A rare duplication on chromosome 16p11.2 is identified in patients with psychosis in Alzheimer's disease

Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer's disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. A chromosome 16p11.2 duplication CNV (chr16: 29,554,843-30,105,652) was identified in 2 of 440 AD+P subjects, but not in 136 AD subjects without psychosis, or in 593 AD subjects with intermediate psychosis status, or in 855 non-AD individuals. The frequency of this duplication CNV in AD+P (0.46%) was similar to that reported previously in schizophrenia (0.46%). This duplication CNV was further validated using the NanoString nCounter CNV Custom CodeSets. The 16p11.2 duplication has been associated with developmental delay, intellectual disability, behavioral problems, autism, schizophrenia (SCZ), and bipolar disorder. These two AD+P patients had no personal of, nor any identified family history of, SCZ, bipolar disorder and autism. To the best of our knowledge, our case report is the first suggestion that 16p11.2 duplication is also linked to AD+P. Although rare, this CNV may have an important role in the development of psychosis

COVID-19 vaccination perceptions and intentions of maternity care consumers and providers in Australia.

IntroductionVaccination against COVID-19 is a key global public health strategy. Health professionals including midwives and doctors support and influence vaccination uptake by childbearing women. There is currently no evidence regarding the COVID-19 vaccination perceptions and intentions of those who receive or provide maternity care in Australia. The aim of this study was to address this gap in knowledge and explore the perceptions and intentions regarding COVID-19 vaccination from consumers and providers of maternity care in Australia.MethodsA national cross-sectional online study conducted in early 2021 in Australia, a country that has had a very low number of COVID-19 cases and deaths. Recruitment was undertaken through parenting and health professional social media sites and professional college distribution lists. A total of 853 completed responses, from women (n = 326), maternity care providers including doctors (n = 58), midwives (n = 391) and midwifery students (n = 78).FindingsPersonal intention to be vaccinated ranged from 48-89% with doctors most likely and women least likely. Doctors and midwifery students were significantly more likely to recommend the vaccine to pregnant women in their care than midwives (pConclusionThis is the first study to explore the perceptions and intentions regarding COVID-19 vaccination from the perspective of those who receive and provide maternity care in Australia. Findings have utility to support targeted public health messaging for these and other cohorts

Experiences of receiving and providing maternity care during the COVID-19 pandemic in Australia: A five-cohort cross-sectional comparison.

Introduction The global COVID-19 pandemic has radically changed the way health care is delivered in many countries around the world. Evidence on the experience of those receiving or providing maternity care is important to guide practice through this challenging time. Methods A cross-sectional study was conducted in Australia. Five key stakeholder cohorts were included to explore and compare the experiences of those receiving or providing care during the COVID-19 pandemic. Women, their partners, midwives, medical practitioners and midwifery students who had received or provided maternity care from March 2020 onwards in Australia were recruited via social media and invited to participate in an online survey released between 13th May and 24th June 2020; a total of 3701 completed responses were received. Findings While anxiety related to COVID-19 was high among all five cohorts, there were statistically significant differences between the responses from each cohort for most survey items. Women were more likely to indicate concern about their own and family’s health and safety in relation to COVID-19 whereas midwives, doctors and midwifery students were more likely to be concerned about occupational exposure to COVID-19 through working in a health setting than those receiving care through attending these environments. Midwifery students and women’s partners were more likely to respond that they felt isolated because of the changes to the way care was provided. Despite concerns about care received or provided not meeting expectations, most respondents were satisfied with the quality of care provided, although midwives and midwifery students were less likely to agree. Conclusion This paper provides a unique exploration and comparison of experiences of receiving and providing maternity care during the COVID-19 pandemic in Australia. Findings are useful to support further service changes and future service redesign. New evidence provided offers unique insight into key stakeholders’ experiences of the rapid changes to health services

PAK1 Protein Expression in the Auditory Cortex of Schizophrenia Subjects

Deficits in auditory processing are among the best documented endophenotypes in schizophrenia, possibly due to loss of excitatory synaptic connections. Dendritic spines, the principal post-synaptic target of excitatory projections, are reduced in schizophrenia. p21-activated kinase 1 (PAK1) regulates both the actin cytoskeleton and dendritic spine density, and is a downstream effector of both kalirin and CDC42, both of which have altered expression in schizophrenia. This study sought to determine if there is decreased auditory cortex PAK1 protein expression in schizophrenia through the use of quantitative western blots of 25 schizophrenia subjects and matched controls. There was no significant change in PAK1 level detected in the schizophrenia subjects in our cohort. PAK1 protein levels within subject pairs correlated positively with prior measures of total kalirin protein in the same pairs. PAK1 level also correlated with levels of a marker of dendritic spines, spinophilin. These latter two findings suggest that the lack of change in PAK1 level in schizophrenia is not due to limited sensitivity of our assay to detect meaningful differences in PAK1 protein expression. Future studies are needed to evaluate whether alterations in PAK1 phosphorylation states, or alterations in protein expression of other members of the PAK family, are present in schizophrenia

Genetic association between APOE*4 and neuropsychiatric symptoms in patients with probable Alzheimer's disease is dependent on the psychosis phenotype

