Sarcoidosis of the hypothalamus and pituitary stalk

We report a rare case of sarcoidosis of the hypothalamic and suprasellar region, with clinical course and the magnetic resonance imaging follow-up

Over-Selectivity is Related to Autism Quotient and Empathizing, But not to Systematizing

The relationships of autism quotient (AQ), systematizing (SQ), and empathizing (EQ), with over-selectivity were explored to assess whether over-selectivity is implicated in complex social skills, which has been assumed, but not experimentally examined. Eighty participants (aged 18–60) were trained on a simultaneous discrimination task (AB+CD−), and tested in extinction on the degree to which they had learned about both elements of the reinforced (AB) compound. Higher AQ and lower EQ scorers demonstrated greater over-selectivity, but there was no relationship between SQ and over-selectivity. These results imply that high AQ scorers perform similarly to individuals with ASD on this cognitive task, and that over-selectivity may be related to some complex social skills, like empathy

Src tyrosine kinase augments taxotere-induced apoptosis through enhanced expression and phosphorylation of Bcl-2

Activation of Src, which has an intrinsic protein tyrosine kinase activity, has been demonstrated in many human tumours, such as colorectal and breast cancers, and is closely associated with the pathogenesis and metastatic potential of these cancers. In this study, we have examined the effect of activated Src on the sensitivity to taxotere, an anticancer drug targeting microtubules, using v-src-transfected HAG-1 human gall bladder epithelial cells. As compared with parental HAG-1 cell line, v-src-transfected HAG/src3-1 cells became 5.9 and 7.0-fold sensitive to taxotere for 2 and 24-h exposure, respectively. By contrast, HAG-1 cells transfected with activated Ras, which acts downstream of Src, acquired approximately 2.5∼4.8-fold taxotere resistance. The taxotere sensitivity in HAG/src3-1 cells was reversed, if not completely, by herbimycin A, a specific inhibitor of Src family protein tyrosine kinase, indicating that Src protein tyrosine kinase augments sensitivity to taxotere. Treatment of HAG/src3-1 cells with taxotere resulted in phosphorylation of Bcl-2 and subsequent induction of apoptotic cell death, whereas neither Bcl-2 phosphorylation nor apoptosis occurred in parental or c-H-ras-transfected HAG-1 cells. Interestingly, the Bcl-2 protein is overexpressed in v-src-transfected cell line, compared to those in parental or Ras-transfected cell line. Treatment of HAG/src3-1 cells with herbimycin A significantly reduced the expression and phosphorylation of Bcl-2, and abrogated taxotere-induced apoptosis, suggesting a potential role for Src protein tyrosine kinase in the taxotere-induced apoptotic events. H-7, a protein kinase C inhibitor and wortmannin, a phosphatidylinositol-3 kinase (PI-3 kinase) inhibitor, neither altered taxotere sensitivity nor inhibited taxotere-induced apoptosis in these cells. These data indicate that the ability of activated Src to increase taxotere sensitivity would be mediated by apoptotic events occurring through Src to downstream signal transduction pathways toward Bcl-2 phosphorylation, but not by activated Ras, PI-3 kinase or protein kinase C

Effect of diindolylmethane supplementation on low-grade cervical cytological abnormalities: double-blind, randomised, controlled trial

This work was supported by a Cancer Research UK project grant (C8162/A4609 project costs) and a programme grant (C8162/A10406)

Mathematical model insights into arsenic detoxification

<p>Abstract</p> <p>Background</p> <p>Arsenic in drinking water, a major health hazard to millions of people in South and East Asia and in other parts of the world, is ingested primarily as trivalent inorganic arsenic (iAs), which then undergoes hepatic methylation to methylarsonic acid (MMAs) and a second methylation to dimethylarsinic acid (DMAs). Although MMAs and DMAs are also known to be toxic, DMAs is more easily excreted in the urine and therefore methylation has generally been considered a detoxification pathway. A collaborative modeling project between epidemiologists, biologists, and mathematicians has the purpose of explaining existing data on methylation in human studies in Bangladesh and also testing, by mathematical modeling, effects of nutritional supplements that could increase As methylation.</p> <p>Methods</p> <p>We develop a whole body mathematical model of arsenic metabolism including arsenic absorption, storage, methylation, and excretion. The parameters for arsenic methylation in the liver were taken from the biochemical literature. The transport parameters between compartments are largely unknown, so we adjust them so that the model accurately predicts the urine excretion rates of time for the iAs, MMAs, and DMAs in single dose experiments on human subjects.</p> <p>Results</p> <p>We test the model by showing that, with no changes in parameters, it predicts accurately the time courses of urinary excretion in mutiple dose experiments conducted on human subjects. Our main purpose is to use the model to study and interpret the data on the effects of folate supplementation on arsenic methylation and excretion in clinical trials in Bangladesh. Folate supplementation of folate-deficient individuals resulted in a 14% decrease in arsenicals in the blood. This is confirmed by the model and the model predicts that arsenicals in the liver will decrease by 19% and arsenicals in other body stores by 26% in these same individuals. In addition, the model predicts that arsenic methyltransferase has been upregulated by a factor of two in this population. Finally, we also show that a modification of the model gives excellent fits to the data on arsenic metabolism in human cultured hepatocytes.</p> <p>Conclusions</p> <p>The analysis of the Bangladesh data using the model suggests that folate supplementation may be more effective at reducing whole body arsenic than previously expected. There is almost no data on the upregulation of arsenic methyltransferase in populations chronically exposed to arsenic. Our model predicts upregulation by a factor of two in the Bangladesh population studied. This prediction should be verified since it could have important public health consequences both for treatment strategies and for setting appropriate limits on arsenic in drinking water. Our model has compartments for the binding of arsenicals to proteins inside of cells and we show that these comparments are necessary to obtain good fits to data. Protein-binding of arsenicals should be explored in future biochemical studies.</p

