Mental health indicators in pregnant women compared with women in the general population during the coronavirus disease 2019 pandemic in Denmark.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic and the associated regulations issued to minimize risk of disease transmission seem to have had an impact on general mental health in most populations, but it may have affected pregnant women even more because of pregnancy-related uncertainties, limited access to healthcare resources, and lack of social support. We aimed to compare the mental health response among pregnant women with that in similarly aged women from the general population during the first wave of the COVID-19 pandemic. MATERIAL AND METHODS: From April 14 to July 3, 2020, 647 pregnant women in their second trimester were enrolled in this study. For comparison, 858 women from the general Danish population (20-46 years) were sampled from an ongoing observational study. Participants responded to a questionnaire including six mental health indicators (concern level, perceived social isolation, quality of life, anxiety, mental health, and loneliness). Loneliness was measured using the UCLA Three-item Loneliness Scale and anxiety by the Common Mental Health Disorder Questionnaire 4-item Anxiety Subscale. RESULTS: The pregnant women had better scores during the entire study period for all mental health indicators, and except for concerns, social isolation, and mental health, the differences were also statistically significant. Pregnant women were more concerned about becoming seriously ill (40.2% vs. 29.5%, p < 0.001), whereas the general population was more concerned about economic consequences and prospects. Many pregnant women reported negative feelings associated with being pregnant during the COVID-19 pandemic and concerns regarding social isolation and regulation-imposed partner absence during hospital appointments and childbirth. All mental health indicators improved as Denmark began to reopen after the first wave of the pandemic. CONCLUSIONS: Pregnant women exhibited lower rates of poor mental health compared with the general population. However, they were more concerned about becoming seriously ill, expressed negative feelings about being pregnant during the pandemic, and were worried about the absence of their partner due to imposed regulations. These finding may be taken into account by policy-makers during pandemics to balance specific preventive measures over the potential mental health deterioration of pregnant women.

Investigating surrogate cerebrospinal fluid matrix compositions for use in quantitative LC-MS analysis of therapeutic antibodies in the cerebrospinal fluid.

As quantitative analysis of biotherapeutics in cerebrospinal fluid (CSF) with LC-MS becomes increasingly widespread, there is a need for method developments towards higher sensitivity. By using artificial CSF (aCSF) in the development phase, the consumption of costly and sparsely available CSF can be limited. The aCSF compositions tested here were made from various dilutions of bovine serum albumin (BSA) or rat plasma to mimic the total protein concentration found in CSF. Focusing on monoclonal antibodies, the aCSF was spiked with human immunoglobulin (hIgG) and prepared with the bottom-up analysis technique using LC-MS. Assuming that the composition of the aCSF would affect the digest, the response from aCSF matrices was compared with CSF from rat, monkey, and dog in terms of estimated sample concentration and matrix effects. The samples were spiked with hIgG in the range of 10 to 1000 ng/mL and volumes of 10 µL were transferred to sample preparation. The results indicate that BSA dilutions from 300 to 2000 µg/mL and rat plasma dilutions of 0.5-2% provide the most accurate concentration estimates when compared with rat CSF. 1000 µg/mL BSA did not produce significantly different concentration estimates for 500 ng/mL samples when compared with CSF from rat, monkey, and dog, and can therefore be used as aCSF for several different species.

Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes.

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.

Characterization of midazolam metabolism in locusts: the role of a CYP3A4-like enzyme in the formation of 1'-OH and 4-OH midazolam.

