Attention-deficit/hyperactivity disorder and other neurodevelopmental disorders in offspring of parents with depression and bipolar disorder.

BACKGROUND: Offspring of parents with major mood disorders (MDDs) are at increased risk for early psychopathology. We aim to compare the rates of neurodevelopmental disorders in offspring of parents with bipolar disorder, major depressive disorder, and controls. METHOD: We established a lifetime diagnosis of neurodevelopmental disorders [attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disabilities, specific learning disorders, and motor disorders] using the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version in 400 participants (mean age 11.3 + s.d. 3.9 years), including 93 offspring of parents with bipolar disorder, 182 offspring of parents with major depressive disorder, and 125 control offspring of parents with no mood disorder. RESULTS: Neurodevelopmental disorders were elevated in offspring of parents with bipolar disorder [odds ratio (OR) 2.34, 95% confidence interval (CI) 1.23-4.47, p = 0.010] and major depressive disorder (OR 1.87, 95% CI 1.03-3.39, p = 0.035) compared to controls. This difference was driven by the rates of ADHD, which were highest among offspring of parents with bipolar disorder (30.1%), intermediate in offspring of parents with major depressive disorder (24.2%), and lowest in controls (14.4%). There were no significant differences in frequencies of other neurodevelopmental disorders between the three groups. Chronic course of mood disorder in parents was associated with higher rates of any neurodevelopmental disorder and higher rates of ADHD in offspring. CONCLUSIONS: Our findings suggest monitoring for ADHD and other neurodevelopmental disorders in offspring of parents with MDDs may be indicated to improve early diagnosis and treatment.

Deep machine learning interatomic potential for liquid silica.

The use of machine learning to develop neural network potentials (NNP) representing the interatomic potential energy surface allows us to achieve an optimal balance between accuracy and efficiency in computer simulation of materials. A key point in developing such potentials is the preparation of a training dataset of ab initio trajectories. Here we apply a deep potential molecular dynamics (DeePMD) approach to develop NNP for silica, which is the representative glassformer widely used as a model system for simulating network-forming liquids and glasses. We show that the use of a relatively small training dataset of high-temperature ab initio configurations is enough to fabricate NNP, which describes well both structural and dynamical properties of liquid silica. In particular, we calculate the pair correlation functions, angular distribution function, velocity autocorrelation functions, vibrational density of states, and mean-square displacement and reveal a close agreement with ab initio data. We show that NNP allows us to expand significantly the time-space scales achievable in simulations and thus calculating dynamical and transport properties with more accuracy than that for ab initio methods. We find that developed NNP allows us to describe the structure of the glassy silica with satisfactory accuracy even though no low-temperature configurations were included in the training procedure. The results obtained open up prospects for simulating structural and dynamical properties of liquids and glasses via NNP.

Low-temperature decomposition and segregation on a surface in carbide-containing solid solutions of the zirconium-niobium-carbon system and in related ternary systems.

The crystal structure and microstructure of pseudobinary (ZrC0.96)1-x(NbC0.97)x carbide solid solutions has been studied. It was found that monocrystalline grains of zirconium carbide are spontaneously isolated on the surface of diluted solid solutions of the pseudobinary system ZrCy-NbCy' containing less than 2.0 mol% of zirconium carbide. It is shown that the appearance of zirconium carbide is a consequence of the solid-phase decomposition of these solid solutions and anisotropy of elastic properties of monocrystalline ZrC carbide grains. The model of subregular solutions was used in the temperature interval from 300 to 3900 K to calculate and plot an equilibrium phase diagram of the ternary Zr-Nb-C system. It is shown that at temperatures above 1210 K in the Zr-Nb-C ternary system, nonstoichiometric carbides ZrCy and NbCy' have unlimited mutual solubility and form a continuous series of (ZrCy)1-x(NbCy')x solid solutions with 0.6 ≤ y ≤ 0.98, 0.7 ≤ y' ≤ 1.0, and 0 ≤ x ≤ 1.0. At temperatures below 1200 K, under equilibrium conditions, a discontinuity of the miscibility of the solid solutions ZrCy-NbCy' is observed and there appears a region of solid phase decomposition. The anisotropy of elastic properties of monocrystalline grains of ZrC was considered. It is predicted that solid-phase decomposition and surface segregation can be observed in such related carbide systems as HfCy-NbCy', HfCy-TaCy', ZrCy-TaCy', VCy-TaCy' and VCy-NbCy'.

