Preconception Diet Interventions in Obese Outbred Mice and the Impact on Female Offspring Metabolic Health and Oocyte Quality.

Obese individuals often suffer from metabolic health disorders and reduced oocyte quality. Preconception diet interventions in obese outbred mice restore metabolic health and oocyte quality and mitochondrial ultrastructure. Also, studies in inbred mice have shown that maternal obesity induces metabolic alterations and reduces oocyte quality in offspring (F1). Until now, the effect of maternal high-fat diet on F1 metabolic health and oocyte quality and the potential beneficial effects of preconception dietary interventions have not been studied together in outbred mice. Therefore, we fed female mice a high-fat/high-sugar (HF/HS) diet for 7 weeks and switched them to a control (CONT) or caloric-restriction (CR) diet or maintained them on the HF/HS diet for 4 weeks before mating, resulting in three treatment groups: diet normalization (DN), CR, and HF/HS. In the fourth group, mice were fed CONT diet for 11 weeks (CONT). HF/HS mice were fed an HF/HS diet from conception until weaning, while all other groups were then fed a CONT diet. After weaning, offspring were kept on chow diet and sacrificed at 11 weeks. We observed significantly elevated serum insulin concentrations in female HF/HS offspring and a slightly increased percentage of mitochondrial ultrastructural abnormalities, mitochondrial size, and mitochondrial mean gray intensity in HF/HS F1 oocytes. Also, global DNA methylation was increased and cellular stress-related proteins were downregulated in HF/HS F1 oocytes. Mostly, these alterations were prevented in the DN group, while, in CR, this was only the case for a few parameters. In conclusion, this research has demonstrated for the first time that a maternal high-fat diet in outbred mice has a moderate impact on female F1 metabolic health and oocyte quality and that preconception DN is a better strategy to alleviate this compared to CR.

Mid-range visual functions in relation to higher-order visual functions after stroke.

INTRODUCTION: We aimed to investigate whether associations between deficits in "mid-range" visual functions and deficits in higher-order visual cognitive functions in stroke patients are more in line with a hierarchical, two-pathway model of the visual brain, or with a patchwork model, which assumes a parallel organization with many processing routes and cross-talk. METHODS: A group of 182 ischemic stroke patients was assessed with a new diagnostic set-up for the investigation of a comprehensive range of visuosensory mid-range functions: color, shape, location, orientation, correlated motion, contrast and texture. With logistic regression analyses we investigated the predictive value of these mid-range functions for deficits in visuoconstruction (Copy of the Rey-Complex Figure Test), visual emotion recognition (Ekman 60 Faces Test of the FEEST) and visual memory (computerized Doors-test). RESULTS: Results showed that performance on most mid-range visual tasks could not predict performance on higher-order visual cognitive tasks. Correlations were low to weak. Impaired visuoconstruction and visual memory were only modestly predicted by a worse location perception. Impaired emotion perception was modestly predicted by a worse orientation perception. In addition, double dissociations were found: there were patients with selective deficits in mid-range visual functions without higher-order visual deficits and vice versa. CONCLUSIONS: Our findings are not in line with the hierarchical, two-pathway model. Instead, the findings are more in line with alternative "patchwork" models, arguing for a parallel organization with many processing routes and cross-talk. However, future studies are needed to test these alternative models.

Risk of preterm birth for placenta previa or low-lying placenta and possible preventive interventions: A systematic review and meta-analysis.

Objective: To investigate the risk of preterm birth in women with a placenta previa or a low-lying placenta for different cut-offs of gestational age and to evaluate preventive interventions. Search and methods: MEDLINE, EMBASE, CENTRAL, Web of Science, WHO-ICTRP and clinicaltrials.gov were searched until December 2021. Randomized controlled trials, cohort studies and case-control studies assessing preterm birth in women with placenta previa or low-lying placenta with a placental edge within 2 cm of the internal os in the second or third trimester were eligible for inclusion. Pooled proportions and odds ratios for the risk of preterm birth before 37, 34, 32 and 28 weeks of gestation were calculated. Additionally, the results of the evaluation of preventive interventions for preterm birth in these women are described. Results: In total, 34 studies were included, 24 reporting on preterm birth and 9 on preventive interventions. The pooled proportions were 46% (95% CI [39 - 53%]), 17% (95% CI [11 - 25%]), 10% (95% CI [7 - 13%]) and 2% (95% CI [1 - 3%]), regarding preterm birth <37, <34, <32 and <28 weeks in women with placenta previa. For low-lying placentas the risk of preterm birth was 30% (95% CI [19 - 43%]) and 1% (95% CI [0 - 6%]) before 37 and 34 weeks, respectively. Women with a placenta previa were more likely to have a preterm birth compared to women with a low-lying placenta or women without a placenta previa for all gestational ages. The studies about preventive interventions all showed potential prolongation of pregnancy with the use of intramuscular progesterone, intramuscular progesterone + cerclage or pessary. Conclusions: Both women with a placenta previa and a low-lying placenta have an increased risk of preterm birth. This increased risk is consistent across all severities of preterm birth between 28-37 weeks of gestation. Women with placenta previa have a higher risk of preterm birth than women with a low-lying placenta have. Cervical cerclage, pessary and intramuscular progesterone all might have benefit for both women with placenta previa and low-lying placenta, but data in this population are lacking and inconsistent, so that solid conclusions about their effectiveness cannot be drawn. Systematic review registration: PROSPERO https://www.crd.york.ac.uk/prospero/, identifier CRD42019123675.

