Under pressure: Response urgency modulates striatal and insula activity during decision-making under risk

When deciding whether to bet in situations that involve potential monetary loss or gain (mixed gambles), a subjective sense of pressure can influence the evaluation of the expected utility associated with each choice option. Here, we explored how gambling decisions, their psychophysiological and neural counterparts are modulated by an induced sense of urgency to respond. Urgency influenced decision times and evoked heart rate responses, interacting with the expected value of each gamble. Using functional MRI, we observed that this interaction was associated with changes in the activity of the striatum, a critical region for both reward and choice selection, and within the insula, a region implicated as the substrate of affective feelings arising from interoceptive signals which influence motivational behavior. Our findings bridge current psychophysiological and neurobiological models of value representation and action-programming, identifying the striatum and insular cortex as the key substrates of decision-making under risk and urgency

Weight and height z-scores improve after initiating ART among HIV-infected children in rural Zambia: a cohort study

<p>Abstract</p> <p>Background</p> <p>Deficits in growth observed in HIV-infected children in resource-poor settings can be reversed with antiretroviral treatment (ART). However, many of the studies have been conducted in urban areas with older pediatric populations. This study was undertaken to evaluate growth patterns after ART initiation in a young pediatric population in rural Zambia with a high prevalence of undernutrition.</p> <p>Methods</p> <p>Between 2007 and 2009, 193 HIV-infected children were enrolled in a cohort study in Macha, Zambia. Children were evaluated every 3 months, at which time a questionnaire was administered, height and weight were measured, and blood specimens were collected. Weight- and height-for-age z-scores were constructed from WHO growth standards. All children receiving ART at enrollment or initiating ART during the study were included in this analysis. Linear mixed effects models were used to model trajectories of weight and height-for-age z-scores.</p> <p>Results</p> <p>A high proportion of study children were underweight (59%) and stunted (72%) at treatment initiation. Improvements in both weight- and height-for-age z-scores were observed, with weight-for-age z-scores increasing during the first 6 months of treatment and then stabilizing, and height-for-age z-scores increasing consistently over time. Trajectories of weight-for-age z-scores differed by underweight status at treatment initiation, with children who were underweight experiencing greater increases in z-scores in the first 6 months of treatment. Trajectories of height-for-age z-scores differed by age, with children older than 5 years of age experiencing smaller increases over time.</p> <p>Conclusions</p> <p>Some of the effects of HIV on growth were reversed with ART initiation, although a high proportion of children remained underweight and stunted after two years of treatment. Partnerships between treatment and nutrition programs should be explored so that HIV-infected children can receive optimal nutritional support.</p

Growth, immune and viral responses in HIV infected African children receiving highly active antiretroviral therapy: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Scale up of paediatric antiretroviral therapy in resource limited settings continues despite limited access to routine laboratory monitoring. We documented the weight and height responses in HIV infected Ugandan children on highly active antiretroviral therapy and determined clinical factors associated with successful treatment outcomes.</p> <p>Methods</p> <p>A prospective cohort of HIV infected children were initiated on HAART and followed for 48 weeks. Body mass index for age z scores(BAZ), weight and height-for-age z scores (WAZ & HAZ) were calculated: CD4 cell % and HIV-1 RNA were measured at baseline and every 12 weeks. Treatment outcomes were classified according to; both virological and immunological success (VS/IS), virological failure and immunological success (VF/IS). virological success and immunological failure (VS/IF) and both virological and immunological failure (VF/IF).</p> <p>Results</p> <p>From March 2004 until May 2006, 124 HIV infected children were initiated on HAART. The median age (IQR) was 5.0 years (2.1 - 7.0) and 49% (61/124) were female. The median [95% confidence interval (CI)] BAZ, WAZ and HAZ at baseline were 0.29 (-2.9, -1.2), -1.2 (-2.1, -0.5) and -2.06 (-2.9, -1.2) respectively. Baseline median CD4 cell % and log10 HIV-1 RNA were; 11.8% (7.5-18.0) and 5.6 (5.2-5.8) copies/ml. By 48 weeks, mean WAZ and HAZ in the VF/IS group, which was younger, increased from - 0.98 (SD 1.7) to + 1.22 (SD 1.2) and from -1.99 (1.7) to + 0.76 (2.4) respectively. Mean increase in WAZ and HAZ in the VS/IF group, an older group was modest, from -1.84 (1.3) to - 0.41 (1.2) and -2.25 (1.2) to -1.16 (1.3) respectively. Baseline CD4 cell % [OR 6.97 95% CI (2.6 -18.6)], age [OR 4.6 95% CI (1.14 -19.1)] and WHO clinical stage [OR 3.5 95%CI (1.05 -12.7)] were associated with successful treatment outcome.</p> <p>Conclusions</p> <p>HIV infected Ugandan children demonstrated a robust increase in height and weight z scores during the first 48 weeks of HAART, including those who failed to completely suppress virus. Older children initiating HAART with severe immune suppression were less likely to achieve a successful treatment outcome. These data emphasize the importance of initiating HAART early to ensure adequate immune and growth responses.</p

