study was to compare/evaluate four therapist supported internet administered treatments. METHOD/RESULTS: Two hundred eighty six participants were included. The treatment period lasted twelve weeks, consisting of the following treatments: 1) physical activity without treatment rational, 2) physical activity with treatment rational, 3) behavioral activation without treatment rational and 4) behavioral activation with treatment rational. All groups (including a control-group) showed a significant decrease in depressive symptoms. When the treatment groups were pooled and compared to the control group, there were significant differences from pretest to posttest (Hedges gav treatment =1.01, control group =0.47). This held true also when each of the four treatment groups was compared to the control group, with one exception: Physical activity without treatment rationale. LIMITATIONS: The differences between how many modules the participants completed could indicate that there are other factors than the treatments that caused the symptom reduction, however, the dose-response analysis did not detect any significant differences on account of modules completed. CONCLUSIONS: The results support the positive effects of internet administered treatments for depression, and highlights the importance of psychoeducation, which tends to affect both the treatment outcome and the probability of remaining in treatment. These aspects need to be considered when developing and conducting new treatments for depression, since they would increase the likelihood of positive treatment outcomes.

Comorbidity in allergic asthma and allergic rhinitis: functional somatic syndromes.

Based on the concept of central sensitisation, the present study tested the hypothesis of comorbidity in allergic asthma and allergic rhinitis with diagnoses of functional somatic syndromes (FSSs), including fibromyalgia, irritable bowel syndrome and migraine. Data were used from the population-based Västerbotten Environmental Health Study (n = 3406). The participants consisted of 164 individuals with allergic asthma and 298 individuals with allergic rhinitis as well as 2876 individuals without allergic or non-allergic asthma, allergic rhinitis or atopic dermatitis. Diagnoses were based on self-reports of having been diagnosed by a physician. Odds ratios (ORs) were calculated from binary logistic regression analysis, both crude and adjusted for age and education. The adjusted ORs (1.87-4.00) for all FSSs differed significantly from unity for both allergic asthma and rhinitis. The results provide support for the hypothesis of comorbidity in allergic asthma and rhinitis with FSSs. Since central sensitisation is likely to underlie FSSs, the present findings raises the question as to whether central sensitisation may also be involved in allergic asthma and rhinitis.

Treating Major Depression with Physical Activity: A Systematic Overview with Recommendations.

UNLABELLED: The purpose of this systematic overview was to determine the most effective mode and dose of physical activity (PA) for treating major depressive disorder (MDD), and to suggest guidelines and recommendations for clinicians. The selection process consisted of a comprehensive search that was conducted up until April 2014 in the following databases: PsycINFO, Medline, PubMed and Scopus. The inclusion criteria were: (1) a randomized controlled trial (RCT) design, (2) complete description of intensity, duration and frequency of the PA, (3) the participants had to be diagnosed with MDD according to Diagnostic Statistical Manual 4 th edition (DSM-IV) or International Classification of Disease tenth Revision (ICD-10) criteria (4) if the controls received any treatment, it had to be specified, (5) published after 1990, (6) consist of aerobic or anaerobic treatment PA, and (7) not be a pilotor preliminary study. A quality assessment of each study was conducted independently by two reviewers; this stringent selection process resulted in 12 reviewed studies. CONCLUSION: individually customized PA, for at least 30 minutes, preferably performed under supervision and with a frequency of at least three times per week is recommended when treating MDD. These recommendations must be viewed in light of the relatively few studies matching the inclusion criteria.

Odor and noise intolerance in persons with self-reported electromagnetic hypersensitivity.

Lack of confirmation of symptoms attributed to electromagnetic fields (EMF) and triggered by EMF exposure has highlighted the role of individual factors. Prior observations indicate intolerance to other types of environmental exposures among persons with electromagnetic hypersensitivity (EHS). This study assessed differences in odor and noise intolerance between persons with EHS and healthy controls by use of subscales and global measures of the Chemical Sensitivity Scale (CSS) and the Noise Sensitivity Scale (NSS). The EHS group scored significantly higher than the controls on all CSS and NSS scales. Correlation coefficients between CSS and NSS scores ranged from 0.60 to 0.65 across measures. The findings suggest an association between EHS and odor and noise intolerance, encouraging further investigation of individual factors for understanding EMF-related symptoms.

'What's in a name?' 'No more than when it's mine own'. Evidence from auditory oddball distraction.