Mid-range visual deficits after stroke: Prevalence and co-occurrence.

Visual deficits are common after stroke and are powerful predictors for the chronic functional outcome. However, while basic visual field and recognition deficits are relatively easy to assess with standardized methods, selective deficits in visual primitives, such as shape or motion, are harder to identify, as they often require a symmetrical bilateral posterior lesion in order to provoke full field deficits. Therefore, we do not know how often they occur. Nevertheless, they can have severe repercussions for daily-life functioning. We aimed to investigate the prevalence and co-occurrence of hemifield "mid-range" visual deficits (i.e. color, shape, location, orientation, correlated motion, contrast, texture and glossiness), using a novel experimental set-up with a gaze-contingent presentation of the stimuli. To this end, a prospective cohort of 220 ischemic (sub)cortical stroke patients and a healthy control group was assessed with this set-up. When comparing performance of patients with controls, the results showed that deficits in motion-perception were most prevalent (26%), followed by color (22%), texture (22%), location (21%), orientation (18%), contrast (14%), shape (14%) and glossiness (13%). 63% of the stroke patients showed one or more mid-range visual deficits. Overlap of deficits was small; they mostly occurred in isolation or co-occurred with only one or two other deficits. To conclude, it was found that deficits in "mid-range" visual functions were very prevalent. These deficits are likely to affect the chronic post-stroke condition. Since we found no strong patterns of co-occurrences, we suggest that an assessment of deficits at this level of visual processing requires screening the full range of visual functions.

Diet normalization or caloric restriction as a preconception care strategy to improve metabolic health and oocyte quality in obese outbred mice.

BACKGROUND: Maternal metabolic disorders are linked to reduced metabolic health and oocyte quality. Obese women are advised to lose weight before conception to increase pregnancy chances. However, as human studies show no univocal guidelines, more research is necessary to provide fundamental insights in the consequences of dietary weight loss on oocyte quality. Therefore, we investigated the impact of diet normalization or calorie restricted diet for two, four or six weeks, as preconception care intervention (PCCI), in obese mice on metabolic health and oocyte quality. METHODS: Outbred female mice were fed a control (CTRL) or high-fat (HF) diet for 7 weeks (7w). Afterwards, HF-mice were put on different PCCIs, resulting in four treatment groups: 1) control diet up to 13w, 2) HF diet up to 13w (HF_HF), switch from a HF (7w) to 3) an ad libitum control diet (HF_CTRL) or 4) 30% calorie restricted control diet (HF_CR) for two, four or six weeks. Body weight, metabolic health, oocyte quality and overall fertility results were assessed. RESULTS: Negative effects of HF diet on metabolic health, oocyte quality and pregnancy rates were confirmed. HF_CTRL mice progressively improved insulin sensitivity, glucose tolerance, serum insulin and cholesterol from PCCI w2 to w4. No further improvements in metabolic health were present at PCCI w6. However, PCCI w6 showed best oocyte quality improvements. Mature oocytes still showed elevated lipid droplet volume and mitochondrial activity but a significant reduction in ROS levels and ROS: active mitochondria ratio compared with HF_HF mice. HF_CR mice restored overall insulin sensitivity and glucose tolerance by PCCI w4. However, serum insulin, cholesterol and ALT remained abnormal. At PCCI w6, glucose tolerance was again reduced. However, only at PCCI w6, oocytes displayed reduced ROS levels and restored mitochondrial activity compared with HF_HF mice. In addition, at PCCI w6, both PCCI groups showed decreased mitochondrial ultrastructural abnormalities compared with the HF_HF group and restored pregnancy rates. CONCLUSIONS: Diet normalization for 4 weeks showed to be the shortest, most promising intervention to improve metabolic health. Most promising improvements in oocyte quality were seen after 6 weeks of intervention in both PCCI groups. This research provides fundamental insights to be considered in developing substantiated preconception guidelines for obese women planning for pregnancy.

Rescue Potential of Supportive Embryo Culture Conditions on Bovine Embryos Derived from Metabolically Compromised Oocytes.