Background: Neuropsychiatric symptoms such as psychosis are prevalent in patients with probable Alzheimer's disease (AD) and are associated with increased morbidity and mortality. Because these disabling symptoms are generally not well tolerated by caregivers, patients with these symptoms tend to be institutionalized earlier than patients without them. The identification of protective and risk factors for neuropsychiatric symptoms in AD would facilitate the development of more specific treatments for these symptoms and thereby decrease morbidity and mortality in AD. The E4 allele of the apolipoprotein E (APOE) gene is a well-documented risk factor for the development of AD. However, genetic association studies of the APOE 4 allele and BPS in AD have produced conflicting findings.Methods: This study investigates the association between APOE and neuropsychiatric symptoms in a large sample of clinically well-characterized subjects with probable AD (n=790) who were systematically evaluated using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Behavioral Rating Scale for Dementia (BRSD).Results: Our study found that hallucinations were significantly more likely to occur in subjects with no APOΕ4 alleles than in subjects with two Ε4 alleles (15% of subjects and 5% of subjects, respectively; p=.0066), whereas there was no association between the occurrence of delusions, aberrant motor behavior, or agitation and the number of Ε4 alleles. However, 94% of the subjects with hallucinations also had delusions (D+H).Conclusion: These findings suggest that in AD the Ε4 allele is differentially associated with D+H but not delusions alone. This is consistent with the hypothesis that distinct psychotic subphenotypes may be associated with the APOE allele. © 2012 Christie et al.; licensee BioMed Central Ltd

Influenza Virus Infection of the Murine Uterus: A New Model for Antiviral Immunity in the Female Reproductive Tract

Secretory IgA (S-IgA) mediates local immunity to influenza virus in the murine upper respiratory tract and may play an important role in local immunity to various microorganisms in the female reproductive tract as well. Although the presence of IgA in cervicovaginal or uterine secretions has been correlated with immunity to a number of pathogens, there has been no direct demonstration of the mediation of uterine antiviral immunity by S-IgA. Influenza virus, although not a normal pathogen of the reproductive tract, was used to develop a model for the investigation of mucosal immunity in the uterus. PR8 (H1N1) influenza virus injected into the ovarian bursa of BALB/c mice grew well, with peak titers between days 3 and 5. Intravenous injection of polymeric IgA anti-influenza virus monoclonal antibody before or 30 min after viral challenge protected mice against viral infection. We believe this work to be the first direct demonstration of S-IgA-mediated antiviral uterine immunity. It provides a model for further investigation of immunity in the female reproductive tract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63226/1/vim.2006.19.613.pd

FastGGM: An Efficient Algorithm for the Inference of Gaussian Graphical Model in Biological Networks

Biological networks provide additional information for the analysis of human diseases, beyond the traditional analysis that focuses on single variables. Gaussian graphical model (GGM), a probability model that characterizes the conditional dependence structure of a set of random variables by a graph, has wide applications in the analysis of biological networks, such as inferring interaction or comparing differential networks. However, existing approaches are either not statistically rigorous or are inefficient for high-dimensional data that include tens of thousands of variables for making inference. In this study, we propose an efficient algorithm to implement the estimation of GGM and obtain p-value and confidence interval for each edge in the graph, based on a recent proposal by Ren et al., 2015. Through simulation studies, we demonstrate that the algorithm is faster by several orders of magnitude than the current implemented algorithm for Ren et al. without losing any accuracy. Then, we apply our algorithm to two real data sets: transcriptomic data from a study of childhood asthma and proteomic data from a study of Alzheimer’s disease. We estimate the global gene or protein interaction networks for the disease and healthy samples. The resulting networks reveal interesting interactions and the differential networks between cases and controls show functional relevance to the diseases. In conclusion, we provide a computationally fast algorithm to implement a statistically sound procedure for constructing Gaussian graphical model and making inference with high-dimensional biological data. The algorithm has been implemented in an R package named “FastGGM”

Male reproductive health and environmental xenoestrogens

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.Supported by EU Contract BMH4-CT96-0314

Synaptic Dysbindin-1 Reductions in Schizophrenia Occur in an Isoform-Specific Manner Indicating Their Subsynaptic Location

Background: An increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific. Methodology/Principal Findings: Using Western blotting of tissue fractions, we first determined the synaptic localization of the three major dysbindin-1 isoforms (A, B, and C). All three were concentrated in synaptosomes of multiple brain areas, including auditory association cortices in the posterior half of the superior temporal gyrus (pSTG) and the hippocampal formation (HF). Tests on the subsynaptic tissue fractions revealed that each isoform is predominantly, if not exclusively, associated with synaptic vesicles (dysbindin-1B) or with postsynaptic densities (dysbindin-1A and -1C). Using Western blotting on pSTG (n = 15) and HF (n = 15) synaptosomal fractions from schizophrenia cases and their matched controls, we discovered that synaptic dysbindin-1 is reduced in an isoform-specific manner in schizophrenia without changes in levels of synaptophysin or PSD-95. In pSTG, about 92% of the schizophrenia cases displayed synaptic dysbindin-1A reductions averaging 48% (p = 0.0007) without alterations in other dysbindin-1 isoforms. In the HF, by contrast, schizophrenia cases displayed normal levels of synaptic dysbindin-1A, but 67% showed synaptic reductions in dysbindin-1B averaging 33% (p = 0.0256), while 80% showed synaptic reductions in dysbindin-1C averaging 35% (p = 0.0171). Conclusions/Significance: Given the distinctive subsynaptic localization of dysbindin-1A, -1B, and -1C across brain regions, the observed pSTG reductions in dysbindin-1A are postsynaptic and may promote dendritic spine loss with consequent disruption of auditory information processing, while the noted HF reductions in dysbindin-1B and -1C are both presynaptic and postsynaptic and could promote deficits in spatial working memory