A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal ...cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, P
<0.05, k
=2198, x=-30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, P
<0.05, k
=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.
Jalview Version 2 is a system for interactive WYSIWYG editing, analysis and annotation of multiple sequence alignments. Core features include keyboard and mouse-based editing, multiple views and ...alignment overviews, and linked structure display with Jmol. Jalview 2 is available in two forms: a lightweight Java applet for use in web applications, and a powerful desktop application that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server. Availability: The Jalview 2 Desktop application and JalviewLite applet are made freely available under the GPL, and can be downloaded from www.jalview.org Contact: g.j.barton@dundee.ac.uk
Our focus here is on the infinitesimal model. In this model, one or several quantitative traits are described as the sum of a genetic and a non-genetic component, the first being distributed within ...families as a normal random variable centred at the average of the parental genetic components, and with a variance independent of the parental traits. Thus, the variance that segregates within families is not perturbed by selection, and can be predicted from the variance components. This does not necessarily imply that the trait distribution across the whole population should be Gaussian, and indeed selection or population structure may have a substantial effect on the overall trait distribution. One of our main aims is to identify some general conditions on the allelic effects for the infinitesimal model to be accurate. We first review the long history of the infinitesimal model in quantitative genetics. Then we formulate the model at the phenotypic level in terms of individual trait values and relationships between individuals, but including different evolutionary processes: genetic drift, recombination, selection, mutation, population structure, …. We give a range of examples of its application to evolutionary questions related to stabilising selection, assortative mating, effective population size and response to selection, habitat preference and speciation. We provide a mathematical justification of the model as the limit as the number M of underlying loci tends to infinity of a model with Mendelian inheritance, mutation and environmental noise, when the genetic component of the trait is purely additive. We also show how the model generalises to include epistatic effects. We prove in particular that, within each family, the genetic components of the individual trait values in the current generation are indeed normally distributed with a variance independent of ancestral traits, up to an error of order 1∕M. Simulations suggest that in some cases the convergence may be as fast as 1∕M.
In this chapter, we introduce core functionality of the Jalview interactive platform for the creation, analysis, and publication of multiple sequence alignments. A workflow is described based on ...Jalview's core functions: from data import to figure generation, including import of alignment reliability scores from T-Coffee and use of Jalview from the command line. The accompanying notes provide background information on the underlying methods and discuss additional options for working with Jalview to perform multiple sequence alignment, functional site analysis, and publication of alignments on the web.
Over the last century, the incidence of placenta accreta, increta, and percreta, collectively referred to as morbidly adherent placenta, has risen dramatically. Planned cesarean hysterectomy at the ...time of cesarean delivery is the standard recommended treatment in the United States. Recently, interest in conservative management has resurged, especially in Europe. The aims of this review are the following: (1) to provide an overview of methods used for conservative management, (2) to discuss clinical implications for both clinicians and patients, and (3) to identify areas in need of further research.
A central concept of attachment theory is that early experiences with close attachment figures shape the way we interact with and relate to other social partners throughout life. As such, early ...experiences of childhood maltreatment (CM) have been suggested as a key precursor of adult insecure attachment representations. As CM has been linked to feelings of loneliness in adulthood, this study examines whether insecure attachment could explain the relationship between CM and loneliness. Also, the moderating role of a diagnosis of persistent depressive disorder (PDD) is investigated, a disorder characterized by high levels of CM and loneliness.
60 patients with PDD (DSM-5) and 60 gender- and age-matched non-clinical control participants (NC) completed self-report questionnaires measuring attachment, loneliness, and CM. Mediation analyses (PDD as a moderator) were performed.
PDD patients reported higher levels of CM, attachment anxiety, attachment avoidance, and loneliness than NC. CM was positively associated with loneliness in both groups. Mediation analyses demonstrated that the relationship between CM and loneliness was mediated by avoidant, but not anxious attachment, regardless of a diagnosis of PDD.
Caution when interpreting these results is crucial as the study lacked a clinical control group, relied on self-report measures, and the cross-sectional design limits the ability to draw causal inferences.
All constructs studied were present to a greater degree in PDD. Above, findings provide initial evidence that avoidant attachment may explain the relationship between CM and loneliness. Potentially, adult avoidant attachment may lead to and maintain feelings of loneliness, regardless of PDD.