1. The metabolism of midazolam was investigated in vivo in locusts in order to evaluate the presence of an enzyme with functionality similar to human CYP3A4/5. 2. Hydroxylated metabolites of midazolam identical to human metabolites were detected in locusts and the apparent affinities (Km values) were in the same range as reported in humans (in locusts: 7-23 and 33-85 µM for the formation of the 1'-OH and 4-OH metabolites, respectively). 3. The formation of hydroxylated metabolites could successfully be inhibited by co-administration of ketoconazole, a known CYP3A4/5 inhibitor. 4. Besides phase I metabolites, a number of conjugated metabolites were detected using high-resolution mass spectrometry. The most abundant metabolites detected were structurally identified by (1)H NMR as two N-glucosides. NMR analysis strongly suggested that the glycosylation occurred at the two nitrogens (either one in each case) of the imidazole ring. 5. Distribution of midazolam and the glucose conjugates were successfully measured using desorption electrospray mass spectrometry imaging revealing time-dependent changes in distribution over time. 6. In conclusion, it appears that an enzyme with functionality similar to human CYP3A4/5 is present in locusts. However, it appears that conjugation with glucose is the main detoxification pathway of midazolam in locusts.

The early intestinal immune response in experimental neonatal ovine cryptosporidiosis is characterized by an increased frequency of perforin expressing NCR1(+) NK cells and by NCR1(-) CD8(+) cell recruitment.

Cryptosporidium parvum, a zoonotic protozoan parasite, causes important losses in neonatal ruminants. Innate immunity plays a key role in controlling the acute phase of this infection. The participation of NCR1+ Natural Killer (NK) cells in the early intestinal innate immune response to the parasite was investigated in neonatal lambs inoculated at birth. The observed increase in the lymphocyte infiltration was further studied by immunohistology and flow cytometry with focus on distribution, density, cellular phenotype related to cytotoxic function and activation status. The frequency of NCR1+ cells did not change with infection, while their absolute number slightly increased in the jejunum and the CD8+/NCR1- T cell density increased markedly. The frequency of perforin+ cells increased significantly with infection in the NCR1+ population (in both NCR1+/CD16+ and NCR1+/CD16- populations) but not in the NCR1-/CD8+ population. The proportion of NCR1+ cells co-expressing CD16+ also increased. The fraction of cells expressing IL2 receptor (CD25), higher in the NCR1+/CD8+ population than among the CD8+/NCR1- cells in jejunal Peyer's patches, remained unchanged during infection. However, contrary to CD8+/NCR1- lymphocytes, the intensity of CD25 expressed by NCR1+ lymphocytes increased in infected lambs. Altogether, the data demonstrating that NK cells are highly activated and possess a high cytotoxic potential very early during infection, concomitant with an up-regulation of the interferon gamma gene in the gut segments, support the hypothesis that they are involved in the innate immune response against C. parvum. The early significant recruitment of CD8+/NCR1- T cells in the small intestine suggests that they could rapidly drive the establishment of the acquired immune response.

Distribution of terfenadine and its metabolites in locusts studied by desorption electrospray ionization mass spectrometry imaging.

Desorption electrospray ionization (DESI) mass spectrometry (MS) imaging was used to image locusts dosed with the antihistamine drug terfenadine. The study was conducted in order to elucidate a relatively high elimination rate of terfenadine from the locust hemolymph. In this one of the few MS imaging studies on insects, a method for cryosectioning of whole locusts was developed, and the distributions of a number of endogenous compounds are reported, including betaine and a number of amino acids and phospholipids. Terfenadine was detected in the stomach region and the intestine walls, whereas three different metabolites-terfenadine acid (fexofenadine), terfenadine glucoside, and terfenadine phosphate-were detected in significantly smaller amounts and only in the unexcreted feces in the lower part of the intestine. The use of MS/MS imaging was necessary in order to detect the metabolites. With use of DESI-MS imaging, no colocalization of the drug and the metabolites was observed, suggesting a very rapid excretion of metabolites into the feces. Additional liquid chromatography-MS investigations were performed on hemolymph and feces and showed some abundance of terfenadine and the three metabolites, although at low levels, in both the hemolymph and the feces.

The Danish 22q11 research initiative.

