Biosilicate (R)-gelatine bone scaffolds by the foam replica technique: development and characterization

The development of bioactive glass-ceramic materials has been a topic of great interest aiming at enhancing the mechanical strength of traditional bioactive scaffolds. In the present study, we test and demonstrate the use of Biosilicate® glass-ceramic powder to fabricate bone scaffolds by the foam replica method. Scaffolds possessing the main requirements for use in bone tissue engineering (95% porosity, 200–500 μm pore size) were successfully produced. Gelatine coating was investigated as a simple approach to increase the mechanical competence of the scaffolds. The gelatine coating did not affect the interconnectivity of the pores and did not significantly affect the bioactivity of the Biosilicate® scaffold. The gelatine coating significantly improved the compressive strength (i.e. 0.80 ± 0.05 MPa of coated versus 0.06 ± 0.01 MPa of uncoated scaffolds) of the Biosilicate® scaffold. The combination of Biosilicate® glass-ceramic and gelatine is attractive for producing novel scaffolds for bone tissue engineering

Sour Taste Responses in Mice Lacking PKD Channels

The polycystic kidney disease-like ion channel PKD2L1 and its associated partner PKD1L3 are potential candidates for sour taste receptors. PKD2L1 is expressed in type III taste cells that respond to sour stimuli and genetic elimination of cells expressing PKD2L1 substantially reduces chorda tympani nerve responses to sour taste stimuli. However, the contribution of PKD2L1 and PKD1L3 to sour taste responses remains unclear.We made mice lacking PKD2L1 and/or PKD1L3 gene and investigated whole nerve responses to taste stimuli in the chorda tympani or the glossopharyngeal nerve and taste responses in type III taste cells. In mice lacking PKD2L1 gene, chorda tympani nerve responses to sour, but not sweet, salty, bitter, and umami tastants were reduced by 25–45% compared with those in wild type mice. In contrast, chorda tympani nerve responses in PKD1L3 knock-out mice and glossopharyngeal nerve responses in single- and double-knock-out mice were similar to those in wild type mice. Sour taste responses of type III fungiform taste cells (GAD67-expressing taste cells) were also reduced by 25–45% by elimination of PKD2L1.These findings suggest that PKD2L1 partly contributes to sour taste responses in mice and that receptors other than PKDs would be involved in sour detection

Familiarization: A theory of repetition suppression predicts interference between overlapping cortical representations

Repetition suppression refers to a reduction in the cortical response to a novel stimulus that results from repeated presentation of the stimulus. We demonstrate repetition suppression in a well established computational model of cortical plasticity, according to which the relative strengths of lateral inhibitory interactions are modified by Hebbian learning. We present the model as an extension to the traditional account of repetition suppression offered by sharpening theory, which emphasises the contribution of afferent plasticity, by instead attributing the effect primarily to plasticity of intra-cortical circuitry. In support, repetition suppression is shown to emerge in simulations with plasticity enabled only in intra-cortical connections. We show in simulation how an extended ‘inhibitory sharpening theory’ can explain the disruption of repetition suppression reported in studies that include an intermediate phase of exposure to additional novel stimuli composed of features similar to those of the original stimulus. The model suggests a re-interpretation of repetition suppression as a manifestation of the process by which an initially distributed representation of a novel object becomes a more localist representation. Thus, inhibitory sharpening may constitute a more general process by which representation emerges from cortical re-organisation

Attention-dependent modulation of cortical taste circuits revealed by granger causality with signal-dependent noise

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention

Downregulation of urokinase plasminogen activator receptor expression inhibits Erk signalling with concomitant suppression of invasiveness due to loss of uPAR–β1 integrin complex in colon cancer cells