A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds.

Mycobacterium tuberculosis (Mtb) is an obligate human pathogen and the causative agent of tuberculosis1-3. Although Mtb can synthesize vitamin B12 (cobalamin) de novo, uptake of cobalamin has been linked to pathogenesis of tuberculosis2. Mtb does not encode any characterized cobalamin transporter4-6; however, the gene rv1819c was found to be essential for uptake of cobalamin1. This result is difficult to reconcile with the original annotation of Rv1819c as a protein implicated in the transport of antimicrobial peptides such as bleomycin7. In addition, uptake of cobalamin seems inconsistent with the amino acid sequence, which suggests that Rv1819c has a bacterial ATP-binding cassette (ABC)-exporter fold1. Here, we present structures of Rv1819c, which reveal that the protein indeed contains the ABC-exporter fold, as well as a large water-filled cavity of about 7,700 Å3, which enables the protein to transport the unrelated hydrophilic compounds bleomycin and cobalamin. On the basis of these structures, we propose that Rv1819c is a multi-solute transporter for hydrophilic molecules, analogous to the multidrug exporters of the ABC transporter family, which pump out structurally diverse hydrophobic compounds from cells8-11.

Observed psychopathology in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia.

BACKGROUND: Children of parents with mood and psychotic disorders are at elevated risk for a range of behavioral and emotional problems. However, as the usual reporter of psychopathology in children is the parent, reports of early problems in children of parents with mood and psychotic disorders may be biased by the parents' own experience of mental illness and their mental state. METHODS: Independent observers rated psychopathology using the Test Observation Form in 378 children and youth between the ages of 4 and 24 (mean = 11.01, s.d. = 4.40) who had a parent with major depressive disorder, bipolar disorder, schizophrenia, or no history of mood and psychotic disorders. RESULTS: Observed attentional problems were elevated in offspring of parents with major depressive disorder, bipolar disorder and schizophrenia (effect sizes ranging between 0.31 and 0.56). Oppositional behavior and language/thought problems showed variable degrees of elevation (effect sizes 0.17 to 0.57) across the three high-risk groups, with the greatest difficulties observed in offspring of parents with bipolar disorder. Observed anxiety was increased in offspring of parents with major depressive disorder and bipolar disorder (effect sizes 0.19 and 0.25 respectively) but not in offspring of parents with schizophrenia. CONCLUSIONS: Our results suggest that externalizing problems and cognitive and language difficulties may represent a general manifestation of familial risk for mood and psychotic disorders, while anxiety may be a specific marker of liability for mood disorders. Observer assessment may improve early identification of risk and selection of youth who may benefit from targeted prevention.

Effectiveness of hand hygiene practices in preventing influenza virus infection in the community setting: A systematic review.