BACKGROUND: Neurodevelopmental brain disorders such as schizophrenia, autism and attention deficit hyperactivity disorder are complex disorders with heterogeneous etiologies. Schizophrenia and autism are difficult to treat and often cause major individual suffering largely owing to our limited understanding of the disease biology. Thus our understanding of the biological pathogenesis needs to be substantiated to enable development of more targeted treatment options with improved efficacy. Insights into the pre-morbid disease dynamics, the morbid condition and the underlying biological disease mechanisms may come from studies of subjects with homogenous etiologies. Breakthroughs in psychiatric genetics have shown that several genetic anomalies predispose for neurodevelopmental brain disorders. We have established a Danish research initiative to study the common microdeletion at chromosome 22q11.2, which is one of the genetic anomalies that confer high risk of schizophrenia, autism and attention deficit hyperactivity disorder. METHODS/DESIGN: The study applies a "cause-to-outcome" strategy to identify pre-morbid pathogenesis and underlying biological disease mechanisms of psychosis and secondarily the morbid condition of autism and attention deficit hyperactivity disorder. We use a population based epidemiological design to inform on disease prevalence, environmental risk factors and familial disposition for mental health disorders and a case control study design to map the functional effects across behavioral and neurophysiological traits of the 22q11 deletion in a recruited sample of Danish individuals. DISCUSSION: Identification of predictive pre-morbid clinical, cognitive, functional and structural brain alterations in 22q11 deletion carriers may alter current clinical practice from symptomatic therapy of manifest mental illness into early intervention strategies, which may also be applicable to at risk subjects without known etiology. Hopefully new insights into the biological disease mechanisms, which are mandatory for novel drug developments, can improve the outcome of the pharmacological interventions in psychiatry.

Identification of a functional homolog of the mammalian CYP3A4 in locusts.

Insects have been proposed as a new tool in early drug development. It was recently demonstrated that locusts have an efflux transporter localized in the blood-brain barrier (BBB) that is functionally similar to the mammalian P-glycoprotein efflux transporter. Two insect BBB models have been put forward, an ex vivo model and an in vivo model. To use the in vivo model it is necessary to fully characterize the locust as an entire organism with regards to metabolic pathways and excretion rate. In the present study, we have characterized the locust metabolism of terfenadine, a compound that in humans is specific to the cytochrome P450 enzyme 3A4. Using high-resolution mass spectrometry coupled to ultra-high-performance liquid chromatography, we have detected metabolites identical to human metabolites of terfenadine. The formation of human metabolites in locusts was inhibited by ketoconazole, a mammalian CYP3A4 inhibitor, suggesting that the enzyme responsible for the human metabolite formation in locusts is functionally similar to human CYP3A4. Besides the human metabolites of terfenadine, additional metabolites were formed in locusts. These were tentatively identified as phosphate and glucose conjugates. In conclusion, not only may locusts be a model useful for determining BBB permeation, but possibly insects could be used in metabolism investigation. However, extensive characterization of the insect model is necessary to determine its applicability.

Stress-free blood sampling in minipigs: A novel method for assessing 24-h cortisol profiles and drug effects on diurnal and ultradian rhythms.

We developed a novel, stress-free blood sampling method for minipigs, allowing continuous cortisol monitoring over 24 h. Baseline cortisol levels exhibited both ultradian and diurnal rhythms. During nighttime, smaller ultradian rhythms overlaid a lower baseline cortisol, which increased in sleeping pigs before lights were turned on. Additionally, we developed an analytical tool based on the R package "pracma" to quantify ultradian peak and circadian components of the cortisol profiles. To validate our model, we investigated the effects of Verucerfont, a CRH receptor antagonist, and Venlafaxine, a serotonin-norepinephrine reuptake inhibitor. Verucerfont reduced cortisol levels during the first 9 h without affecting diurnal rhythm. Cortisol peak parameters decreased, with a 31% reduction in overall area under the curve (AUC) and a 38% reduction in ultradian average AUC. Ultradian peaks decreased from 7 to 4.5, with 34% lower amplitude. Venlafaxine maintained plasma concentrations within the targeted human effective range. This method enables us to enhance our understanding of cortisol regulation and provide valuable insights for the impact of investigation drugs on the diurnal and ultradian rhythms of cortisol.