Elevated non-esterified fatty acid (NEFA), predominantly palmitic acid (PA), concentrations in blood and follicular fluid are a common feature in maternal metabolic disorders such as obesity. This has a direct negative impact on oocyte developmental competence and the resulting blastocyst quality. We use NEFA-exposure during bovine oocyte in vitro maturation (IVM) as a model to mimic oocyte maturation under maternal metabolic stress conditions. However, the impact of supportive embryo culture conditions on these metabolically compromised zygotes are not known yet. We investigated if the addition of anti-apoptotic, antioxidative and mitogenic factors (namely, Insulin-Transferrin-Selenium (ITS) or serum) to embryo culture media would rescue development and important embryo quality parameters (cell proliferation, apoptosis, cellular metabolism and gene expression patterns) of bovine embryos derived from high PA- or high NEFA-exposed oocytes when compared to controls (exposed to basal NEFA concentrations). ITS supplementation during in vitro culture of PA-exposed oocytes supported the development of lower quality embryos during earlier development. However, surviving blastocysts were of inferior quality. In contrast, addition of serum to the culture medium did not improve developmental competence of PA-exposed oocytes. Furthermore, surviving embryos displayed higher apoptotic cell indices and an aberrant cellular metabolism. We conclude that some supportive embryo culture supplements like ITS and serum may increase IVF success rates of metabolically compromised oocytes but this may increase the risk of reduced embryo quality and may thus have other long-term consequences.

Differential effects of high fat diet-induced obesity on oocyte mitochondrial functions in inbred and outbred mice.

Maternal obesity can cause reduced oocyte quality and subfertility. Mitochondrial dysfunction plays a central role here, and most often inbred mouse models are used to study these pathways. We hypothesized that the mouse genetic background can influence the impact of high fat diet (HFD)-induced obesity on oocyte quality. We compared the inbred C57BL/6 (B6) and the outbred Swiss strains after feeding a HFD for 13w. HFD-mice had increased body weight gain, hypercholesterolemia, and increased oocyte lipid droplet (LD) accumulation in both strains. LD distribution was strain-dependent. In Swiss mouse oocytes, HFD significantly increased mitochondrial inner membrane potential (MMP), reactive oxygen species concentrations, mitochondrial ultrastructural abnormalities (by 46.4%), and endoplasmic reticulum (ER) swelling, and decreased mtDNA copy numbers compared with Swiss controls (P < 0.05). Surprisingly, B6-control oocytes exhibited signs of cellular stress compared to the Swiss controls (P < 0.05); upregulated gene expression of ER- and oxidative stress markers, high mitochondrial ultrastructural abnormalities (48.6%) and ER swelling. Consequently, the HFD impact on B6 oocyte quality was less obvious, with 9% higher mitochondrial abnormalities, and no additive effect on MMP and stress marks compared to B6 control (P > 0.1). Interestingly, mtDNA in B6-HFD oocytes was increased suggesting defective mitophagy. In conclusion, we show evidence that the genetic background or inbreeding can affect mitochondrial functions in oocytes and may influence the impact of HFD on oocyte quality. These results should create awareness when choosing and interpreting data obtained from different mouse models before extrapolating to human applications.

Exploratory study of the course of posttraumatic stress disorder after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Posttraumatic stress disorder (PTSD) occurs often in aneurysmal subarachnoid hemorrhage (aSAH) survivors, but how PTSD develops over time post-aSAH is still unclear. We examined the course of PTSD symptoms during the first year after aSAH. METHOD: In this prospective cohort study, the Impact of Event Scale (IES) was applied in 128 patients 3, 6 and 12 months after aSAH. Multilevel modelling was used to assess changes in levels of PTSD symptoms over time and to explore if demographic characteristics, aSAH characteristics, level of education, cognitive functioning and neuroticism are associated to the course of PTSD symptoms. RESULTS: Multilevel analyses showed at group level no differences in the average level of PTSD symptoms between 3, 6 of 12 months post-aSAH (p = 0.22). At individual level, changes in PTSD symptoms over time were present (X2 (121) = 149.73 p = 0.04). None of the factors could explain the variance in change of PTSD symptoms over time. CONCLUSIONS: The course of PTSD appears to differ between individuals after aSAH. We found no factors that explain these differences. There is not one optimal moment in time to assess PTSD. Therefore, it is important to assess PTSD at several time points after aSAH.

Developmental differences in higher-order resting-state networks in Autism Spectrum Disorder.

OBJECTIVE: Autism Spectrum Disorder (ASD) has been associated with a complex pattern of increases and decreases in resting-state functional connectivity. The developmental disconnection hypothesis of ASD poses that shorter connections become overly well established with development in this disorder, at the cost of long-range connections. Here, we investigated resting-state connectivity in relatively young boys with ASD and typically developing children. We hypothesized that ASD would be associated with reduced connectivity between networks, and increased connectivity within networks, reflecting poorer integration and segregation of functional networks in ASD. METHODS: We acquired resting-state fMRI from 27 boys with ASD and 29 age- and IQ-matched typically developing boys between 6 and 16 years of age. Functional connectivity networks were identified using Independent Component Analysis (ICA). Group comparisons were conducted using permutation testing, with and without voxel-wise correction for grey matter density. RESULTS: We found no between-group differences in within-network connectivity. However, we did find reduced functional connectivity between two higher-order cognitive networks in ASD. Furthermore, we found an interaction effect with age in the DMN: insula connectivity increased with age in ASD, whereas it decreased in typically developing children. CONCLUSIONS: These results show subtle changes in between network connectivity in relatively young boys with ASD. However, the global architecture of resting-state networks appeared to be intact. This argues against recent suggestions that changes in connectivity in ASD may be the most prominent during development.