DNA methylation and mRNA expression of imprinted genes in blastocysts derived from an improved in vitro maturation method for oocytes from small antral follicles in polycystic ovary syndrome patients.

STUDY QUESTION: Does imprinted DNA methylation or imprinted gene expression differ between human blastocysts from conventional ovarian stimulation (COS) and an optimized two-step IVM method (CAPA-IVM) in age-matched polycystic ovary syndrome (PCOS) patients? SUMMARY ANSWER: No significant differences in imprinted DNA methylation and gene expression were detected between COS and CAPA-IVM blastocysts. WHAT IS KNOWN ALREADY: Animal models have revealed alterations in DNA methylation maintenance at imprinted germline differentially methylated regions (gDMRs) after use of ARTs. This effect increases as more ART interventions are applied to oocytes or embryos. IVM is a minimal-stimulation ART with reduced hormone-related side effects and risks for patients. CAPA-IVM is an improved IVM system that includes a pre-maturation step (CAPA), followed by an IVM step, both in the presence of physiological compounds that promote oocyte developmental capacity. STUDY DESIGN, SIZE, DURATION: For DNA methylation analysis 20 CAPA-IVM blastocysts were compared to 12 COS blastocysts. For RNA-Seq analysis a separate set of 15 CAPA-IVM blastocysts were compared to 5 COS blastocysts. PARTICIPANTS/MATERIALS, SETTING, METHODS: COS embryos originated from 12 patients with PCOS (according to Rotterdam criteria) who underwent conventional ovarian stimulation. For CAPA-IVM 23 women were treated for 3-5 days with highly purified hMG (HP-hMG) and no hCG trigger was given before oocyte retrieval. Oocytes were first cultured in pre-maturation medium (CAPA for 24 h containing C-type natriuretic peptide), followed by an IVM step (30 h) in medium containing FSH and Amphiregulin. After ICSI, Day 5 or 6 embryos in both groups were vitrified and used for post-bisulphite adaptor tagging (PBAT) DNA methylation analysis or RNA-seq gene expression analysis of individual embryos. Data from specific genes and gDMRs were extracted from the PABT and RNA-seq datasets. MAIN RESULTS AND THE ROLE OF CHANCE: CAPA-IVM blastocysts showed similar rates of methylation and gene expression at gDMRs compared to COS embryos. In addition, expression of major epigenetic regulators was similar between the groups. LIMITATIONS, REASONS FOR CAUTION: The embryos from the COS group were generated in a range of culture media. The CAPA-IVM embryos were all generated using the same sperm donor. The DNA methylation level of gDMRs in purely in vivo-derived human blastocysts is not known. WIDER IMPLICATIONS OF THE FINDINGS: A follow-up of children born after CAPA-IVM is important as it is for other new ARTs, which are generally introduced into clinical practice without prior epigenetic safety studies on human blastocysts. CAPA-IVM opens new perspectives for patient-friendly ART in PCOS. STUDY FUNDING/COMPETING INTEREST(S): IVM research at the Vrije Universiteit Brussel has been supported by grants from the Institute for the Promotion of Innovation by Science and Technology in Flanders (Agentschap voor Innovatie door Wetenschap en Technologie-IWT, project 110680), the Fund for Research Flanders (Fonds voor Wetenschappelijk Onderzoek-Vlaanderen-FWO-AL 679 project, project G.0343.13), the Belgian Foundation Against Cancer (HOPE project, Dossier C69Ref Nr 2016-119) and the Vrije Universiteit Brussel (IOF Project 4R-ART Nr 2042). Work in G.K.'s laboratory is supported by the UK Biotechnology and Biological Sciences Research Council and Medical Research Council. The authors have no conflicts of interest.

Anosognosia for behavioral disturbances in frontotemporal dementia and corticobasal syndrome: A voxel-based morphometry study.

BACKGROUND: Patients with syndromes of the frontotemporal dementia spectrum are frequently unaware of their behavioral changes. METHODS: Seventy patients with a clinical diagnosis of behavioral variant frontotemporal dementia (bv-FTD, n = 27), aphasic variant frontotemporal dementia (a-FTD, n = 12) and corticobasal syndrome (CBS, n = 31) participated in the study. Anosognosia for behavioral disturbances was measured as discrepancy between caregiver's and patient's ratings on the Frontal Systems Behavior Scale for present and premorbid behavioral symptoms. Voxel-based morphometry analysis of MRI data was performed to explore the association between anosognosia and gray matter loss. RESULTS: Although behavioral symptoms were reported in all the groups, the comparison between present and premorbid anosognosia revealed that bv-FTD patients not only underestimated their present behavioral disturbances compared to their caregivers, but also overestimated their premorbid behavioral disturbances. Across all groups, the degree of anosognosia for present behavioral impairment correlated with gray matter atrophy in a posterior region of the right superior temporal sulcus (adjacent to the temporoparietal junction). CONCLUSION: These results confirm the role of the right temporoparietal cortex in the genesis of anosognosia and suggest that, in clinical syndromes of the frontotemporal dementia spectrum, anosognosia is associated with the dysfunction of temporoparietal mechanisms of self versus others knowledge.