Cancer invasion is regulated by cell surface proteinases and adhesion molecules. Interaction between specific cell surface molecules such as urokinase plasminogen activator receptor (uPAR) and integrins is crucial for tumour invasion and metastasis. In this study, we examined whether uPAR and beta1 integrin form a functional complex to mediate signalling required for tumour invasion. We assessed the expression of uPAR/beta1 integrin complex, Erk signalling pathway, adhesion, uPA and matrix metalloproteinase (MMP) expression, migration/invasion and matrix degradation in a colon cancer cell line in which uPAR expression was modified. Antisense inhibition of the cell surface expression of uPAR by 50% in human colon carcinoma HCT116 cells (A/S) suppressed Erk-MAP kinase activity by two-fold. Urokinase plasminogen activator receptor antisense treatment of HCT116 cells was associated with a 1.3-fold inhibition of adhesion, approximately four-fold suppression of HMW-uPA secretion and inhibition of pro-MMP-9 secretion. At a functional level, uPAR antisense resulted in a four-fold decline in migration/invasion and abatement of plasmin-mediated matrix degradation. In empty vector-transfected cells (mock), uPA strongly elevated basal Erk activation. In contrast, in A/S cells, uPA induction of Erk activation was not observed. Urokinase plasminogen activator receptor associated with beta1 integrin in mock-transfected cells. Disruption of uPAR-beta1 integrin complex in mock-transfected cells with a specific peptide (P25) inhibited uPA-mediated Erk-MAP kinase pathway and inhibited migration/invasion and plasmin-dependent matrix degradation through suppression of pro-MMP-9/MMP-2 expression. This novel paradigm of uPAR-integrin signalling may afford opportunities for alternative therapeutic strategies for the treatment of cancer

Breast cancer risk and drinking water contaminated by wastewater: a case control study

BACKGROUND: Drinking water contaminated by wastewater is a potential source of exposure to mammary carcinogens and endocrine disrupting compounds from commercial products and excreted natural and pharmaceutical hormones. These contaminants are hypothesized to increase breast cancer risk. Cape Cod, Massachusetts, has a history of wastewater contamination in many, but not all, of its public water supplies; and the region has a history of higher breast cancer incidence that is unexplained by the population's age, in-migration, mammography use, or established breast cancer risk factors. We conducted a case-control study to investigate whether exposure to drinking water contaminated by wastewater increases the risk of breast cancer. METHODS: Participants were 824 Cape Cod women diagnosed with breast cancer in 1988–1995 and 745 controls who lived in homes served by public drinking water supplies and never lived in a home served by a Cape Cod private well. We assessed each woman's exposure yearly since 1972 at each of her Cape Cod addresses, using nitrate nitrogen (nitrate-N) levels measured in public wells and pumping volumes for the wells. Nitrate-N is an established wastewater indicator in the region. As an alternative drinking water quality indicator, we calculated the fraction of recharge zones in residential, commercial, and pesticide land use areas. RESULTS: After controlling for established breast cancer risk factors, mammography, and length of residence on Cape Cod, results showed no consistent association between breast cancer and average annual nitrate-N (OR = 1.8; 95% CI 0.6 – 5.0 for ≥ 1.2 vs. < .3 mg/L), the sum of annual nitrate-N concentrations (OR = 0.9; 95% CI 0.6 – 1.5 for ≥ 10 vs. 1 to < 10 mg/L), or the number of years exposed to nitrate-N over 1 mg/L (OR = 0.9; 95% CI 0.5 – 1.5 for ≥ 8 vs. 0 years). Variation in exposure levels was limited, with 99% of women receiving some of their water from supplies with nitrate-N levels in excess of background. The total fraction of residential, commercial, and pesticide use land in recharge zones of public supply wells was associated with a small statistically unstable higher breast cancer incidence (OR = 1.4; 95% CI 0.8–2.4 for highest compared with lowest land use), but risk did not increase for increasing land use fractions. CONCLUSION: Results did not provide evidence of an association between breast cancer and drinking water contaminated by wastewater. The computer mapping methods used in this study to link routine measurements required by the Safe Drinking Water Act with interview data can enhance individual-level epidemiologic studies of multiple health outcomes, including diseases with substantial latency