•Attachment insecurity in depression and in persistent depressive disorder is linked to childhood maltreatment.•High levels of experienced maltreatment in childhood, and feelings of loneliness in adulthood are a common feature in patients with persistent depressive disorder.•Attachment insecurity, i.e. attachment avoidance, mediates the relationship between childhood maltreatment and feelings of loneliness in adulthood in persistent depressive disorder and in a non-clinical sample.
We performed a multicenter, International analysis of solid organ transplant (SOT)‐related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD ...patients, median time of SOT‐to‐PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93%; additional first‐line therapy included high‐dose methotrexate (48%), high‐dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment‐related mortality was 13%. With 42‐month median follow‐up, three‐year progression‐free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high‐dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32–5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29–13.46, p = 0.02). Moreover, lack of response to first‐line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56–29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.
In an international analysis of solid organ transplant recipients with primary central nervous system posttransplant lymphoproliferative disease, the authors find that the disease is associated with renal transplantation, typically occurs late and retains EBV positivity, and the dominant prognostic factor for survival is response to first‐line therapy.
Ecosystem services and ethics Jax, Kurt; Barton, David N.; Chan, Kai M.A. ...
Ecological economics,
09/2013, Volume:
93
Journal Article
Peer reviewed
A major strength of the ecosystem services (ESS) concept is that it allows a succinct description of how human well-being depends on nature, showing that the neglect of such dependencies has negative ...consequences on human well-being and the economy. As ESS refer to human needs and interests, values are to be considered when dealing with the concept in practice. As a result we argue that in using the concept there is a need to be clear about what different dimensions of value are involved, and be aware of ethical issues that might be associated with the concept. A systematic analysis of the ethical implications associated to the ESS concept is still lacking. We address this deficiency by scrutinising value dimensions associated with the concept, and use this to explore the associated ethical implications. We then highlight how improved transparency in the use of the ESS concept can contribute to using its strengths without succumbing to possible drawbacks arising from ethical problems. These problems concern the dangers that some uses of the concept have in obscuring certain types of value, and in masking unevenness in the distribution of costs and benefits that can arise in the management of ESS.
•We scrutinise the value dimensions of the ecosystem services (ESS) concept.•We examine possible ethical implications of applying the ESS concept.•Simple juxtaposition of an economic vs. an ethical perspective is not useful.•Ethical implications of the ESS concept depend on context and purpose of its use.•Ethical problems can be attenuated by improving transparency and clarity.
Does Nitisinone prevent the clinical progression of the Alkaptonuria?
In this observational study on 39 patients, 2 mg of daily nitisinone inhibited ochronosis and significantly slowed the ...progression of AKU over a three-year period.
Nitisinone is a beneficial therapy in Alkaptonuria.
Nitisinone decreases homogentisic acid (HGA), but has not been shown to modify progression of Alkaptonuria (AKU).
Thirty-nine AKU patients attended the National AKU Centre (NAC) in Liverpool for assessments and treatment. Nitisinone was commenced at V1 or baseline. Thirty nine, 34 and 22 AKU patients completed 1, 2 and 3 years of monitoring respectively (V2, V3 and V4) in the VAR group. Seventeen patients also attended a pre-baseline visit (V0) in the VAR group. Within the 39 patients, a subgroup of the same ten patients attended V0, V1, V2, V3 and V4 visits constituting the SAME Group.
Severity of AKU was assessed by calculation of the AKU Severity Score Index (AKUSSI) allowing comparison between the pre-nitisinone and the nitisinone treatment phases.
The ALL (sum of clinical, joint and spine AKUSSI features) AKUSSI rate of change of scores/patient/month, in the SAME group, was significantly lower at two (0.32 ± 0.19) and three (0.15 ± 0.13) years post-nitisinone when compared to pre-nitisinone (0.65 ± 0.15) (p < .01 for both comparisons). Similarly, the ALL AKUSSI rate of change of scores/patient/month, in the VAR group, was significantly lower at one (0.16 ± 0.08) and three (0.19 ± 0.06) years post-nitisinone when compared to pre-nitisinone (0.59 ± 0.13) (p < .01 for both comparisons). Combined ear and ocular ochronosis rate of change of scores/patient/month was significantly lower at one, two and three year's post-nitisinone in both VAR and SAME groups compared with pre-nitisinone (p < .05).
This is the first indication that a 2 mg dose of nitisinone slows down the clinical progression of AKU. Combined ocular and ear ochronosis progression was arrested by nitisinone.
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