Recent findings suggest that tau oligomers, which form before neurofibrillary tangles (NFTs), are the true neurotoxic tau entities in neurodegenerative tauopathies, including Alzheimer's disease ...(AD). Studies in animal models of tauopathy suggest that tau oligomers play a key role in eliciting behavioral and cognitive impairments. Here, we used a novel tau oligomer-specific monoclonal antibody (TOMA) for passive immunization in mice expressing mutant human tau. A single dose of TOMA administered either intravenously or intracerebroventricularly was sufficient to reverse both locomotor and memory deficits in a mouse model of tauopathy for 60 d, coincident with rapid reduction of tau oligomers but not phosphorylated NFTs or monomeric tau. Our data demonstrate that antibody protection is mediated by extracellular and rapid peripheral clearance. These findings provide the first direct evidence in support of a critical role for tau oligomers in disease progression and validate tau oligomers as a target for the treatment of AD and other neurodegenerative tauopathies.
Objectives The aim of this study was to determine the efficacy of implantable cardioverter-defibrillators (ICDs) in children and adolescents with hypertrophic cardiomyopathy (HCM). Background HCM is ...the most common cause of sudden death in the young. The availability of ICDs over the past decade for HCM has demonstrated the potential for sudden death prevention, predominantly in adult patients. Methods A multicenter international registry of ICDs implanted (1987 to 2011) in 224 unrelated children and adolescents with HCM judged at high risk for sudden death was assembled. Patients received ICDs for primary (n = 188) or secondary (n = 36) prevention after undergoing evaluation at 22 referral and nonreferral institutions in the United States, Canada, Europe, and Australia. Results Defibrillators were activated appropriately to terminate ventricular tachycardia or ventricular fibrillation in 43 of 224 patients (19%) over a mean of 4.3 ± 3.3 years. ICD intervention rates were 4.5% per year overall, 14.0% per year for secondary prevention after cardiac arrest, and 3.1% per year for primary prevention on the basis of risk factors (5-year cumulative probability 17%). The mean time from implantation to first appropriate discharge was 2.9 ± 2.7 years (range to 8.6 years). The primary prevention discharge rate terminating ventricular tachycardia or ventricular fibrillation was the same in patients who underwent implantation for 1, 2, or ≥3 risk factors (12 of 88 14%, 10 of 71 14%, and 4 of 29 14%, respectively, p = 1.00). Extreme left ventricular hypertrophy was the most common risk factor present (alone or in combination with other markers) in patients experiencing primary prevention interventions (17 of 26 65%). ICD-related complications, particularly inappropriate shocks and lead malfunction, occurred in 91 patients (41%) at 17 ± 5 years of age. Conclusions In a high-risk pediatric HCM cohort, ICD interventions terminating life-threatening ventricular tachyarrhythmias were frequent. Extreme left ventricular hypertrophy was most frequently associated with appropriate interventions. The rate of device complications adds a measure of complexity to ICD decisions in this age group.
Burkholderia mallei, the etiologic agent of the disease known as glanders, is primarily a disease affecting horses and is transmitted to humans by direct contact with infected animals. The use of B. ...mallei as a biological weapon has been reported and currently, there is no vaccine available for either humans or animals. Despite the history and highly infective nature of B. mallei, as well as its potential use as a bio-weapon, B. mallei research to understand the pathogenesis and the host responses to infection remains limited. Therefore, this minireview will focus on current efforts to elucidate B. mallei virulence, the associated host immune responses elicited during infection and discuss the feasibility of vaccine development.
