Plasma cholesterol levels and brain development in preterm newborns.

BackgroundTo assess whether postnatal plasma cholesterol levels are associated with microstructural and macrostructural regional brain development in preterm newborns.MethodsSixty preterm newborns (born 24-32 weeks gestational age) were assessed using MRI studies soon after birth and again at term-equivalent age. Blood samples were obtained within 7 days of each MRI scan to analyze for plasma cholesterol and lathosterol (a marker of endogenous cholesterol synthesis) levels. Outcomes were assessed at 3 years using the Bayley Scales of Infant Development, Third Edition.ResultsEarly plasma lathosterol levels were associated with increased axial and radial diffusivities and increased volume of the subcortical white matter. Early plasma cholesterol levels were associated with increased volume of the cerebellum. Early plasma lathosterol levels were associated with a 2-point decrease in motor scores at 3 years.ConclusionsHigher early endogenous cholesterol synthesis is associated with worse microstructural measures and larger volumes in the subcortical white matter that may signify regional edema and worse motor outcomes. Higher early cholesterol is associated with improved cerebellar volumes. Further work is needed to better understand how the balance of cholesterol supply and endogenous synthesis impacts preterm brain development, especially if these may be modifiable factors to improve outcomes

Conjugation with L, L-diphenylalanine Self-Assemblies Enhances In Vitro Antitumor Activity of Phthalocyanine Photosensitizer

We present the synthesis and characterization of new peptide conjugates obtained by hierarchical co-assembly of L,L-diphenylalanine (FF) and zinc phthalocyanine complexes (ZnPc) in water. Self-assembly capabilities under defined conditions were investigated by scanning electron microscopy, and photophysical properties were evaluated using UV-Vis and fluorescence spectroscopy. AFM observations demonstrated that these ZnPcs form different highly ordered arrays on the crystalline faces of the FF microplates and that surface roughness significantly changes with the presence of differently substituted phthalocyanine units. XRD assays showed that the overall molecular packing of the conjugates is organized according to a hexagonal symmetry, with ZnPcs hosted in the interstices of the peptide phase. In vitro photodynamic studies were conducted on human breast cancer MCF-7 cells to investigate both cellular uptake and cytotoxicity. It was shown that FF self-assemblies are not toxicity and enhance accumulation of ZnPc in MCF-7 cells, improving apoptotic cell death upon irradiation. Our findings demonstrate enhancement of ZnPc antitumor efficiency by FF conjugates and a proof-of-concept for new photosensitizer carriers based on peptide conjugates

Epidemiologic heterogeneity of common mood and anxiety disorders over the lifecourse in the general population: a systematic review

Background Clinical evidence has long suggested there may be heterogeneity in the patterns and predictors of common mood and anxiety disorders; however, epidemiologic studies have generally treated these outcomes as homogenous entities. The objective of this study was to systematically review the epidemiologic evidence for potential patterns of heterogeneity of common mood and anxiety disorders over the lifecourse in the general population. Methods We reviewed epidemiologic studies examining heterogeneity in either the nature of symptoms experienced ( symptom syndromes ) or in patterns of symptoms over time ( symptom trajectories ). To be included, studies of syndromes were required to identify distinct symptom subtypes, and studies of trajectories were required to identify distinct longitudinal patterns of symptoms in at least three waves of follow-up. Studies based on clinical or patient populations were excluded. Results While research in this field is in its infancy, we found growing evidence that, not only can mood and anxiety disorders be differentiated by symptom syndromes and trajectories, but that the factors associated with these disorders may vary between these subtypes. Whether this reflects a causal pathway, where genetic or environmental factors influence the nature of the symptom or trajectory subtype experienced by an individual, or whether individuals with different subtypes differed in their susceptibility to different environmental factors, could not be determined. Few studies addressed issues of comorbidity or transitions in symptoms between common disorders. Conclusion Understanding the diversity of these conditions may help us identify preventable factors that are only associated with some subtypes of these common disorders

The genetic basis of DOORS syndrome: an exome-sequencing study.

Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Comparative transcriptome profiling of amyloid precursor protein family members in the adult cortex

<p>Abstract</p> <p>Background</p> <p>The β-amyloid precursor protein (APP) and the related β-amyloid precursor-like proteins (APLPs) undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that Aβ accumulation is a central trigger for Alzheimer's disease, the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsα ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The γ-secretase-generated APP intracellular domain (AICD) functions as a transcriptional regulator in heterologous reporter assays although its role for endogenous gene regulation has remained controversial.</p> <p>Results</p> <p>To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators, we performed DNA microarray transcriptome profiling of prefrontal cortex of adult wild-type (WT), APP knockout (APP^-/-), APLP2 knockout (APLP2^-/-) and APPsα knockin mice (APP^α/α) expressing solely the secreted APPsα ectodomain. Biological pathways affected by the lack of APP family members included neurogenesis, transcription, and kinase activity. Comparative analysis of transcriptome changes between mutant and wild-type mice, followed by qPCR validation, identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity-related genes that were both down-regulated in knockout cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including <it>Bace1</it>, <it>Kai1</it>, <it>Gsk3b</it>, <it>p53</it>, <it>Tip60</it>, and <it>Vglut2</it>. Only <it>Egfr </it>was slightly up-regulated in APLP2^-/-mice. Comparison of APP^-/-and APP^α/αwith wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2^-/-on different genetic backgrounds revealed that background-related transcriptome changes may dominate over changes due to the knockout of a single gene.</p> <p>Conclusion</p> <p>Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells.</p