White matter reduced streamline coherence in young men with autism and mental retardation.

BACKGROUND AND PURPOSE: It has been proposed that white matter alterations might play a role in autistic disorders; however, published data are mainly limited to high-functioning autism. The goal of this study was to apply diffusion tensor imaging (DTI) and fiber tractography (FT) to study white matter in low-functioning autism and the relationship between white matter and cognitive impairment. METHODS: Ten low-functioning males with autism (mean age: 19.7 +/- 2.83 years) and 10 age-matched healthy males (mean age: 19.9 +/- 2.64 years) underwent DTI-MRI scanning. fractional anisotropy (FA) maps were analyzed with whole brain voxel-wise and tract-of-interest statistics. Using FT algorithms, white matter tracts connecting the orbitofrontal cortex (OFC) with other brain regions were identified and compared between the two groups. FA mean values of the autistic group were correlated with intelligence quotient (IQ) scores. RESULTS: Low-functioning autistic subjects showed a reduced tract volume and lower mean FA values in the left OFC network compared with controls. In the autistic group, lower FA values were associated with lower IQ scores. CONCLUSIONS: We showed evidence of OFC white matter network abnormalities in low-functioning autistic individuals. Our results point to a relationship between the severity of the intellectual impairment and the extent of white matter alterations.

Acquired alexithymia following damage to the anterior insula.

Alexithymia is a subclinical condition characterized by impaired awareness of one's emotional states, which has profound effects on mental health and social interaction. Despite the clinical significance of this condition, the neurocognitive impairment(s) that lead to alexithymia remain unclear. Recent theoretical models suggest that impaired anterior insula (AI) functioning might be involved in alexithymia, but conclusive evidence for this hypothesis is lacking. We measured alexithymia levels in a large sample of brain-injured patients (N=129) and non-brain-injured control participants (N=33), to determine whether alexithymia can be acquired after pronounced damage to the AI. Alexithymia levels were first analysed as a function of group, with patients separated into four groups based on AI damage: patients with >15% damage to AI, patients with <15% damage to AI, patients with no damage to AI, and healthy controls. An ANOVA revealed that alexithymia levels varied across groups (p=0.009), with >15% AI damage causing higher alexithymia relative to all other groups (all p<0.01). Next, a multiple linear regression model was fit with the degree of damage to AI, the degree of damage to a related region (the anterior cingulate cortex, ACC), and the degree of damage to the whole brain as predictor variables, and alexithymia as the dependent variable. Critically, increased AI damage predicted increased alexithymia after controlling for the other two regressors (ACC damage; total lesion volume). Collectively, our results suggest that pronounced AI damage causes increased levels of alexithymia, providing critical evidence that this region supports emotional awareness.

Carbonaceous matter in cometary dust and coma.

The analysis of carbonaceous matter in p/Halley's dust and coma via mass spectrometry of positive ions is reviewed. Dust impact generated ions were analyzed by the PUMA instrument aboard VEGA I, and coma plasma ions by the PICCA instrument aboard GIOTTO. For the organic molecules results an overall C:H:O:N ratio of 1.:1.4:0.6:0.1. Most of this polymer material can formally be understood as an aggregation of monomers C2H2, CH2O, and HCN. Special emphasis is given to possible aromatic, especially heterocyclic, and other unsaturated ions, and their importance for abiotic chemical and prebiotic evolution. Aspects of the potential heterogeneous catalysis in liquid water at the inorganic grain backbone structure found by this analysis, too, are also treated.

Mass-spectrometric in situ studies of cometary organics for p/Halley and options for the future.