BACKGROUND: Hand hygiene is known to be an effective infection prevention and control measure in health care settings. However, the effectiveness of hand hygiene practices in preventing influenza infection and transmission in the community setting is not clear. OBJECTIVE: To identify, review and synthesize available evidence on the effectiveness of hand hygiene in preventing laboratory-confirmed or possible influenza infection and transmission in the community setting. METHODS: A systematic review protocol was established prior to conducting the review. Three electronic databases (MEDLINE, Embase and the Cochrane Library) were searched to identify relevant studies. Two reviewers independently screened the titles, abstracts and full-texts of studies retrieved from the database searches for potential eligibility. Data extraction and quality assessment of included studies were performed by a single reviewer and validated by a second reviewer. Included studies were synthesized and analyzed narratively. RESULTS: A total of 16 studies were included for review. Studies were of low methodological quality and there was high variability in study design, setting, context and outcome measures. Nine studies evaluated the effectiveness of hand hygiene interventions or practices in preventing laboratory-confirmed or possible influenza infection in the community setting; six studies showed a significant difference, three studies did not. Seven studies assessed the effectiveness of hand hygiene practices in preventing laboratory-confirmed or possible influenza transmission in the community setting; two studies found a significant difference and five studies did not. CONCLUSION: The effectiveness of hand hygiene against influenza virus infection and transmission in the community setting is difficult to determine based on the available evidence. In light of its proven effectiveness in other settings, there is no compelling evidence to stop using good hand hygiene practice to reduce the risk of influenza infection and transmission in the community setting.

ECF-Type ATP-Binding Cassette Transporters.

Energy-coupling factor (ECF)-type ATP-binding cassette (ABC) transporters catalyze membrane transport of micronutrients in prokaryotes. Crystal structures and biochemical characterization have revealed that ECF transporters are mechanistically distinct from other ABC transport systems. Notably, ECF transporters make use of small integral membrane subunits (S-components) that are predicted to topple over in the membrane when carrying the bound substrate from the extracellular side of the bilayer to the cytosol. Here, we review the phylogenetic diversity of ECF transporters as well as recent structural and biochemical advancements that have led to the postulation of conceptually different mechanistic models. These models can be described as power stroke and thermal ratchet. Structural data indicate that the lipid composition and bilayer structure are likely to have great impact on the transport function. We argue that study of ECF transporters could lead to generic insight into membrane protein structure, dynamics, and interaction.

Cysteine-mediated decyanation of vitamin B12 by the predicted membrane transporter BtuM.

Uptake of vitamin B12 is essential for many prokaryotes, but in most cases the membrane proteins involved are yet to be identified. We present the biochemical characterization and high-resolution crystal structure of BtuM, a predicted bacterial vitamin B12 uptake system. BtuM binds vitamin B12 in its base-off conformation, with a cysteine residue as axial ligand of the corrin cobalt ion. Spectroscopic analysis indicates that the unusual thiolate coordination allows for decyanation of vitamin B12. Chemical modification of the substrate is a property other characterized vitamin B12-transport proteins do not exhibit.

Outbreak of acute hepatitis B virus infection associated with exposure to acupuncture.

BACKGROUND: The most common risk factors for acute hepatitis B virus (HBV) infection are sexual contact, injection drug use and perinatal, or nosocomial exposure. Acupuncture, used in China for over 2,500 years, has been gaining popularity as an alternative medical therapy in the western world, but when associated with poor infection control practices, is also a risk for blood-borne infections. OBJECTIVE: To describe the outbreak investigation following detection of two cases of acute HBV infection associated with acupuncture services from the same provider within four months of symptom onset. METHODS: The outbreak investigation included genotyping of HBV from the identified cases, on-site assessment of the acupuncturist's infection prevention and control practices and chart review of known clients. RESULTS: Both cases had HBV genotype D1 with an identical fingerprint and both clients had visited the clinic on the same day denying other recent risk exposures. Inspection of the acupuncturist's practice revealed high-risk re-use and inappropriate storage of disposable needles. The Regional Health Authority ordered cessation of clinic practice until infection control measures were remediated. A public service announcement and mailed notifications to clients identified from practitioner records recommended that all clients be tested for HBV, human immunodeficiency virus (HIV) and hepatitis C. CONCLUSIONS: A clear epidemiological linkage of these two acute HBV infections to the same acupuncture clinic, evidence of substandard infection control practice in the clinic and identical HBV molecular and genotypic profiles of the two cases are highly suggestive that contaminated acupuncture needles likely resulted in at least two cases of acute HBV infection. This is the first known reported transmission of HBV from acupuncturists re-use of disposable needles and the first HBV outbreak associated with exposure to acupuncture reported this century in an industrialized country. Increased provider oversight and patient education may prevent future outbreaks.