Necropsy findings, meat control pathology and causes of loss in semi-domesticated reindeer (Rangifer tarandus tarandus) in northern Norway.

BACKGROUND: Reindeer herding in Norway is based on traditional Sámi pastoralism with the animals free ranging throughout the year. The animals move over large areas in varying terrain and often in challenging weather conditions. Winter crises, such as difficult grazing conditions caused by icing or large amounts of snow, are survival bottlenecks for reindeer. Calves are especially vulnerable, and many may die from starvation during winter crises. Predation and starvation are the predominant narratives to explain losses, however, carcasses are difficult to find and often little remains after scavenging and decay. Documentation of the causes of death is therefore scarce. RESULTS: In this study, we investigated the cause of reindeer mortality in Troms and Finnmark, Nordland and Trøndelag during 2017-2019. Necropsies (n = 125) and organ investigation (n = 13) were performed to document cause of death. Body condition was evaluated using visual fat score and bone marrow fat index. A wide range of causes of death was detected. The diagnoses were categorized into the following main categories: predation (n = 40), emaciation (n = 35), infectious disease (n = 20), trauma (n = 11), feeding related disease (n = 5), neoplasia (n = 4), others (n = 6) and unknown (n = 17). Co-morbidities were seen in a number of diagnoses (n = 16). Reindeer herders are entitled to economic compensation for reindeer killed by endangered predators, but a lack of documentation leads to a gap between the amount of compensation requested and what is awarded. An important finding of our study was that predators, during winter, killed animals in good as well as poor body condition. Emaciation was also shown to be associated with infectious diseases, and not only attributable to winter grazing conditions. CONCLUSIONS: This study highlights the importance of examining dead reindeer to gain knowledge about why they die on winter pasture. The work presented herein also shows the feasibility and value of increased documentation of reindeer losses during winter.

The grasshopper: a novel model for assessing vertebrate brain uptake.

The aim of the present study was to develop a blood-brain barrier (BBB) permeability model that is applicable in the drug discovery phase. The BBB ensures proper neural function, but it restricts many drugs from entering the brain, and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability, but the permeability characteristics of the human BBB are notoriously complex and hard to predict. Consequently, one single suitable BBB permeability screening model, which is generally applicable in the early drug discovery phase, does not yet exist. A new refined ex vivo insect-based BBB screening model that uses an intact, viable whole brain under controlled in vitro-like exposure conditions is presented. This model uses intact brains from desert locusts, which are placed in a well containing the compound solubilized in an insect buffer. After a limited time, the brain is removed and the compound concentration in the brain is measured by conventional liquid chromatography-mass spectrometry. The data presented here include 25 known drugs, and the data show that the ex vivo insect model can be used to measure the brain uptake over the hemolymph-brain barrier of drugs and that the brain uptake shows linear correlation with in situ perfusion data obtained in vertebrates. Moreover, this study shows that the insect ex vivo model is able to identify P-glycoprotein (Pgp) substrates, and the model allows differentiation between low-permeability compounds and compounds that are Pgp substrates.

Characterization of NCR1+ cells residing in lymphoid tissues in the gut of lambs indicates that the majority are NK cells.

Natural killer (NK) cells are important for immune protection of the gut mucosa. Previous studies have shown that under pathologic conditions NK cells, T cells and dendritic cells are found co-localised in secondary lymphoid organs where their interaction coordinates immune responses. However, in the gut-associated lymphoid tissues (GALTs), there are few detailed reports on the distribution of NK cells. Sheep harbour several types of organised lymphoid tissues in the gut that have different functions. The ileal Peyer's patch (IPP) functions as a primary lymphoid tissue for B cell generation, while the jejunal Peyer's patches (JPPs) and colon patches (CPs) are considered secondary lymphoid tissues. In the present study, we analysed tissues from healthy lambs by flow cytometry and in situ multicolour immunofluorescence, using recently described NCR1 antibodies to identify ovine NK cells. Most NCR1+ cells isolated from all tissues were negative for the pan T cell marker CD3, and thus comply with the general definition of NK cells. The majority of NCR1+ cells in blood as well as secondary lymphoid organs expressed CD16, but in the GALT around half of the NCR1+ cells were negative for CD16. A semi-quantitative morphometric study on tissue sections was used to compare the density of NK cells in four compartments of the IPPs, JPP and CPs. NCR1+ cells were found in all gut segments. Statistical analysis revealed significant differences between compartments of the primary lymphoid organ IPP and the secondary lymphoid organs of the JPPs and CP. NK cells co-localised and made close contact with T cells, dendritic cells and other NK cells, but did not show signs of proliferation. We conclude that NK cells are present in all investigated segments of the sheep gut, but that presence of other innate lymphoid cells expressing NCR1 cannot be excluded.