Research of the distractor value of hearing the own name has shown that this self-referring stimulus captures attention in an involuntary fashion and create distraction. The behavioral studies are few and the outcomes are not always clear cut. In this study the distraction by own name compared to a control name was investigated by using a cross-modal oddball task in two experiments. In the first experiment, thirty-nine participants were conducting a computerized categorization task while exposed to, to-be ignored own and matched control names (controlling for familiarity, gender and number of syllables) as unexpected auditory deviant stimulus (12.5% trials for each name category) and a sine wave tone as a standard stimulus (75% of the trials). In the second experiment, another group of thirty-nine participants completed the same task but with the additional deviant stimulus of an irrelevant word added (10% trials for each deviant type and 70% trials with the standard stimulus). Results showed deviant distraction by exposure to both the irrelevant word, own and the control name compared to the standard tone but no differences were found showing that the own name captured attention and distracted the participants more than an irrelevant word or a control name. The results elucidate the role of the own name as a potent auditory distractor and possible limitations with its theoretical significance for general theories of attention are discussed.

Overlap in prevalence between various types of environmental intolerance.

Environmental intolerance (EI) is characterized by attribution of several, multisystem symptoms to specific environmental exposures, such as exposure to odorous/pungent chemicals, certain buildings, electromagnetic fields (EMFs) and everyday sounds. The symptoms are medically unexplained, non-specific and the symptoms overlap between different types of EI. To approach the issue of underlying mechanisms the matter of overlap in prevalence between intolerances can provide valuable information. The aim of the study was to examine if the overlap between intolerance to odorous/pungent chemicals, certain buildings, EMFs and sounds is larger than the expected overlap if no association would exist between them. The study was using cross-sectional data from the Västerbotten Environmental Health Study in Sweden; a large questionnaire-based survey. 8520 adults (18-79 years) were randomly selected after stratification for age and sex, of whom 3406 (40%) participated. Individuals with the four types of intolerance were identified either through self-report, or by having been physician-diagnosed with a specific EI. The overlaps between the four EIs were greater than predictions based on coincidence for both self-reported and diagnosed cases (except for the overlap between diagnosed intolerance to sounds and EMFs). The results raise the question whether different types of EI share similar underlying mechanisms, or at least that the sufferers of EI share some predisposition to acquire the conditions.

The amyotrophic lateral sclerosis 8 protein, VAP, is required for ER protein quality control.

A familial form of Amyotrophic lateral sclerosis (ALS8) is caused by a point mutation (P56S) in the vesicle-associated membrane protein associated protein B (VapB). Human VapB and Drosophila Vap-33-1 (Vap) are homologous type II transmembrane proteins that are localized to the ER. However, the precise consequences of the defects associated with the P56S mutation in the endoplasmic reticulum (ER) and its role in the pathology of ALS are not well understood. Here we show that Vap is required for ER protein quality control (ERQC). Loss of Vap in flies shows various ERQC associated defects, including protein accumulation, ER expansion, and ER stress. We also show that wild type Vap, but not the ALS8 mutant Vap, interacts with a lipid-binding protein, Oxysterol binding protein (Osbp), and that Vap is required for the proper localization of Osbp to the ER. Restoring the expression of Osbp in the ER suppresses the defects associated with loss of Vap and the ALS8 mutant Vap. Hence, we propose that the ALS8 mutation impairs the interaction of Vap with Osbp, resulting in hypomorphic defects that might contribute to the pathology of ALS8.

Stress and odor sensitivity in persons with noise sensitivity.

Previous research has indicated that sensory sensitivity/intolerance to a specific modality may be part of a more general environmental hypersensitivity, and possibly mediated by stress. This study investigated the relationship between noise sensitivity, perceived stress, and odor sensitivity in a group of men. A quasi-experimental design was used. One-hundred and thirty-four male undergraduate students completed Weinstein's noise sensitivity scale from which a low-sensitivity group (n = 16) and a high-sensitivity (n = 16) group were formed. These two groups were screened for loss in auditory and olfactory detection sensitivity, and completed the perceived stress questionnaire (PSQ) and the chemical sensitivity scale (CSS). One-way analysis of variance and Spearman correlational analyses were performed. Significantly higher scores on the PSQ (P < 0.05) and the CSS (P < 0.05) were found in the high noise-sensitivity group compared to the low noise-sensitivity group. These findings raise the question of whether the relation between noise and odor sensitivity reflects a general environmental sensitivity.

Vav1 is essential for mechanotactic crawling and migration of neutrophils out of the inflamed microvasculature.