When the VEGA and GIOTTO spacecrafts flew by comet p/Halley in 1986 the mass-spectrometers Puma and PIA measured the composition of cometary dust particles impacting at speeds of well above 65 km/s. Ion formation upon impact lead to mostly atomic ions. However, a small fraction of the ions measured could be related to molecules. A sophisticated analysis allowed for the first time to point to the chemical nature of cometary organics based on actual mass spectra. With the instrument CoMA for the NASA-BMFT mission CRAF much higher mass-resolution and molecule masses become accessible for in situ measurement, and will yield complementary information to the gas chromatograph CIDEX also onboard CRAF.

Gustatory cortical lesions affect motivation for snack foods.

Most neuropsychological research using food as a reward uses single-bid auctions. We wished to determine whether focal brain lesions would affect the ability and motivation to win snack food items in a computerized auction allowing multiple bids. This allowed us to assess participants' abilities under more complex conditions. We enrolled 154 male penetrating traumatic brain injury (pTBI) veterans, mean age 58, from the Vietnam Head Injury Study registry, and 53 male uninjured veterans, mean age 59. We used voxel-based lesion symptom mapping (VLSM) to identify effects of brain lesions on the ability to win items and on participants' answers to statements regarding their level of motivation and evaluation of how well they performed. Number of items won was not significantly associated with any lesions; however, lesions in gustatory cortex (GC) affected motivation and self-evaluation. Our findings provide further evidence of the primary GC's role in motivation for food and drink.

Fatty-acid amide hydrolase polymorphisms and post-traumatic stress disorder after penetrating brain injury.

The past few years have seen an increase in the clinical awareness of post-traumatic stress disorder (PTSD), one of the most disabling and least understood behavioral disorders. Although the biological bases of PTSD are poorly understood, fatty-acid amide hydrolase (FAAH) activity has been linked with arousability and aversive-memories extinction, that is, two key features of PTSD. In this study, we investigated the association between the FAAH genetic polymorphisms and PTSD development and maintenance. We assessed PTSD frequency in a group of male Vietnam war veterans who suffered combat-related penetrating traumatic brain injury, that is, a relatively homogeneous population regarding the nature of the events that led to PTSD. We showed that rs2295633, a single-nucleotide polymorphism of FAAH, was significantly associated with PTSD diagnosis in subjects without lesions in the ventromedial prefrontal cortex. Moreover, the presence of the C allele was associated with more severe re-experiencing of trauma and more negative reported childhood experiences. In conclusion, our data suggest that FAAH has an important role in PTSD through modulation of aversive memories and point to both a novel therapeutic target and a possible risk marker for this condition.

Prefrontal cortex lesions and MAO-A modulate aggression in penetrating traumatic brain injury.

OBJECTIVE: This study investigates the interaction between brain lesion location and monoamine oxidase A (MAO-A) in the genesis of aggression in patients with penetrating traumatic brain injury (PTBI). METHODS: We enrolled 155 patients with PTBI and 42 controls drawn from the Vietnam Head Injury Study registry. Patients with PTBI were divided according to lesion localization (prefrontal cortex [PFC] vs non-PFC) and were genotyped for the MAO-A polymorphism linked to low and high transcriptional activity. Aggression was assessed with the aggression/agitation subscale of the Neuropsychiatric Inventory (NPI-a). RESULTS: Patients with the highest levels of aggression preferentially presented lesions in PFC territories. A significant interaction between MAO-A transcriptional activity and lesion localization on aggression was revealed. In the control group, carriers of the low-activity allele demonstrated higher aggression than high-activity allele carriers. In the PFC lesion group, no significant differences in aggression were observed between carriers of the 2 MAO-A alleles, whereas in the non-PFC lesion group higher aggression was observed in the high-activity allele than in the low-activity allele carriers. Higher NPI-a scores were linked to more severe childhood psychological traumatic experiences and posttraumatic stress disorder symptomatology in the control and non-PFC lesion groups but not in the PFC lesion group. CONCLUSIONS: Lesion location and MAO-A genotype interact in mediating aggression in PTBI. Importantly, PFC integrity is necessary for modulation of aggressive behaviors by genetic susceptibilities and traumatic experiences. Potentially, lesion localization and MAO-A genotype data could be combined to develop risk-stratification algorithms and individualized treatments for aggression in PTBI.

Executive dysfunction in frontotemporal dementia and corticobasal syndrome.