Constituents in kava extracts potentially involved in hepatotoxicity: a review.

Aqueous kava root preparations have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava extracts in Western countries, where mainly ethanolic or acetonic extracts are used. The mechanism of toxicity has not been established, although several theories have been put forward. The composition of the major constituents, the kava lactones, varies according to preparation method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain composition of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chemical structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones have been identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addition of GSH to kava extracts has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava extract, such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries.

Does Exercise Influence the Susceptibility to Arterial Thrombosis? An Integrative Perspective.

Arterial thrombosis is the primary cause of death worldwide, with the most important risk factors being smoking, unhealthy diet, and physical inactivity. However, although there are clear indications in the literature of beneficial effects of physical activity in lowering the risk of cardiovascular events, exercise can be considered a double-edged sword in that physical exertion can induce an immediate pro-thrombotic environment. Epidemiological studies show an increased risk of cardiovascular events after acute exercise, a risk, which appear to be particularly apparent in individuals with lifestyle-related disease. Factors that cause the increased susceptibility to arterial thrombosis with exercise are both chemical and mechanical in nature and include circulating catecholamines and vascular shear stress. Exercise intensity plays a marked role on such parameters, and evidence in the literature accordingly points at a greater susceptibility to thrombus formation at high compared to light and moderate intensity exercise. Of importance is, however, that the susceptibility to arterial thrombosis appears to be lower in exercise-conditioned individuals compared to sedentary individuals. There is currently limited data on the role of acute and chronic exercise on the susceptibility to arterial thrombosis, and many studies include incomplete assessments of thrombogenic clotting profile. Thus, further studies on the role of exercise, involving valid biomarkers, are clearly warranted.

Aerobic High-Intensity Exercise Training Improves Cardiovascular Health in Older Post-menopausal Women.

The aim of this study was to determine the effect of a period of aerobic high intensity training on central- and peripheral cardiovascular parameters in older post-menopausal women. Eleven healthy post-menopausal (>10 years after menopause) women (mean age: 64 years; BMI: 25.3 kg m-2) completed an 8-week period of supervised, high intensity cycle training, with sessions conducted three times per week. Before and after the training period maximal oxygen uptake, body composition, popliteal artery flow mediated dilation, exercise hyperemia, arterial blood pressure, and plasma lipids were assessed. In addition, levels of estrogen related receptor α (ERRα) and vasodilator enzymes were determined in muscle biopsy samples. Training induced an 18% increase (P < 0.001) in maximal oxygen uptake. Plasma High-density lipoprotein (HDL) was higher (P < 0.05) after than before the training period. Fat mass was reduced (4.9%; P < 0.01), whereas lean body mass was unaltered. Mean arterial blood pressure was unchanged (91 vs. 88 mmHg; P = 0.058) with training. Training did not induce a change in popliteal flow mediated dilation. Exercise hyperemia at submaximal exercise was lower (P < 0.01; 11 and 4.6% at 10 and 16 W, respectively) after compared to before training. Muscle ERRα (~1.7-fold; P < 0.01) and eNOS (~1.4-fold; P < 0.05) were higher after the training intervention. The current study demonstrates that, in older post-menopausal women, a period of aerobic high intensity training effectively increases maximal oxygen uptake and improves the cardiovascular health profile, without a parallel improvement in conduit artery function.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies at Delivery in Women, Partners, and Newborns.