Electrophysiological Evidence of Atypical Spatial Attention in Those with a High Level of Self-reported Autistic Traits

Selective attention is atypical in individuals with autism spectrum conditions. Evidence suggests this is also the case for those with high levels of autistic traits. Here we investigated the neural basis of spatial attention in those with high and low levels of self-reported autistic traits via analysis of ERP deflections associated with covert attention, target selection and distractor suppression (the N2pc, NT and PD). Larger N2pc and smaller PD amplitude was observed in those with high levels of autistic traits. These data provide neural evidence for differences in spatial attention, specifically, reduced distractor suppression in those with high levels of autistic traits, and may provide insight into the experience of perceptual overload often reported by individuals on the autism spectrum

Incidence and predictors of immune reconstitution inflammatory syndrome in a rural area of Mozambique.

There is limited data on the epidemiology of Immune Reconstitution Inflammatory Syndrome (IRIS) in rural sub-Saharan Africa. A prospective observational cohort study was conducted to assess the incidence, clinical characteristics, outcome and predictors of IRIS in rural Mozambique

Neuronal activity in medial superior temporal area (MST) during memory-based smooth pursuit eye movements in monkeys

We examined recently neuronal substrates for predictive pursuit using a memory-based smooth pursuit task that distinguishes the discharge related to memory of visual motion-direction from that related to movement preparation. We found that the supplementary eye fields (SEF) contain separate signals coding memory and assessment of visual motion-direction, decision not-to-pursue, and preparation for pursuit. Since medial superior temporal area (MST) is essential for visual motion processing and projects to SEF, we examined whether MST carried similar signals. We analyzed the discharge of 108 MSTd neurons responding to visual motion stimuli. The majority (69/108 = 64%) were also modulated during smooth pursuit. However, in nearly all (104/108 = 96%) of the MSTd neurons tested, there was no significant discharge modulation during the delay periods that required memory of visual motion-direction or preparation for smooth pursuit or not-to-pursue. Only 4 neurons of the 108 (4%) exhibited significantly higher discharge rates during the delay periods; however, their responses were non-directional and not instruction specific. Representative signals in the MSTd clearly differed from those in the SEF during memory-based smooth pursuit. MSTd neurons are unlikely to provide signals for memory of visual motion-direction or preparation for smooth pursuit eye movements

Risk factors for virological failure and subtherapeutic antiretroviral drug concentrations in HIV-positive adults treated in rural northwestern Uganda

ABSTRACT: BACKGROUND: Little is known about immunovirological treatment outcomes and adherence in HIV/AIDS patients on antiretroviral therapy (ART) treated using a simplified management approach in rural areas of developing countries, or about the main factors influencing those outcomes in clinical practice. METHODS: Cross-sectional immunovirological, pharmacological, and adherence outcomes were evaluated in all patients alive and on fixed-dose ART combinations for 24 months, and in a random sample of those treated for 12 months. Risk factors for virological failure (>1,000 copies/mL) and subtherapeutic antiretroviral (ARV) concentrations were investigated with multiple logistic regression. RESULTS: At 12 and 24 months of ART, 72% (n=701) and 70% (n=369) of patients, respectively, were alive and in care. About 8% and 38% of patients, respectively, were diagnosed with immunological failure; and 75% and 72% of patients, respectively, had undetectable HIV RNA (<400 copies/mL). Risk factors for virological failure (>1,000 copies/mL) were poor adherence, tuberculosis diagnosed after ART initiation, subtherapeutic NNRTI concentrations, general clinical symptoms, and lower weight than at baseline. About 14% of patients had low ARV plasma concentrations. Digestive symptoms and poor adherence to ART were risk factors for low ARV plasma concentrations. CONCLUSIONS: Efforts to improve both access to care and patient management to achieve better immunological and virological outcomes on ART are necessary to maximize the duration of first-line therapy