BSE Case Associated with Prion Protein Gene Mutation

Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle and was first detected in 1986 in the United Kingdom. It is the most likely cause of variant Creutzfeldt-Jakob disease (CJD) in humans. The origin of BSE remains an enigma. Here we report an H-type BSE case associated with the novel mutation E211K within the prion protein gene (Prnp). Sequence analysis revealed that the animal with H-type BSE was heterozygous at Prnp nucleotides 631 through 633. An identical pathogenic mutation at the homologous codon position (E200K) in the human Prnp has been described as the most common cause of genetic CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. A recent epidemiological study revealed that the K211 allele was not detected in 6062 cattle from commercial beef processing plants and 42 cattle breeds, indicating an extremely low prevalence of the E211K variant (less than 1 in 2000) in cattle

Fluorescent Transgenic Zebrafish Tg(nkx2.2a:mEGFP) Provides a Highly Sensitive Monitoring Tool for Neurotoxins

10.1371/journal.pone.0055474PLoS ONE82

Does Lack of Multinutrient Supplementation During Early Pregnancy Increase Vulnerability to Alcohol-Related Preterm or Small-for-Gestational-Age Births?

The objective of this study was to assess whether women who do not take multinutrient supplements during early pregnancy are more susceptible to the effects of low-to-moderate alcohol consumption on preterm birth and small-for-gestational-age birth (SGA) compared to women who do take multinutrients. This analysis included 800 singleton live births to mothers from a cohort of pregnant women recruited for a population-based cohort study conducted in the Kaiser Permanente Medical Care Program in Northern California. Participants were recruited in their first trimester of pregnancy and information about their alcohol use and supplement intake during pregnancy was collected. Preterm birth (n = 53, 7%) was defined as a delivery prior to 37 completed weeks of gestation and SGA birth (n = 124, 16%) was defined as birth weight less than the 10th percentile for the infant’s gestational age and sex compared to US singleton live births. A twofold increase in the odds of SGA birth attributed to low-to-moderate alcohol intake was found among multinutrient supplement non-users (95% CI: 1.1, 5.3). Yet, among multinutrient supplement users, there was no increased risk of an SGA birth for women who drank low-to-moderately compared to women who abstained (aOR: 0.97, 95% CI: 0.6, 1.6). Similar results emerged for preterm birth. Our findings provide marginal evidence that multinutrient supplementation during early pregnancy may modify the risk of SGA births and preterm birth associated with alcohol consumption during pregnancy and may have important implications for pregnant women and women of child-bearing age. However, future research needs to be conducted

HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors

Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation

The Cognitive Impact of the ANK3 Risk Variant for Bipolar Disorder: Initial Evidence of Selectivity to Signal Detection during Sustained Attention

BACKGROUND: Abnormalities in cognition have been reported in patients with Bipolar Disorder (BD) and their first degree relatives, suggesting that susceptibility genes for BD may impact on cognitive processes. Recent genome-wide genetic studies have reported a strong association with BD in a single nucleotide polymorphism (SNP) (rs10994336) within ANK3, which codes for Ankyrin 3. This protein is involved in facilitating the propagation of action potentials by regulating the assembly of sodium gated ion channels. Since ANK3 influences the efficiency of transmission of neuronal impulses, allelic variation in this gene may have widespread cognitive effects. Preclinical data suggest that this may principally apply to sequential signal detection, a core process of sustained attention. METHODOLOGY/PRINCIPAL FINDINGS: One hundred and eighty-nine individuals of white British descent were genotyped for the ANK3 rs10994336 polymorphism and received diagnostic interviews and comprehensive neurocognitive assessment of their general intellectual ability, memory, decision making, response inhibition and sustained attention. Participants comprised euthymic BD patients (n = 47), their unaffected first-degree relatives (n = 75) and healthy controls (n = 67). The risk allele T was associated with reduced sensitivity in target detection (p = 0.0004) and increased errors of commission (p = 0.0018) during sustained attention regardless of diagnosis. We found no effect of the ANK3 genotype on general intellectual ability, memory, decision making and response inhibition. CONCLUSIONS/SIGNIFICANCE: Our results suggest that allelic variation in ANK3 impacts cognitive processes associated with signal detection and this mechanism may relate to risk for BD. However, our results require independent replication and confirmation that ANK3 (rs10994336) is a direct functional variant

Association Analysis of 94 Candidate Genes and Schizophrenia-Related Endophenotypes

While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis

Identifying the domains of context important to implementation science: a study protocol