OBJECTIVE: To investigate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in parturient women, their partners, and their newborns and the association of such antibodies with obstetric and neonatal outcomes. METHODS: From April 4 to July 3, 2020, in a single university hospital in Denmark, all parturient women and their partners were invited to participate in the study, along with their newborns. Participating women and partners had a pharyngeal swab and a blood sample taken at admission; immediately after delivery, a blood sample was drawn from the umbilical cord. The swabs were analyzed for SARS-CoV-2 RNA by polymerase chain reaction, and the blood samples were analyzed for SARS-CoV-2 antibodies. Full medical history and obstetric and neonatal information were available. RESULTS: A total of 1,313 parturient women (72.5.% of all women admitted for delivery at the hospital in the study period), 1,188 partners, and 1,206 newborns participated in the study. The adjusted serologic prevalence was 2.6% in women and 3.5% in partners. Seventeen newborns had SARS-CoV-2 immunoglobulin G (IgG) antibodies, and none had immunoglobulin M antibodies. No associations between SARS-CoV-2 antibodies and obstetric or neonatal complications were found (eg, preterm birth, preeclampsia, cesarean delivery, Apgar score, low birth weight, umbilical arterial pH, need for continuous positive airway pressure, or neonatal admission), but statistical power to detect such differences was low. Full serologic data from 1,051 families showed an absolute risk of maternal infection of 39% if the partner had antibodies. CONCLUSION: We found no association between SARS-CoV-2 infection and obstetric or neonatal complications. Sixty-seven percent of newborns delivered by mothers with antibodies had SARS-CoV-2 IgG antibodies. A limitation of our study is that we lacked statistical power to detect small but potentially meaningful differences between those with and without evidence of infection.

Can Animal Models of Copy Number Variants That Predispose to Schizophrenia Elucidate Underlying Biology?

The diagnosis of schizophrenia rests on clinical criteria that cannot be assessed in animal models. Together with absence of a clear underlying pathology and understanding of what causes schizophrenia, this has hindered development of informative animal models. However, recent large-scale genomic studies have identified copy number variants (CNVs) that confer high risk of schizophrenia and have opened a new avenue for generation of relevant animal models. Eight recurrent CNVs have reproducibly been shown to increase the risk of schizophrenia by severalfold: 22q11.2(del), 15q13.3(del), 1q21(del), 1q21(dup), NRXN1(del), 3q29(del), 7q11.23(dup), and 16p11.2(dup). Five of these CNVs have been modeled in animals, mainly mice, but also rats, flies, and zebrafish, and have been shown to recapitulate behavioral and electrophysiological aspects of schizophrenia. Here, we provide an overview of the schizophrenia-related phenotypes found in animal models of schizophrenia high-risk CNVs. We also discuss strengths and limitations of the CNV models, and how they can advance our biological understanding of mechanisms that can lead to schizophrenia and can be used to develop new and better treatments for schizophrenia.

Individuals with 22q11.2 deletion syndrome show intact prediction but reduced adaptation in responses to repeated sounds: Evidence from Bayesian mapping.

One of the most common copy number variants, the 22q11.2 microdeletion, confers an increased risk for schizophrenia. Since schizophrenia has been associated with an aberrant neural response to repeated stimuli through both reduced adaptation and prediction, we here hypothesized that this may also be the case in nonpsychotic individuals with a 22q11.2 deletion. We recorded high-density EEG from 19 individuals with 22q11.2 deletion syndrome (12-25 years), as well as 27 healthy volunteers with comparable age and sex distribution, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Using posterior probability maps and dynamic causal modelling we tested three different models accounting for repetition dependent changes in cortical responses as well as in effective connectivity; namely an adaptation model, a prediction model, and a model including both adaptation and prediction. Repetition-dependent changes were parametrically modulated by a combination of adaptation and prediction and were apparent in both cortical responses and in the underlying effective connectivity. This effect was reduced in individuals with a 22q11.2 deletion and was negatively correlated with negative symptom severity. Follow-up analysis showed that the reduced effect of the combined adaptation and prediction model seen in individuals with 22q11.2 deletion was driven by reduced adaptation rather than prediction failure. Our findings suggest that adaptation is reduced in individuals with a 22q11.2 deletion, which can be interpreted in light of the framework of predictive coding as a failure to suppress prediction errors.