Surveillance summary of hospitalized pediatric enterovirus D68 cases in Canada, September 2014.

BACKGROUND: Enterovirus D68 (EV-D68) has been detected infrequently and has not been associated with severe disease in Canada. In the early fall of 2014, following an unusual case increase in the United States, clusters of EV-D68 among children and some adults manifesting severe symptoms were reported in Canada. OBJECTIVE: To provide an initial epidemiological summary of pediatric cases hospitalized with EV-D68 in Canada. METHODS: A time-limited surveillance pilot was conducted collecting information on pediatric cases (less than 18 years of age) hospitalized with EV-D68 between September 1 and 30, 2014. RESULTS: In total, 268 cases were reported from Ontario (n=210), Alberta (n=45), and British Columbia (n=13). Of the 268 reported cases, 64.9% (n=174) were male; the sex difference was statistically significant (p<0.01). Age was reported for 255 cases, with a mean age for males of 5.4 years and for females of 5.3 years. For cases with data available, 6.8% (18/266) were admitted to an intensive care unit. Of those where clinical illness was recorded, respiratory illness alone was present in 98.3% (227/231), neurologic illness alone was present in 0.4% (n=1), and both illnesses were present in 0.9% of cases (n=2); cases with neither respiratory nor neurologic illness were rare (n=1). Of the 90 cases with additional clinical information available, 43.3% were reported as having asthma. No deaths were reported among the 268 cases. CONCLUSION: The EV-D68 outbreak in Canada in September 2014 represents the beginning of a novel outbreak associated with severe illness in children. These findings provide the first epidemiological summary of severe cases of EV-D68 as an emergent respiratory pathogen in Canada. The continued investigation of this pathogen is necessary to build on these results and capture the full spectrum of associated illness.

Correlation of perfusion parameters with genes related to angiogenesis regulation in glioblastoma: a feasibility study.

BACKGROUND AND PURPOSE: Integration of imaging and genomic data is critical for a better understanding of gliomas, particularly considering the increasing focus on the use of imaging biomarkers for patient survival and treatment response. The purpose of this study was to correlate CBV and PS measured by using PCT with the genes regulating angiogenesis in GBM. MATERIALS AND METHODS: Eighteen patients with WHO grade IV gliomas underwent pretreatment PCT and measurement of CBV and PS values from enhancing tumor. Tumor specimens were analyzed by TCGA by using Human Gene Expression Microarrays and were interrogated for correlation between CBV and PS estimates across the genome. We used the GO biologic process pathways for angiogenesis regulation to select genes of interest. RESULTS: We observed expression levels for 92 angiogenesis-associated genes (332 probes), 19 of which had significant correlation with PS and 9 of which had significant correlation with CBV (P < .05). Proangiogenic genes such as TNFRSF1A (PS = 0.53, P = .024), HIF1A (PS = 0.62, P = .0065), KDR (CBV = 0.60, P = .0084; PS = 0.59, P = .0097), TIE1 (CBV = 0.54, P = .022; PS = 0.49, P = .039), and TIE2/TEK (CBV = 0.58, P = .012) showed a significant positive correlation; whereas antiangiogenic genes such as VASH2 (PS = -0.72, P = .00011) showed a significant inverse correlation. CONCLUSIONS: Our findings are provocative, with some of the proangiogenic genes showing a positive correlation and some of the antiangiogenic genes showing an inverse correlation with tumor perfusion parameters, suggesting a molecular basis for these imaging biomarkers; however, this should be confirmed in a larger patient population.

Splenic and immune alterations of the Sparc-null mouse accompany a lack of immune response.

