Neurodevelopment and Endocrine Disruption

In this article I explore the possibility that contaminants contribute to the increasing prevalence of attention deficit hyperactivity disorder, autism, and associated neurodevelopmental and behavioral problems in developed countries. I discuss the exquisite sensitivity of the embryo and fetus to thyroid disturbance and provide evidence of human in utero exposure to contaminants that can interfere with the thyroid. Because it may never be possible to link prenatal exposure to a specific chemical with neurodevelopmental damage in humans, I also present alternate models where associations have been made between exposure to specific chemicals or chemical classes and developmental difficulties in laboratory animals, wildlife, and humans

Validity of the Clock Drawing Test in predicting reports of driving problems in the elderly

BACKGROUND: This study examined the use of the Folstein Mini Mental Status Exam (MMSE) and the Clock Drawing Test (CDT) in predicting retrospective reports of driving problems among the elderly. The utility of existing scoring systems for the CDT was also examined. METHODS: Archival chart records of 325 patients of a geriatric outpatient clinic were reviewed, of which 162 had CDT results (including original clock drawings). T-test, correlation, and regression procedures were used to analyze the data. RESULTS: Both CDT and MMSE scores were significantly worse among non-drivers than individuals who were currently or recently driving. Among current or recent drivers, scores on both instruments correlated significantly with the total number of reported accidents or near misses, although the magnitude of the respective correlations was small. Only MMSE scores, however, significantly predicted whether or not any accidents or near misses were reported at all. Neither MMSE nor CDT scores predicted unique variance in the regressions. CONCLUSIONS: The overall results suggest that both the MMSE and CDT have limited utility as potential indicators of driving problems in the elderly. The demonstrated predictive power for these instruments appears to be redundant, such that both appear to assess general cognitive function versus more specific abilities. Furthermore, the lack of robust prediction suggests that neither are sufficient to serve as stand-alone instruments on which to solely base decisions of driving capacity. Rather, individuals who evidence impairment should be provided a more thorough and comprehensive assessment than can be obtained through screening tools

Relative effects of sensory modalities and importance of fatty acid sensitivity on fat perception in a real food model

Fat can be perceived through mouthfeel, odour and taste, but the influence of these modalities on fat perception remains undefined. Fatty acids are stimuli. Individual’s sensitivity to fatty acids varies. Studies show association between fatty acid sensitivity, dietary intake and BMI, but results are conflicting. Therefore, this study examined this association, and the effects of modalities on fat perception. Two sub-studies conducted. In Study 1 (n=46), fat intensity was assessed by milk/cream mixtures varying by five fat levels. Fat intensity was rated under four conditions: mouthfeel-odour masked, mouthfeel masked, odour masking and no masking. Mouthfeel masking was achieved using thickener and paraffin, odour masking using nose-clips. Fatty acid sensitivity was measured by 3-AFC-staircase method using milk containing oleic acid (0.31-31.4mM). In Study 2 (n=51), more fat levels were added in fat intensity rating. A 2-AFC discrimination test was used to confirm whether fat levels could be distinguished. In the sensitivity test, a wider range of oleic acid was included. Fat intensity was rated higher without nose-clips (p<0.0001), implying that odour increased fat perception. Samples with mouthfeel-masked were rated higher, showing that increased viscosity and lubricity enhanced fat perception (p<0.0001). Participants could distinguish fat levels based on “taste” in rating tests and 2-AFC-tests. Participants were divided into high/medium/low-sensitivity groups. No significant difference found in fat intensity between groups, however, high-sensitivity group discriminated more fat levels. No association between sensitivity groups, nutrient intake or BMI found

Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. METHODS AND FINDINGS: To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. CONCLUSIONS: The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life

Metal-macrofauna interactions determine microbial community structure and function in copper contaminated sediments

Peer reviewedPublisher PD

Occult Transthyretin Cardiac Amyloid in Severe Calcific Aortic Stenosis. Prevalence and Prognosis in Patients Undergoing Surgical Aortic Valve Replacement

BACKGROUND: Calcific aortic stenosis (cAS) affects 3% of individuals aged >75 years, leading to heart failure and death unless the valve is replaced. Wild-type transthyretin cardiac amyloid is also a disorder of ageing individuals. Prevalence and clinical significance of dual pathology are unknown. This study explored the prevalence of wild-type transthyretin amyloid in cAS by myocardial biopsy, its imaging phenotype and prognostic significance. METHODS AND RESULTS: A total of 146 patients with severe AS requiring surgical valve replacement underwent cardiovascular magnetic resonance and intraoperative biopsies; 112 had cAS (75±6 years; 57% men). Amyloid was sought histologically using Congo red staining and then typed using immunohistochemistry and mass spectrometry; patients with amyloid underwent clinical evaluation including genotyping and ⁹⁹^m^TC-3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) bone scintigraphy. Amyloid was identified in 6 of 146 patients, all with cAS and >65 years (prevalence 5.6% in cAS >65). All 6 patients had wild-type transthyretin amyloid (mean age 75 years; range, 69–85; 4 men), not suspected on echocardiography. Cardiovascular magnetic resonance findings were of definite cardiac amyloidosis in 2, but could be explained solely by AS in the other 4. Postoperative DPD scans demonstrated cardiac localization in all 4 patients who had this investigation (2 died prior). At follow-up (median, 2.3 years), 50% with amyloid had died (versus 7.5% in cAS; 6.9% in age >65 years). In univariable analyses, the presence of transthyretin amyloidosis amyloid had the highest hazard ratio for death (9.5 [95% confidence interval, 2.5–35.8]; P=0.001). CONCLUSIONS: Occult wild-type transthyretin cardiac amyloid had a prevalence of 6% among patients with AS aged >65 years undergoing surgical aortic valve replacement and was associated with a poor outcome

