An association between reduced interhemispheric EEG coherence in the temporal lobe and genetic risk for schizophrenia

Previous studies have suggested that schizophrenic patients show resting changes such as frequency-slowing and decreased coherence in the frontal and temporal area. We sought to determine whether these findings are also found in clinically unaffected siblings of schizophrenics and estimate heritability by calculating relative risk. We investigated two independent data sets: (1) from the NIMH St. Elisabeth's campus (59 schizophrenics, 76 unaffected siblings and 32 unrelated normal controls) and (2) from the NIH-campus (Bethesda) (59 schizophrenics, 90 unaffected siblings and 26 unrelated normal controls). We computed power spectra and coherence on the first data set and then tried to replicate the results on the second data set. Power spectrum analysis suggested that schizophrenics are cortically hypoactivated, whereas in unaffected siblings, a tendency for hyperactivation was found. In contrast, spectral coherences (0.5-5Hz) were reduced in both data sets in the temporal lobe areas in schizophrenics and in their unaffected siblings. Changes were most pronounced for the interhemispheric coherence linking both posterior temporal lobe areas. Relative risk calculations (lambda(S)) ranged between 3.7 and 9.8, depending on phenotype definition. Thus, while power spectrum EEG abnormalities may be state-dependent, reduced coherence as a possible measure of neuronal synchronization is familial and potentially a heritable trait related to genetic risk for schizophrenia.     

Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils

Through chemical screening, we identified a pyrazolone that reversibly blocked the activation of phagocyte oxidase (phox) in human neutrophils in response to tumor necrosis factor (TNF) or formylated peptide. The pyrazolone spared activation of phox by phorbol ester or bacteria, bacterial killing, TNF-induced granule exocytosis and phox assembly, and endothelial transmigration. We traced the pyrazolone's mechanism of action to inhibition of TNF-induced intracellular Ca2+ elevations, and identified a nontransmembrane ("soluble") adenylyl cyclase (sAC) in neutrophils as a Ca2+-sensing source of cAMP. A sAC inhibitor mimicked the pyrazolone's effect on phox. Both compounds blocked TNF-induced activation of Rap1A, a phox-associated guanosine triphosphatase that is regulated by cAMP. Thus, TNF turns on phox through a Ca2+-triggered, sAC-dependent process that may involve activation of Rap1A. This pathway may offer opportunities to suppress oxidative damage during inflammation without blocking antimicrobial function.     

Evidence‐based selection of theories for designing behaviour change interventions: Using methods based on theoretical construct domains to understand clinicians' blood transfusion behaviour

Background Many theories of behaviour are potentially relevant to predictive and intervention studies but most studies investigate a narrow range of theories. Michie et al. (2005) agreed 12 ‘theoretical domains’ from 33 theories that explain behaviour change. They developed a ‘Theoretical Domains Interview’ (TDI) for identifying relevant domains for specific clinical behaviours, but the framework has not been used for selecting theories for predictive studies. It was used here to investigate clinicians' transfusion behaviour in intensive care units (ICU). Evidence suggests that red blood cells transfusion could be reduced for some patients without reducing quality of care. Objectives (1) To identify the domains relevant to transfusion practice in ICUs and neonatal intensive care units (NICUs), using the TDI. (2) To use the identified domains to select appropriate theories for a study predicting transfusion behaviour. Methods An adapted TDI about managing a patient with borderline haemoglobin by watching and waiting instead of transfusing red blood cells was used to conduct semi‐structured, one‐to‐one interviews with 18 intensive care consultants and neonatologists across the UK. Results Relevant theoretical domains were: knowledge, beliefs about capabilities, beliefs about consequences, social influences, behavioural regulation. Further analysis at the construct level resulted in selection of seven theoretical approaches relevant to this context: Knowledge‐Attitude‐Behaviour Model, Theory of Planned Behaviour, Social Cognitive Theory, Operant Learning Theory, Control Theory, Normative Model of Work Team Effectiveness and Action Planning Approaches. Conclusions This study illustrated, the use of the TDI to identify relevant domains in a complex area of inpatient care. This approach is potentially valuable for selecting theories relevant to predictive studies and resulted in greater breadth of potential explanations than would be achieved if a single theoretical model had been adopted.     