Sparc-null mice have been used as models to assess tumor-host immune cell interactions. However, it is not known if they have a competent immune system. In this study, the immune systems of Sparc wild-type and null mice were compared. Mice were assessed for differences in total body weight, spleen weight and spleen-to-body weight ratios. Spleens were compared with respect to morphology, and Sparc, Ki-67, MOMA-1 and IgM expression. Immune cells in blood, bone marrow and spleen were assessed by blood smears, automated blood panel, and flow cytometry. Additionally, the ability of Sparc-null mice to respond to immune challenge was evaluated using a footpad model. The morphological and immunohistochemical results indicated that Sparc-null spleens had more white pulp, hyperproliferative B cells in the germinal centers, and decreased marginal zones. Sparc-null spleens lacked normal Sparc expression in red and white pulp, marginal zones, endothelial and sinusoidal cells. By flow analysis, B cells were decreased and T cells were increased in the bone marrow. Finally, Sparc-null mice were unable to mount an immune response following footpad lipopolysaccharide challenge. These data confirm that Sparc-null mice have an impaired immune system.

PIKE-A is a proto-oncogene promoting cell growth, transformation and invasion.

PIKE-A (phosphoinositide 3-kinases (PI 3)-kinase enhancer) is a ubiquitously expressed GTPase, which binds to and enhances protein kinase B (Akt) kinase activity in a guanine nucleotide-dependent manner. PIKE-A is one of the components of the CDK4 amplicon that is amplified in numerous human cancers. However, whether PIKE-A itself can mediate cell transformation, proliferation and migration remains unknown. Here, we show that PIKE-A is overexpressed in various human cancer samples, escalates U87MG glioblastoma invasion and provokes NIH3T3 cell transformation. Overexpression of wild-type (WT) PIKE-A enhances NIH3T3 and U87MG cell growth, which is further increased by cancer cell-derived PIKE-A active mutants. In contrast, both the dominant-negative mutant and the phosphoinositide lipids interaction-defective mutant antagonize cell proliferation. Moreover, PIKE-A and its active and inactive mutants similarly enhance or antagonize U87MG cell survival and invasion, and their ability to do so is coupled with the catalytic effect they have on Akt activation. Furthermore, PIKE-A WT and its active mutants significantly elicit NIH3T3 cell transformation. Thus, our findings support the concept that PIKE-A acts as a proto-oncogene, promoting cell transformation through Akt activation.

Quantitative fluorescence spectra and quantum yield map of synthetic pheomelanin.

Spectroscopic studies of pheomelanin and its constituents have been sparse. These data present what is by far the most complete description of the fluorescence characteristics of synthetic pheomelanin. Emission spectra between 260 and 600 nm were acquired for excitation wavelengths between 250 and 500 nm at 1-nm intervals. A quantum yield map is also presented, correcting the fluorescence intensities for differences in species concentration and molar absorptivity. These fluorescence features exhibit interesting similarities and differences to eumelanin, and these data are interpreted with respect to possible chemical structures. Overall, these data suggest that pheomelanin oligomers may be more tightly coupled than those of eumelanin. Finally, the quantum yield is shown to be on the order of 10(-4) and exhibit a complex dependence on excitation energy, varying by a factor of 4 across the energies employed here.

SPARC modulates cell growth, attachment and migration of U87 glioma cells on brain extracellular matrix proteins.