Experimental study of dense pyroclastic density currents using sustained, gas-fluidized granular flows

© 2014, Springer-Verlag Berlin Heidelberg. We present the results of laboratory experiments on the behaviour of sustained, dense granular flows in a horizontal flume, in which high-gas pore pressure was maintained throughout the flow duration by continuous injection of gas through the flume base. The flows were fed by a sustained (0.5–30 s) supply of fine (75 ± 15 μm) particles from a hopper; the falling particles impacted an impingement surface at concentrations of ~3 to 45 %, where they densified rapidly to generate horizontally moving, dense granular flows. When the gas supplied through the flume base was below the minimum fluidization velocity of the particles (i.e. aerated flow conditions), three flow phases were identified: (i) an initial dilute spray of particles travelling at 1–2 m s−1, followed by (ii) a dense granular flow travelling at 0.5–1 m s−1, then by (iii) sustained aggradation of the deposit by a prolonged succession of thin flow pulses. The maximum runout of the phase 2 flow was linearly dependent on the initial mass flux, and the frontal velocity had a square-root dependence on mass flux. The frontal propagation speed during phase 3 had a linear relationship with mass flux. The total mass of particles released had no significant control on either flow velocity or runout in any of the phases. High-frequency flow unsteadiness during phase 3 generated deposit architectures with progradational and retrogradational packages and multiple internal erosive contacts. When the gas supplied through the flume base was equal to the minimum fluidization velocity of the particles (i.e. fluidized flow conditions), the flows remained within phase 2 for their entire runout, no deposit formed and the particles ran off the end of the flume. Sustained granular flows differ significantly from instantaneous flows generated by lock-exchange mechanisms, in that the sustained flows generate (by prolonged progressive aggradation) deposits that are much thicker than the flowing layer of particles at any given moment. The experiments offer a first attempt to investigate the physics of the sustained pyroclastic flows that generate thick, voluminous ignimbrites

MicroRNA-199b-5p Impairs Cancer Stem Cells through Negative Regulation of HES1 in Medulloblastoma

BACKGROUND: Through negative regulation of gene expression, microRNAs (miRNAs) can function in cancers as oncosuppressors, and they can show altered expression in various tumor types. Here we have investigated medulloblastoma tumors (MBs), which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many cell-fate-determining stages. MBs occur bimodally, with the peak incidence seen between 3-4 years and 8-9 years of age, although it can also occur in adults. Notch regulates a subset of the MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulated these phenomena, and can be used in anti-cancer therapies. METHODOLOGY/PRINCIPAL FINDINGS: In a screening of MB cell lines, the miRNA miR-199b-5p was seen to be a regulator of the Notch pathway through its targeting of the transcription factor HES1. Down-regulation of HES1 expression by miR-199b-5p negatively regulates the proliferation rate and anchorage-independent growth of MB cells. MiR-199b-5p over-expression blocks expression of several cancer stem-cell genes, impairs the engrafting potential of MB cells in the cerebellum of athymic/nude mice, and of particular interest, decreases the MB stem-cell-like (CD133+) subpopulation of cells. In our analysis of 61 patients with MB, the expression of miR-199b-5p in the non-metastatic cases was significantly higher than in the metastatic cases (P = 0.001). Correlation with survival for these patients with high levels of miR-199b expression showed a positive trend to better overall survival than for the low-expressing patients. These data showing the down-regulation of miR-199b-5p in metastatic MBs suggest a potential silencing mechanism through epigenetic or genetic alterations. Upon induction of de-methylation using 5-aza-deoxycytidine, lower miR-199b-5p expression was seen in a panel of MB cell lines, supported an epigenetic mechanism of regulation. Furthermore, two cell lines (Med8a and UW228) showed significant up-regulation of miR-199b-5p upon treatment. Infection with MB cells in an induced xenograft model in the mouse cerebellum and the use of an adenovirus carrying miR-199b-5p indicate a clinical benefit through this negative influence of miR-199b-5p on tumor growth and on the subset of MB stem-cell-like cells, providing further proof of concept. CONCLUSIONS/SIGNIFICANCE: Despite advances in our understanding of the pathogenesis of MB, one-third of these patients remain incurable and current treatments can significantly damage long-term survivors. Here we show that miR-199b-5p expression correlates with metastasis spread, identifying a new molecular marker for a poor-risk class in patients with MB. We further show that in a xenograft model, MB tumor burden can be reduced, indicating the use of miR199b-5p as an adjuvant therapy after surgery, in combination with radiation and chemotherapy, for the improvement of anti-cancer MB therapies and patient quality of life. To date, this is the first report that expression of a miRNA can deplete the tumor stem cells, indicating an interesting therapeutic approach for the targeting of these cells in brain tumors

Spin dynamics in semiconductors

This article reviews the current status of spin dynamics in semiconductors which has achieved a lot of progress in the past years due to the fast growing field of semiconductor spintronics. The primary focus is the theoretical and experimental developments of spin relaxation and dephasing in both spin precession in time domain and spin diffusion and transport in spacial domain. A fully microscopic many-body investigation on spin dynamics based on the kinetic spin Bloch equation approach is reviewed comprehensively.Comment: a review article with 193 pages and 1103 references. To be published in Physics Reports