New insights into the role of age and carcinoembryonic antigen in the prognosis of colorectal cancer

The aim of this study was to verify through relative survival (an estimate of cancer-specific survival) the true prognostic factors of colorectal cancer. The study involved 506 patients who underwent locally radical resection. All the clinical, histological and laboratory parameters were prognostically analysed for both overall and relative survival. This latter was calculated from the expected survival of the general population with identical age, sex and calendar years of observation. Univariate and multivariate analyses were applied to the proportional hazards model. Liver metastases, age, lymph node involvement and depth of bowel wall involvement were independent prognosticators of both overall and relative survival, whereas carcinoembryonic antigen (CEA) was predictive only of relative survival. Increasing age was unfavourably related to overall survival, but mildly protective with regard to relative survival. Three out of the five prognostic factors identified are the cornerstones of the current staging systems, and were confirmed as adequate by the analysis of relative survival. The results regarding age explain the conflicting findings so far obtained from studies considering overall survival only and advise against the adoption of absolute age limits in therapeutic protocols. Moreover, the prechemotherapy CEA level showed a high clinical value

A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology

BACKGROUND: Understanding variations in the incidence of schizophrenia is a crucial step in unravelling the aetiology of this group of disorders. The aims of this review are to systematically identify studies related to the incidence of schizophrenia, to describe the key features of these studies, and to explore the distribution of rates derived from these studies. METHODS: Studies with original data related to the incidence of schizophrenia (published 1965–2001) were identified via searching electronic databases, reviewing citations and writing to authors. These studies were divided into core studies, migrant studies, cohort studies and studies based on Other Special Groups. Between- and within-study filters were applied in order to identify discrete rates. Cumulative plots of these rates were made and these distributions were compared when the underlying rates were sorted according to sex, urbanicity, migrant status and various methodological features. RESULTS: We identified 100 core studies, 24 migrant studies, 23 cohort studies and 14 studies based on Other Special Groups. These studies, which were drawn from 33 countries, generated a total of 1,458 rates. Based on discrete core data for persons (55 studies and 170 rates), the distribution of rates was asymmetric and had a median value (10%–90% quantile) of 15.2 (7.7–43.0) per 100,000. The distribution of rates was significantly higher in males compared to females; the male/female rate ratio median (10%–90% quantile) was 1.40 (0.9–2.4). Those studies conducted in urban versus mixed urban-rural catchment areas generated significantly higher rate distributions. The distribution of rates in migrants was significantly higher compared to native-born; the migrant/native-born rate ratio median (10%–90% quantile) was 4.6 (1.0–12.8). Apart from the finding that older studies reported higher rates, other study features were not associated with significantly different rate distributions (e.g. overall quality, methods related to case finding, diagnostic confirmation and criteria, the use of age-standardization and age range). CONCLUSIONS: There is a wealth of data available on the incidence of schizophrenia. The width and skew of the rate distribution, and the significant impact of sex, urbanicity and migrant status on these distributions, indicate substantial variations in the incidence of schizophrenia

Medical conditions in autism spectrum disorders

Autism spectrum disorder (ASD) is a behaviourally defined syndrome where the etiology and pathophysiology is only partially understood. In a small proportion of children with the condition, a specific medical disorder is identified, but the causal significance in many instances is unclear. Currently, the medical conditions that are best established as probable causes of ASD include Fragile X syndrome, Tuberous Sclerosis and abnormalities of chromosome 15 involving the 15q11-13 region. Various other single gene mutations, genetic syndromes, chromosomal abnormalities and rare de novo copy number variants have been reported as being possibly implicated in etiology, as have several ante and post natal exposures and complications. However, in most instances the evidence base for an association with ASD is very limited and largely derives from case reports or findings from small, highly selected and uncontrolled case series. Not only therefore, is there uncertainty over whether the condition is associated, but the potential basis for the association is very poorly understood. In some cases the medical condition may be a consequence of autism or simply represent an associated feature deriving from an underlying shared etiology. Nevertheless, it is clear that in a growing proportion of individuals potentially causal medical conditions are being identified and clarification of their role in etio-pathogenesis is necessary. Indeed, investigations into the causal mechanisms underlying the association between conditions such as tuberous sclerosis, Fragile X and chromosome 15 abnormalities are beginning to cast light on the molecular and neurobiological pathways involved in the pathophysiology of ASD. It is evident therefore, that much can be learnt from the study of probably causal medical disorders as they represent simpler and more tractable model systems in which to investigate causal mechanisms. Recent advances in genetics, molecular and systems biology and neuroscience now mean that there are unparalleled opportunities to test causal hypotheses and gain fundamental insights into the nature of autism and its development