Paradoxical Evidence Integration in Rapid Decision Processes

Decisions about noisy stimuli require evidence integration over time. Traditionally, evidence integration and decision making are described as a one-stage process: a decision is made when evidence for the presence of a stimulus crosses a threshold. Here, we show that one-stage models cannot explain psychophysical experiments on feature fusion, where two visual stimuli are presented in rapid succession. Paradoxically, the second stimulus biases decisions more strongly than the first one, contrary to predictions of one-stage models and intuition. We present a two-stage model where sensory information is integrated and buffered before it is fed into a drift diffusion process. The model is tested in a series of psychophysical experiments and explains both accuracy and reaction time distributions

The role of sialomucin CD164 (MGC-24v or endolyn) in prostate cancer metastasis

BACKGROUND: The chemokine stromal derived factor-1 (SDF-1 or CXCL12) and its receptor CXCR4 have been demonstrated to be crucial for the homing of stem cells and prostate cancers to the marrow. While screening prostate cancers for CXCL12-responsive adhesion molecules, we identified CD164 (MGC-24) as a potential regulator of homing. CD164 is known to function as a receptor that regulates stem cell localization to the bone marrow. RESULTS: Using prostate cancer cell lines, it was demonstrated that CXCL12 induced both the expression of CD164 mRNA and protein. Functional studies demonstrated that blocking CD164 on prostate cancer cell lines reduced the ability of these cells to adhere to human bone marrow endothelial cells, and invade into extracellular matrices. Human tissue microarrays stained for CD164 demonstrated a positive correlation with prostate-specific antigen levels, while its expression was negatively correlated with the expression of androgen receptor. CONCLUSION: Our findings suggest that CD164 may participate in the localization of prostate cancer cells to the marrow and is further evidence that tumor metastasis and hematopoietic stem cell trafficking may involve similar processes

Concave Pit-Containing Scaffold Surfaces Improve Stem Cell-Derived Osteoblast Performance and Lead to Significant Bone Tissue Formation

Scaffold surface features are thought to be important regulators of stem cell performance and endurance in tissue engineering applications, but details about these fundamental aspects of stem cell biology remain largely unclear.In the present study, smooth clinical-grade lactide-coglyolic acid 85:15 (PLGA) scaffolds were carved as membranes and treated with NMP (N-metil-pyrrolidone) to create controlled subtractive pits or microcavities. Scanning electron and confocal microscopy revealed that the NMP-treated membranes contained: (i) large microcavities of 80-120 microm in diameter and 40-100 microm in depth, which we termed primary; and (ii) smaller microcavities of 10-20 microm in diameter and 3-10 microm in depth located within the primary cavities, which we termed secondary. We asked whether a microcavity-rich scaffold had distinct bone-forming capabilities compared to a smooth one. To do so, mesenchymal stem cells derived from human dental pulp were seeded onto the two types of scaffold and monitored over time for cytoarchitectural characteristics, differentiation status and production of important factors, including bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF). We found that the microcavity-rich scaffold enhanced cell adhesion: the cells created intimate contact with secondary microcavities and were polarized. These cytological responses were not seen with the smooth-surface scaffold. Moreover, cells on the microcavity-rich scaffold released larger amounts of BMP-2 and VEGF into the culture medium and expressed higher alkaline phosphatase activity. When this type of scaffold was transplanted into rats, superior bone formation was elicited compared to cells seeded on the smooth scaffold.In conclusion, surface microcavities appear to support a more vigorous osteogenic response of stem cells and should be used in the design of therapeutic substrates to improve bone repair and bioengineering applications in the future