Mac-1-dependent crawling is a new step in the leukocyte recruitment cascade that follows LFA-1-dependent adhesion and precedes emigration. Neutrophil adhesion via LFA-1 has been shown to induce cytoskeletal reorganization through Vav1-dependent signaling, and the current study investigates the role of Vav1 in the leukocyte recruitment process in vivo with particular attention to the events immediately downstream of LFA-1-dependent adhesion. Intravital and spinning-disk-confocal microscopy was used to investigate intravascular crawling in relation to endothelial junctions in vivo in wild-type and Vav1(-/-) mice. Adherent wild-type neutrophils almost immediately began crawling perpendicular to blood flow via Mac-1 until they reached an endothelial junction where they often changed direction. This pattern of perpendicular, mechanotactic crawling was recapitulated in vitro when shear was applied. In sharp contrast, the movement of Vav1(-/-) neutrophils was always in the direction of flow and appeared more passive as if the cells were dragged in the direction of flow in vivo and in vitro. More than 80% of Vav1(-/-) neutrophils moved independent of Mac-1 and could be detached with LFA-1 Abs. An inability to release the uropod was frequently noted for Vav1(-/-) neutrophils, leading to greatly elongated tails. The Vav1(-/-) neutrophils failed to stop or follow junctions and ultimately detached, leading to fewer emigrated neutrophils. The Vav1(-/-) phenotype resulted in fewer neutrophils recruited in a relevant model of infectious peritonitis. Clearly, Vav1 is critical for the complex interplay between LFA-1 and Mac-1 that underlies the programmed intravascular crawling of neutrophils.

Accidents in family forestry's firewood production.

Firewood is commonly used around the world, but little is known about the work involved in its production and associated accidents. The objectives were to identify relationships between accidents and time exposure, workers' age and sex, equipment used and work activities in family forestry's firewood production. Data from a postal survey in Northern Sweden were compared to a database of injuries in the same region. Most accidents occurred to 50-69 year old men, who also worked most hours. No significant differences in sex and age were found between expected and recorded accident frequencies when calculated from total work hours; however, when calculated using numbers of active persons significant differences were found for both age and sex. Frequency of accidents per unit worked time was higher for machine involving activities than for other activities. Accidents that occurred when using wedge splitter machines were responsible for most of this overrepresentation. Fingers were the most commonly injured body parts. Mean accident rate for the equipment used was 87 accidents per million work hours, and the rate was highest for wedge splitters (122 accidents per million work hours). Exposure to elevated risks due to violation of safety procedures is discussed, as well as possible preventative measures.

Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes.

Type-2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Recent studies place altered mitochondrial oxidative phosphorylation (OxPhos) as an underlying genetic element of insulin resistance. However, the causative or compensatory nature of these OxPhos changes has yet to be proven. Here, we show that muscle- and liver-specific AIF ablation in mice initiates a pattern of OxPhos deficiency closely mimicking that of human insulin resistance, and contrary to current expectations, results in increased glucose tolerance, reduced fat mass, and increased insulin sensitivity. These results are maintained upon high-fat feeding and in both genetic mosaic and ubiquitous OxPhos-deficient mutants. Importantly, the effects of AIF on glucose metabolism are acutely inducible and reversible. These findings establish that tissue-specific as well as global OxPhos defects in mice can counteract the development of insulin resistance, diabetes, and obesity.

Cognitive after-effects of vibration and noise exposure and the role of subjective noise sensitivity.

This study investigated the effects on attention performance after exposure to noise and whole-body vibration in relation to subjective noise sensitivity. Sixteen high and 16 low sensitivity male students, as determined by the Weinstein Noise Sensitivity Questionnaire, participated in a within-subjects experiment. Noise and vibration stimuli similar to those usually occurring in forestry vehicles were presented either individually, combined or not at all in four separate sessions lasting approximately 44 min. After exposure, participants completed an attention task and made subjective ratings of alertness. No main effect of noise sensitivity was observed in MANOVA, thus the data was pooled with the data from a pilot study using the exact same procedure without using a noise sensitivity inclusion criterion. The combined data revealed performance degradation in the attention task after exposure to vibration, regardless as to whether it was presented alone or in combination with noise. Increased ratings of alertness after vibration exposure and decreased ratings of alertness after noise exposure were also found. Neither synergistic nor antagonistic effects were observed from the combined noise and vibration exposure.

Acne fulminans: a case report.

Acne Fulminans (AF) is a severe form of cystic acne primarily affecting Caucasian adolescent males. The systemic clinical manifestations of the disease make it likely that the patient will present to his or her primary care provider rather than to a dermatologist. Promptly recognizing this disorder will aid in appropriate management, avoiding costly and invasive diagnostic procedures, multiple consultations, unnecessary pharmacologic treatments, and residual scarring of the skin. We report a case and a brief review of the literature regarding this enigmatic disorder.