The estrogen hypothesis of schizophrenia implicates glucose metabolism: association study in three independent samples.

BACKGROUND: Schizophrenia is a highly heritable complex psychiatric disorder with an underlying pathophysiology that is still not well understood. Metaanalyses of schizophrenia linkage studies indicate numerous but rather large disease-associated genomic regions, whereas accumulating gene- and protein expression studies have indicated an equally large set of candidate genes that only partially overlap linkage genes. A thorough assessment, beyond the resolution of current GWA studies, of the disease risk conferred by the numerous schizophrenia candidate genes is a daunting and presently not feasible task. We undertook these challenges by using an established clinical paradigm, the estrogen hypothesis of schizophrenia, as the criterion to select candidates among the numerous genes experimentally implicated in schizophrenia. Bioinformatic tools were used to build and priorities the signaling networks implicated by the candidate genes resulting from the estrogen selection. We identified ten candidate genes using this approach that are all active in glucose metabolism and particularly in the glycolysis. Thus, we tested the hypothesis that variants of the glycolytic genes are associated with schizophrenia or at least with gender-associated aspects of the illness. RESULTS: We genotyped 185 SNPs in three independent case-control samples of Scandinavian origin (a total of 765 patients and 1274 control subjects). Variants of the mitogen-activated protein kinase 14 gene (MAPK14) and the phosphoenolpyruvate carboxykinase 1 (PCK1) and fructose-1,6-biphosphatase (FBP1) were nominal significantly associated with schizophrenia, and several haplotypes within enolase 2 gene (ENO2) consist of the same SNP allele having elevated risk of schizophrenia. Importantly, we find no evidence of stratification due to nationality or gender. CONCLUSION: Several gene variants in the Glycolysis were associated with schizophrenia in three independent samples. However, the findings are weak and not resistant to correction for multiple testing, which may indicate that they are either spurious or may relate to a particular subtype or aspect of the illness.

22q11.2 Deletion Syndrome Is Associated With Impaired Auditory Steady-State Gamma Response.

Background: The 22q11.2 deletion syndrome confers a markedly increased risk for schizophrenia. 22q11.2 deletion carriers without manifest psychotic disorder offer the possibility to identify functional abnormalities that precede clinical onset. Since schizophrenia is associated with a reduced cortical gamma response to auditory stimulation at 40 Hz, we hypothesized that the 40 Hz auditory steady-state response (ASSR) may be attenuated in nonpsychotic individuals with a 22q11.2 deletion. Methods: Eighteen young nonpsychotic 22q11.2 deletion carriers and a control group of 27 noncarriers with comparable age range (12-25 years) and sex ratio underwent 128-channel EEG. We recorded the cortical ASSR to a 40 Hz train of clicks, given either at a regular inter-stimulus interval of 25 ms or at irregular intervals jittered between 11 and 37 ms. Results: Healthy noncarriers expressed a stable ASSR to regular but not in the irregular 40 Hz click stimulation. Both gamma power and inter-trial phase coherence of the ASSR were markedly reduced in the 22q11.2 deletion group. The ability to phase lock cortical gamma activity to regular auditory 40 Hz stimulation correlated with the individual expression of negative symptoms in deletion carriers (ρ = -0.487, P = .041). Conclusions: Nonpsychotic 22q11.2 deletion carriers lack efficient phase locking of evoked gamma activity to regular 40 Hz auditory stimulation. This abnormality indicates a dysfunction of fast intracortical oscillatory processing in the gamma-band. Since ASSR was attenuated in nonpsychotic deletion carriers, ASSR deficiency may constitute a premorbid risk marker of schizophrenia.