A Cross-Species Analysis of a Mouse Model of Breast Cancer-Specific Osteolysis and Human Bone Metastases Using Gene Expression Profiling

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the second leading cause of cancer-related death in women in the United States. During the advanced stages of disease, many breast cancer patients suffer from bone metastasis. These metastases are predominantly osteolytic and develop when tumor cells interact with bone. <it>In vivo </it>models that mimic the breast cancer-specific osteolytic bone microenvironment are limited. Previously, we developed a mouse model of tumor-bone interaction in which three mouse breast cancer cell lines were implanted onto the calvaria. Analysis of tumors from this model revealed that they exhibited strong bone resorption, induction of osteoclasts and intracranial penetration at the tumor bone (TB)-interface.</p> <p>Methods</p> <p>In this study, we identified and used a TB microenvironment-specific gene expression signature from this model to extend our understanding of the metastatic bone microenvironment in human disease and to predict potential therapeutic targets.</p> <p>Results</p> <p>We identified a TB signature consisting of 934 genes that were commonly (among our 3 cell lines) and specifically (as compared to tumor-alone area within the bone microenvironment) up- and down-regulated >2-fold at the TB interface in our mouse osteolytic model. By comparing the TB signature with gene expression profiles from human breast metastases and an <it>in vitro </it>osteoclast model, we demonstrate that our model mimics both the human breast cancer bone microenvironment and osteoclastogenesis. Furthermore, we observed enrichment in various signaling pathways specific to the TB interface; that is, TGF-β and myeloid self-renewal pathways were activated and the Wnt pathway was inactivated. Lastly, we used the TB-signature to predict cyclopenthiazide as a potential inhibitor of the TB interface.</p> <p>Conclusion</p> <p>Our mouse breast cancer model morphologically and genetically resembles the osteoclastic bone microenvironment observed in human disease. Characterization of the gene expression signature specific to the TB interface in our model revealed signaling mechanisms operative in human breast cancer metastases and predicted a therapeutic inhibitor of cancer-mediated osteolysis.</p

Bone Morphogenetic Protein (BMP)-4 and BMP-7 regulate differentially Transforming Growth Factor (TGF)-beta 1 in normal human lung fibroblasts (NHLF)

<p>Abstract</p> <p>Background</p> <p>Airway remodelling is thought to be under the control of a complex group of molecules belonging to the Transforming Growth Factor <b>(</b>TGF)-superfamily. The Bone Morphogenetic Proteins <b>(</b>BMPs) belong to this family and have been shown to regulate fibrosis in kidney and liver diseases. However, the role of BMPs in lung remodelling remains unclear. BMPs may regulate tissue remodelling in asthma by controlling TGF-β-induced profibrotic functions in lung fibroblasts.</p> <p>Methods</p> <p>Cell cultures were exposed to TGF-β1 alone or in the presence of BMP-4 or BMP-7; control cultures were exposed to medium only. Cell proliferation was assessed by quantification of the incorporation of [3H]-thymidine. The expression of the mRNA encoding collagen type I and IV, tenascin C and fibronectin in normal human lung fibroblasts (NHLF) was determined by real-time quantitative PCR and the main results were confirmed by ELISA. Cell differentiation was determined by the analysis of the expression of α-smooth muscle actin (α-SMA) by western blot and immunohistochemistry. The effect on matrix metalloproteinase (MMP) activity was assessed by zymography.</p> <p>Results</p> <p>We have demonstrated TGF-β1 induced upregulation of mRNAs encoding the extracellular matrix proteins, tenascin C, fibronectin and collagen type I and IV when compared to unstimulated NHLF, and confirmed these results at the protein level. BMP-4, but not BMP-7, reduced TGF-β1-induced extracellular matrix protein production. TGF-β1 induced an increase in the activity of the pro-form of MMP-2 which was inhibited by BMP-7 but not BMP-4. Both BMP-4 and BMP-7 downregulated TGF-β1-induced MMP-13 release compared to untreated and TGF-β1-treated cells. TGF-β1 also induced a myofibroblast-like transformation which was partially inhibited by BMP-7 but not BMP-4.</p> <p>Conclusions</p> <p>Our study suggests that some regulatory properties of BMP-7 may be tissue or cell type specific and unveil a potential regulatory role for BMP-4 in the regulation of lung fibroblast function.</p