OBJECTIVE: To determine the pattern of executive dysfunction in frontotemporal dementia (FTD) and corticobasal syndrome (CBS) and to determine the brain areas associated with executive dysfunction in these illnesses. METHOD: We administered the Delis-Kaplan Executive Function System (D-KEFS), a collection of standardized executive function tests, to 51 patients with behavioral-variant FTD and 50 patients with CBS. We also performed a discriminant analysis on the D-KEFS to determine which executive function tests best distinguished the clinical diagnoses of FTD and CBS. Finally, we used voxel-based morphometry (VBM) to determine regional gray matter volume loss associated with executive dysfunction. RESULTS: Patients with FTD and patients with CBS showed executive dysfunction greater than memory dysfunction. Executive function was better preserved in the patients with CBS than the patients with FTD with the exception of tests that required motor, visuospatial ability, or both. In patients with CBS, dorsal frontal and parietal and temporal-parietal cortex was associated with executive function. In FTD, tests with a language component (Verbal Fluency) were associated with left perisylvian cortex, sorting with the left dorsolateral prefrontal cortex, and reasoning (the Twenty Questions task) with the left anterior frontal cortex. The Twenty Questions test best distinguished the clinical diagnoses of CBS and FTD. CONCLUSIONS: The neuroanatomic findings (especially in frontotemporal dementia [FTD]) agree with the previous literature on this topic. Patients with FTD and patients with corticobasal syndrome (CBS) show disparate performance on higher-order executive functions, especially the Twenty Questions test. It may be difficult to distinguish motor and visuospatial ability from executive function in patients with CBS using tests with significant motor and visuospatial demands such as Trail Making.

Apathy and disinhibition in frontotemporal dementia: Insights into their neural correlates.

BACKGROUND: Aberrant social behavior is a defining symptom of frontotemporal dementia (FTD) and may eventually occur in all syndromes composing the FTD spectrum. Two main behavioral abnormalities have been described: apathy and disinhibition, but their neuroanatomical correlates remain underspecified. METHODS: Sixty-two patients with a clinical diagnosis of FTD participated in the study. Voxel-based morphometry of MRI data was performed to explore the association between gray matter loss and severity of the two behavioral profiles as measured by the Apathy and Disinhibition subscales of the Frontal Systems Behavior Scale. RESULTS: Compared with a group of controls, the FTD group showed extensive bilateral atrophy predominantly involving frontal and temporal lobes. Within the FTD group, the severity of apathy correlated with atrophy in the right dorsolateral prefrontal cortex. The severity of disinhibition correlated with atrophy in the right nucleus accumbens, right superior temporal sulcus, and right mediotemporal limbic structures. CONCLUSIONS: Prefrontal and temporal regions are differentially associated with apathy and disinhibition. Our results support the view that successful execution of complex social behaviors relies on the integration of social knowledge and executive functions, represented in the prefrontal cortex, and reward attribution and emotional processing, represented in mesolimbic structures.

Time-of-flight mass spectrometric analysis of ion formation in hypervelocity impact of organic polymer microspheres: comparison with secondary ion mass spectrometry, (252)Cf mass spectrometry and laser mass spectrometry.

Unisized 1.6-microm polystyrene microspheres coated with PEDOT (polyethylene-dioxythiophene) were accelerated to speeds of 6-16 km/s and shot onto a silver target. Either positive or negative ions, both instantaneously formed by the impact process, have been analyzed by time-of-flight mass spectrometry (TOF). Apparently, the processes that control the formation of ions of either polarity depend on the impact velocity. Comparing the results with those of secondary ion mass spectrometry with primary ion energy in both the elastic and the inelastic ((252)Cf-MS) energy loss regimes, some reaction mechanisms of the polymer ions for different energy densities could be elucidated. Some aspects of ion formation are also related to those found in pulsed laser ion generation from these microspheres. This investigation was performed in order to further improve the method of analyzing the organic fraction of interstellar, interplanetary, and cometary dust particles impinging on the targets of the "CIDA" time-of-flight (TOF) mass spectrometers on-board the NASA comet missions "STARDUST" and "CONTOUR".

The Cometary and Interstellar Dust Analyzer at comet 81P/Wild 2.

The CIDA (Cometary and Interstellar Dust Analyzer) instrument on the Stardust spacecraft is a time-of-flight mass spectrometer used to analyze ions formed when fast dust particles strike the instrument's target. In the spectra of 45 presumably interstellar particles, quinone derivates were identified as constituents in the organic component. The 29 spectra obtained during the flyby of Comet 81P/Wild 2 confirm the predominance of organic matter. In moving from interstellar to cometary dust, the organic material seems to lose most of its hydrogen and oxygen as water and carbon monoxide. These are now present in the comet as gas phases, whereas the dust is rich in nitrogen-containing species. No traces of amino acids were found. We detected sulfur ions in one spectrum, which suggests that sulfur species are important in cometary organics.