Background There is growing recognition that “context” can and does modify the effects of implementation interventions aimed at increasing healthcare professionals’ use of research evidence in clinical practice. However, conceptual clarity about what exactly comprises “context” is lacking. The purpose of this research program is to develop, refine, and validate a framework that identifies the key domains of context (and their features) that can facilitate or hinder (1) healthcare professionals’ use of evidence in clinical practice and (2) the effectiveness of implementation interventions. Methods/design A multi-phased investigation of context using mixed methods will be conducted. The first phase is a concept analysis of context using the Walker and Avant method to distinguish between the defining and irrelevant attributes of context. This phase will result in a preliminary framework for context that identifies its important domains and their features according to the published literature. The second phase is a secondary analysis of qualitative data from 13 studies of interviews with 312 healthcare professionals on the perceived barriers and enablers to their application of research evidence in clinical practice. These data will be analyzed inductively using constant comparative analysis. For the third phase, we will conduct semi-structured interviews with key health system stakeholders and change agents to elicit their knowledge and beliefs about the contextual features that influence the effectiveness of implementation interventions and healthcare professionals’ use of evidence in clinical practice. Results from all three phases will be synthesized using a triangulation protocol to refine the context framework drawn from the concept analysis. The framework will then be assessed for content validity using an iterative Delphi approach with international experts (researchers and health system stakeholders/change agents). Discussion This research program will result in a framework that identifies the domains of context and their features that can facilitate or hinder: (1) healthcare professionals’ use of evidence in clinical practice and (2) the effectiveness of implementation interventions. The framework will increase the conceptual clarity of the term “context” for advancing implementation science, improving healthcare professionals’ use of evidence in clinical practice, and providing greater understanding of what interventions are likely to be effective in which contexts

Do Children and Adolescents with Anorexia Nervosa Display an Inefficient Cognitive Processing Style?

Objective: This study aimed to examine neuropsychological processing in children and adolescents with Anorexia Nervosa (AN). The relationship of clinical and demographic variables to neuropsychological functioning within the AN group was also explored.  Method: The performance of 41 children and adolescents with a diagnosis of AN were compared to 43 healthy control (HC) participants on a number of neuropsychological measures.  Results: There were no differences in IQ between AN and HC groups. However, children and adolescents with AN displayed significantly more perseverative errors on the Wisconsin Card Sorting Test, and lower Style and Central Coherence scores on the Rey Osterrieth Complex Figure Test relative to HCs.  Conclusion: Inefficient cognitive processing in the AN group was independent of clinical and demographic variables, suggesting it might represent an underlying trait for AN. The implications of these findings are discussed

Color afterimages in autistic adults

It has been suggested that attenuated adaptation to visual stimuli in autism is the result of atypical perceptual priors (e.g., Pellicano and Burr in Trends Cogn Sci 16(10):504–510, 2012. doi:10.​1016/​j.​tics.​2012.​08.​009). This study investigated adaptation to color in autistic adults, measuring both strength of afterimage and the influence of top-down knowledge. We found no difference in color afterimage strength between autistic and typical adults. Effects of top-down knowledge on afterimage intensity shown by Lupyan (Acta Psychol 161:117–130, 2015. doi:10.​1016/​j.​actpsy.​2015.​08.​006) were not replicated for either group. This study finds intact color adaptation in autistic adults. This is in contrast to findings of attenuated adaptation to faces and numerosity in autistic children. Future research should investigate the possibility of developmental differences in adaptation and further examine top-down effects on adaptation

Neurocognitive Consequences of HIV Infection in Older Adults: An Evaluation of the “Cortical” Hypothesis

The incidence and prevalence of older adults living with HIV infection is increasing. Recent reports of increased neuropathologic and metabolic alterations in older HIV+ samples, including increased cortical beta-amyloid, have led some researchers to suggest that aging with HIV may produce a neuropsychological profile akin to that which is observed in “cortical” dementias (e.g., impairment in memory consolidation). To evaluate this possibility, we examined four groups classified by HIV serostatus and age (i.e., younger ≤40 years and older ≥50 years): (1) Younger HIV− (n = 24); (2) Younger HIV+ (n = 24); (3) Older HIV− (n = 20); and (4) Older HIV+ (n = 48). Main effects of aging were observed on episodic learning and memory, executive functions, and visuoconstruction, and main effects of HIV were observed on measures of verbal learning and memory. The interaction of age and HIV was observed on a measure of verbal recognition memory, which post hoc analyses showed to be exclusively attributed to the superior performance of the younger HIV seronegative group. Thus, in this sample of older HIV-infected individuals, the combined effects of HIV and aging do not appear to result in a “cortical” pattern of cognitive deficits