Heart rate and reinforcement sensitivity in ADHD

BACKGROUND: Both theoretical and clinical accounts of attention-deficit/hyperactivity disorder (ADHD) implicate a dysfunctional reinforcement system. This study investigated heart rate parameters in response to feedback associated with reward and response cost in ADHD children and controls aged 8 to 12. METHODS: Heart rate responses (HRRs) following feedback and heart rate variability (HRV) in the low frequency band (.04-.08 Hz), a measure of mental effort, were calculated during a time production paradigm. Performance was coupled to monetary gain, loss or feedback-only in a cross-over design. RESULTS: Children with ADHD exhibited smaller HRRs to feedback compared to controls. HRV of children with ADHD decreased when performance was coupled to reward or response cost compared to feedback-only. HRV of controls was similar across conditions. CONCLUSIONS: Children with ADHD were characterised by (a) possible abnormalities in feedback monitoring and (b) motivational deficits, when no external reinforcement is present.     

Do harsh and positive parenting predict parent reports of deceitful‐callous behavior in early childhood?

Background: The relationship between parenting and the development of antisocial behavior in children is well established. However, evidence for associations between dimensions of parenting and callous‐unemotional (CU) traits is mixed. As CU traits appear critical to understanding a subgroup of youth with antisocial behavior, more research addressing the link between early parenting and CU traits is needed. Methods: The current study investigated longitudinal predictions between measures of harsh and positive parenting, and early CU behavior. Data from mother‐child dyads (N = 731; 49% female) were collected from a multi‐ethnic, high‐risk sample with young children, and included self‐reported and multi‐method observed parenting. CU behavior was assessed using a previously validated measure of deceitful‐callous behavior ( Hyde et al., 2011 ). Results: Results suggest that dimensions of harsh parenting, but not positive parenting, contribute to the development of child deceitful‐callous behavior. Nevertheless, deceitful‐callous behavior showed strong stability over time and the effects of harsh parenting, especially observed harshness, were modest. Conclusions: The current findings have implications for developmental psychopathology and early interventions for antisocial behavior. The results also raise a number of issues about measuring emerging CU behavior in very young children, including the interrelation between parent perceptions and reports of child behavior, parent reactions, and the subsequent development of severe antisocial behavior.     

Microglandular adenosis: a prime suspect in triple‐negative breast cancer development

Microglandular adenosis (MGA) and atypical MGA (AMGA) are unusual lesions of the breast. They were once regarded as benign proliferative lesions and innocent bystanders. Several lines of evidence suggested that they could be neoplastic, clonal lesions and a non‐obligate precursor for triple‐negative breast cancers (TNBC). Recent work published in The Journal of Pathology by Guerini‐Rocco and colleagues provided further evidence regarding the precursor–product relationship between MGA/AMGA and TNBC. Using a massively parallel sequencing approach, they demonstrated that MGA/AMGA, particularly those associated with TNBC, could be clonal neoplastic lesions showing clonal non‐synonymous mutations, but none in pure MGA. Importantly, those alterations were observed in the associated TNBC. They were also able to identify recurrent alterations in TP53 in those MGA/AMGA cases as well as their associated TNBC. The findings, in conjunction with others, underscore the significance for MGA in clinical diagnosis. The potential of a benign lesion to progress into an aggressive malignant tumour implies that modification of the current management approach may be necessary. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Web-Based Virtual Microscopy of Digitized Blood Slides for Malaria Diagnosis: An Effective Tool for Skills Assessment in Different Countries and Environments

BackgroundMorphological examination of blood films remains the reference standard for malaria diagnosis. Supporting the skills required to make an accurate morphological diagnosis is therefore essential. However, providing support across different countries and environments is a substantial challenge.ObjectiveThis paper reports a scheme supplying digital slides of malaria-infected blood within an Internet-based virtual microscope environment to users with different access to training and computing facilities. The feasibility of the approach was established, allowing users to test, record, and compare their own performance with that of other users.MethodsFrom Giemsa stained thick and thin blood films, 56 large high-resolution digital slides were prepared, using high-quality image capture and 63x oil-immersion objective lens. The individual images were combined using the photomerge function of Adobe Photoshop and then adjusted to ensure resolution and reproduction of essential diagnostic features. Web delivery employed the Digital Slidebox platform allowing digital microscope viewing facilities and image annotation with data gathering from participants.ResultsEngagement was high with images viewed by 38 participants in five countries in a range of environments and a mean completion rate of 42/56 cases. The rate of parasite detection was 78% and accuracy of species identification was 53%, which was comparable with results of similar studies using glass slides. Data collection allowed users to compare performance with other users over time or for each individual case.ConclusionsOverall, these results demonstrate that users worldwide can effectively engage with the system in a range of environments, with the potential to enhance personal performance through education, external quality assessment, and personal professional development, especially in regions where educational resources are difficult to access.     

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.