Contorted and ordinary body postures in the human brain

Social interaction and comprehension of non-verbal behaviour requires a representation of people’s bodies. Research into the neural underpinnings of body representation implicates several brain regions including extrastriate and fusiform body areas (EBA and FBA), superior temporal sulcus (STS), inferior frontal gyrus (IFG) and inferior parietal lobule (IPL). The different roles played by these regions in parsing familiar and unfamiliar body postures remain unclear. We examined the responses of this body observation network to static images of ordinary and contorted postures by using a repetition suppression design in functional neuroimaging. Participants were scanned whilst observing static images of a contortionist or a group of objects in either ordinary or unusual configurations, presented from different viewpoints. Greater activity emerged in EBA and FBA when participants viewed contorted compared to ordinary body postures. Repeated presentation of the same posture from different viewpoints lead to suppressed responses in the fusiform gyrus as well as three regions that are characteristically activated by observing moving bodies, namely STS, IFG and IPL. These four regions did not distinguish the image viewpoint or the plausibility of the posture. Together, these data define a broad cortical network for processing static body postures, including regions classically associated with action observation

Extrastriate body area underlies aesthetic evaluation of body stimuli

Humans appear to be the only animals to have developed the practice and culture of art. This practice presumably relies on special processing circuits within the human brain associated with a distinct subjective experience, termed aesthetic experience, and preferentially evoked by artistic stimuli. We assume that positive or negative aesthetic judgments are an important function of neuroaesthetic circuits. The localization of these circuits in the brain remains unclear, though neuroimaging studies have suggested several possible neural correlates of aesthetic preference. We applied repetitive transcranial magnetic stimulation (rTMS) over candidate brain areas to disrupt aesthetic processing while healthy volunteers made aesthetic preference judgments between pairs of dance postures, or control non-body stimuli. Based on evidence from visual body perception studies, we targeted the ventral premotor cortex (vPMC) and extrastriate body area (EBA), in the left and right hemispheres. rTMS over EBA reduced aesthetic sensitivity for body stimuli relative to rTMS over vPMC, while no such difference was found for non-body stimuli. We interpret our results within the framework of dual routes for visual body processing. rTMS over either EBA or vPMC reduced the contributions of the stimulated area to body processing, leaving processing more reliant on the unaffected route. Disruption of EBA reduces the local processing of the stimuli, and reduced observers’ aesthetic sensitivity. Conversely, disruption of the global route via vPMC increased the relative contribution of the local route via EBA, and thus increased aesthetic sensitivity. In this way, we suggest a complementary contribution of both local and global routes to aesthetic processing

Differential effect of vinorelbine versus paclitaxel on ERK2 kinase activity during apoptosis in MCF-7 cells

The effects of vinorelbine and paclitaxel on the activity of extracellular signal-regulated protein kinase2 (ERK2), a member of MAP kinase, and its role in the induction of bcl-2 phosphorylation and apoptosis were evaluated in MCF-7 cells. We demonstrated that ERK2 was activated rapidly by vinorelbine, and was inhibited by either paclitaxel or estramustine. A 3-fold increase of ERK2 kinase activity was observed within 30 min when MCF-7 cells were treated with 0.1 μM vinorelbine. In contrast, the same treatment with paclitaxel resulted in a significant decrease of ERK2 kinase activity. We also demonstrated that elevated bcl-2 phosphorylation induced by vinorelbine is paralleled by decrease of a complex formation between bcl-2 and bax, cleavage of poly (ADP) ribose polymerase (PARP) protein, activation of caspase-7, and apoptosis. The levels of bcl-2 phosphorylation, bax, and PARP were not significantly affected by 2′-amino-3′-methoxyflavone (PD 98059), an ERK kinase specific inhibitor. Thus, our data suggest that the apoptosis induced by vinorelbine in MCF-7 cells is mediated through the bcl-2 phosphorylation/bax/caspases pathways, and that activation of ERK2 by vinorelbine does not directly lead to the drug-mediated apoptosis. Since decrease of PARP occurred quickly following the treatment of MCF-7 cells with either 0.1 μM of vinorelbine or paclitaxel, this protein may serve as an early indicator of apoptosis induced not only by DNA damaging agents, but also by antimicrotubule drugs.   http://www.bjcancer.com © 2001 Cancer Research Campaig

Oligomeric Structure of the MALT1 Tandem Ig-Like Domains

Mucosa-associated lymphoid tissue 1 (MALT1) plays an important role in the adaptive immune program. During TCR- or BCR-induced NF-κB activation, MALT1 serves to mediate the activation of the IKK (IκB kinase) complex, which subsequently regulates the activation of NF-κB. Aggregation of MALT1 is important for E3 ligase activation and NF-κB signaling.Unlike the isolated CARD or paracaspase domains, which behave as monomers, the tandem Ig-like domains of MALT1 exists as a mixture of dimer and tetramer in solution. High-resolution structures reveals a protein-protein interface that is stabilized by a buried surface area of 1256 Å(2) and contains numerous hydrogen and salt bonds. In conjunction with a second interface, these interactions may represent the basis of MALT1 oligomerization.The crystal structure of the tandem Ig-like domains reveals the oligomerization potential of MALT1 and a potential intermediate in the activation of the adaptive inflammatory pathway.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1