We have identified secreted protein acidic and rich in cysteine (SPARC) as a potential glioma invasion-promoting gene. To determine whether SPARC alters the growth, attachment, or migration of gliomas, we have used U87T2 and doxycycline-regulatable SPARC-transfected clones to examine the effects of SPARC on (1) cell growth, (2) cell cycle progression, (3) cell attachment, and (4) cell migration, using growth curves, flow cytometry, attachment, and migration analyses on different brain ECMs, including collagen IV, laminin, fibronectin, vitronectin, hyaluronic acid, and tenascin. Our data indicate that SPARC delays tumor cell growth in the log phase of the growth curve. The clones secreted different levels of SPARC. The clone secreting the lowest level of SPARC was associated with a higher percentage of cells in G2M, whereas the clones secreting the higher levels of SPARC were associated with a greater percentage of cells in G0/G1. In comparison to the parental U87T2 clone, the SPARC-transfected clones demonstrated increased attachment to collagen, laminin, hyaluronic acid, and tenascin, but not to vitronectin or fibronectin. SPARC-transfected clones also demonstrated altered migration on the different extracellular matrix proteins. The modulation of migration, either positive or negative, was associated with changes in the level of secreted SPARC. These data suggest that SPARC may modulate glioma proliferation and invasion by modulating both the growth and migration of glioma cells.

Molecular biology of nervous system tumors.

Many genetic alterations that contribute to CNS tumorigenesis and progression have been identified. One goal of such studies is to identify loci that would serve as diagnostic prognostic markers or both. A significant advance is the observation that chromosome 1p loss identified anaplastic oligodendroglioma and a subset of high-grade glioma patients who responded to chemotherapy and had longer survival times. Combined 1p and 19q loss was a predictor of prolonged survival of patients having pure oligodendrogliomas. Such markers eventually may be used to identify patients upfront who would benefit from treatment, while sparing patients who would not benefit. Although many molecular participants involved in the biologic pathways that promote proliferation, angiogenesis, and invasion have been elucidated, there are still many gaps in clinicians' knowledge. It is expected that the use of the human genome project information and databases such as SAGEmap, in combination with techniques such as cDNA arrays and proteomics, will facilitate greatly the identification of novel genes that contribute to CNS tumors. cDNA arrays and tissue arrays will permit the construction of CNS-specific screening tools that will permit the identification of tumor-specific mutations and alterations so that patient-specific therapies can be designed.

A study of SPARC and vitronectin localization and expression in pediatric and adult gliomas: high SPARC secretion correlates with decreased migration on vitronectin.

SPARC is a secreted glycoprotein that interacts with extracellular matrix (ECM) proteins to promote de-adhesion of cells from the matrix, thereby inducing a biological state conducive to cell migration. We have demonstrated that SPARC is highly expressed in gliomas (grades II-IV) and promotes glioma invasion in vitro. Therefore, the protein itself or its mechanisms of action might become therapeutic targets to arrest glioma invasion. Vitronectin is an ECM protein found in the blood vessel basement membranes and may promote glioma invasion along these structures. It binds to SPARC in vitro. However, it is not known whether SPARC and vitronectin colocalize and/or interact to contribute to brain tumor cell migration in vivo. In this study, we immuno-histochemically determined if the grade I juvenile pilocytic astrocytomas (JPAs) also express SPARC, if vitronectin is expressed in grades I, II, and IV astrocytomas, and if the proteins colocalize in brain tumors in vivo. We performed western blot analyses to determine if different grades of tumors had different intracellular and/or secreted levels of SPARC and vitronectin. We performed migration assays to determine whether vitronectin is a permissive substrate for glioma migration, and whether the extent of migration correlates with the level of secreted SPARC. Our data demonstrated that JPAs expressed SPARC and secreted significantly higher levels than glioblastomas multiforme (GBMs). Vitronectin was absent from well-preserved tumor but present in areas of disrupted tumor, such as degeneration and/or necrosis. SPARC and vitronectin colocalized only in regions of angiogenesis. We observed that the extent of migration on vitronectin inversely correlated with the level of secreted SPARC: the higher the level, the lesser the migration. These data suggest that the outcome of SPARC - ECM interactions may depend on local SPARC concentrations. The high levels of SPARC secreted by the JPAs, paradoxically, may be more prohibitive for migration on vitronectin than the lower levels secreted by the GBMs. This may account, in part, for the lack of JPA invasion into brain tissue along blood vessel membranes.