Mycobacterium tuberculosis (M.tb) is the second leading infectious cause of death worldwide and the primary cause of death in people living with HIV/AIDS. There are several excellent animal models ...employed to study tuberculosis (TB), but many have limitations for reproducing human pathology and none are amenable to the direct study of HIV/M.tb co-infection. The humanized mouse has been increasingly employed to explore HIV infection and other pathogens where animal models are limiting. Our goal was to develop a small animal model of M.tb infection using the bone marrow, liver, thymus (BLT) humanized mouse. NOD-SCID/γc(null) mice were engrafted with human fetal liver and thymus tissue, and supplemented with CD34(+) fetal liver cells. Excellent reconstitution, as measured by expression of the human CD45 pan leukocyte marker by peripheral blood populations, was observed at 12 weeks after engraftment. Human T cells (CD3, CD4, CD8), as well as natural killer cells and monocyte/macrophages were all observed within the human leukocyte (CD45(+)) population. Importantly, human T cells were functionally competent as determined by proliferative capacity and effector molecule (e.g. IFN-γ, granulysin, perforin) expression in response to positive stimuli. Animals infected intranasally with M.tb had progressive bacterial infection in the lung and dissemination to spleen and liver from 2-8 weeks post infection. Sites of infection in the lung were characterized by the formation of organized granulomatous lesions, caseous necrosis, bronchial obstruction, and crystallization of cholesterol deposits. Human T cells were distributed throughout the lung, liver, and spleen at sites of inflammation and bacterial growth and were organized to the periphery of granulomas. These preliminary results demonstrate the potential to use the humanized mouse as a model of experimental TB.
To address the lack of predictors of IVF success by using proteomic biometrics.
Experimental study of follicular fluid specimens from a prospective cohort of IVF patients.
Academic research ...laboratory and IVF program.
Women <or=32 years old with <11 oocytes retrieved and no pregnancy were matched to women who had >or=11 oocytes and live birth (10 pairs). Year of cycle start and IVF down-regulation protocol were also matched.
Follicular fluid was separated by two-dimensional polyacrylamide gel electrophoresis followed by Sypro Ruby staining and comparison with PDQuest software. Logistic regression was incorporated to calculate the likelihood of live birth in relation to the protein spot of interest.
Protein markers.
Liquid chromatography-tandem mass spectrometry and searching of sequence databases revealed 11 potential protein candidates. Haptoglobin alpha, predominantly fetal expressed T1 domain, mitochondrial integrity genome (ATPase), apolipoprotein H (beta-2 glycoprotein I), dihydrolipoyl dehydrogenase, lyzozyme C, fibrinogen alpha-chain, and immunoglobulin heavy chain V-III (region BRO) were found to have increased expression in the live birth group, whereas antithrombin, vitamin D-binding protein, and complement 3 were decreased. An ELISA confirmed a significantly lower level of antithrombin.
Proteomic evaluation of follicular fluid is able to identify potential biomarkers of good versus poor responders in matched pairs of IVF patients.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early ...interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% 95% confidence interval (CI), 62.9 to 100, correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3). These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD.
Background: Prevalence and morbidity of allergic diseases have increased over the last decades. Based on the recently recognized differences in asthma prevalence between the sexes, we have examined ...the effect of endogenous estrogens on a key element of the allergic response. Some lipophilic pollutants have estrogen-like activities and are termed environmental estrogens. These pollutants tend to degrade slowly in the environment and to bioaccumulate and bioconcentrate in the food chain; they also have long biological half-lives. Objectives: Our goal in this study was to identify possible pathogenic roles for environmental estrogens in the development of allergic diseases. Methods: We screened a number of environmental estrogens for their ability to modulate the release of allergic mediators from mast cells. We incubated a human mast cell line and primary mast cell cultures derived from bone marrow of wild type and estrogen receptor a (ER-α)-deficient mice with environmental estrogens with and without estradiol or IgE and allergens. We assessed degranulation of mast cells by quantifying the release of (β-hexosaminidase. Results: All of the environmental estrogens tested caused rapid, dose-related release of β-hexosaminidase from mast cells and enhanced IgE-mediated release. The combination of physiologic concentrations of 17β-estradiol and several concentrations of environmental estrogens had additive effects on mast cell degranulation. Comparison of bone marrow mast cells from ER-α-sufficient and ER-α-deficient mice indicated that much of the effect of environmental estrogens was mediated by ER-α. Conclusions: Our findings suggest that estrogenic environmental pollutants might promote allergic diseases by inducing and enhancing mast cell degranulation by physiologic estrogens and exposure to allergens.
Sleep patterns in children with autism spectrum disorder (ASD) appear to diverge from typical development in the second or third year of life. Little is known, however, about the occurrence of sleep ...problems in infants who later develop ASD and possible effects on early brain development. In a longitudinal neuroimaging study of infants at familial high or low risk for ASD, parent-reported sleep onset problems were examined in relation to subcortical brain volumes in the first 2 years of life.
A total of 432 infants were included across three study groups: infants at high risk who developed ASD (N=71), infants at high risk who did not develop ASD (N=234), and infants at low risk (N=127). Sleep onset problem scores (derived from an infant temperament measure) were evaluated in relation to longitudinal high-resolution T
and T
structural imaging data acquired at 6, 12, and 24 months of age.
Sleep onset problems were more common at 6-12 months among infants who later developed ASD. Infant sleep onset problems were related to hippocampal volume trajectories from 6 to 24 months only for infants at high risk who developed ASD. Brain-sleep relationships were specific to the hippocampus; no significant relationships were found with volume trajectories of other subcortical structures examined (the amygdala, caudate, globus pallidus, putamen, and thalamus).
These findings provide initial evidence that sleep onset problems in the first year of life precede ASD diagnosis and are associated with altered neurodevelopmental trajectories in infants at high familial risk who go on to develop ASD. If replicated, these findings could provide new insights into a potential role of sleep difficulties in the development of ASD.
Sex differences in the prevalence of neurodevelopmental disorders are particularly evident in autism spectrum disorder (ASD). Heterogeneous symptom presentation and the potential of measurement bias ...hinder early ASD detection in females and may contribute to discrepant prevalence estimates. We examined trajectories of social communication (SC) and restricted and repetitive behaviors (RRBs) in a sample of infant siblings of children with ASD, adjusting for age- and sex-based measurement bias. We hypothesized that leveraging a prospective elevated familial likelihood sample, deriving data-driven behavioral constructs, and accounting for measurement bias would reveal less discrepant sex ratios than are typically seen in ASD.
We conducted direct assessments of ASD symptoms at 6 to 9, 12 to 15, 24, and 36 to 60 months of age (total nobservations = 1254) with infant siblings of children with ASD (n = 377) and a lower ASD-familial-likelihood comparison group (n = 168; nobservations = 527). We established measurement invariance across age and sex for separate models of SC and RRB. We then conducted latent class growth mixture modeling with the longitudinal data and evaluated for sex differences in trajectory membership.
We identified 2 latent classes in the SC and RRB models with equal sex ratios in the high-concern cluster for both SC and RRB. Sex differences were also observed in the SC high-concern cluster, indicating that girls classified as having elevated social concerns demonstrated milder symptoms than boys in this group.
This novel approach for characterizing ASD symptom progression highlights the utility of assessing and adjusting for sex-related measurement bias and identifying sex-specific patterns of symptom emergence.
The corpus callosum (CC) is the largest connective pathway in the human brain, linking cerebral hemispheres. There is longstanding debate in the scientific literature whether sex differences are ...evident in this structure, with many studies indicating the structure is larger in females. However, there are few data pertaining to this issue in infancy, during which time the most rapid developmental changes to the CC occur. In this study, we examined longitudinal brain imaging data collected from 104 infants at ages 6, 12, and 24 months. We identified sex differences in brain-size adjusted CC area and thickness characterized by a steeper rate of growth in males versus females from ages 6–24 months. In contrast to studies of older children and adults, CC size was larger for male compared to female infants. Based on diffusion tensor imaging data, we found that CC thickness is significantly associated with underlying microstructural organization. However, we observed no sex differences in the association between microstructure and thickness, suggesting that the role of factors such as axon density and/or myelination in determining CC size is generally equivalent between sexes. Finally, we found that CC length was negatively associated with nonverbal ability among females.
•Sex differences observed in corpus callosum among children from ages 6–24 months.•Males showed a steeper growth rate for corpus callosum area and thickness.•Diffusion MRI data indicate underlying callosal structure is similar between sexes.•Pattern of results suggests developmental effects specific to infancy.
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