Long-Term Stable Adhesion for Conducting Polymers in Biomedical Applications: IrOx and Nanostructured Platinum Solve the Chronic Challenge

Conducting polymers (CPs) have frequently been described as outstanding coating materials for neural microelectrodes, providing significantly reduced impedance or higher charge injection compared to pure metals. Usability has until now, however, been limited by poor adhesion of polymers like poly(3,4-ethylenedioxythiophene) (PEDOT) to metallic substrates, ultimately precluding long-term applications. The aim of this study was to overcome this weakness of CPs by introducing two novel adhesion improvement strategies that can easily be integrated with standard microelectrode fabrication processes. Iridium Oxide (IrOx) demonstrated exceptional stability for PEDOT coatings, resulting in polymer survival over 10 000 redox cycles and 110 days under accelerated aging conditions at 60 °C. Nanostructured Pt was furthermore introduced as a purely mechanical adhesion promoter providing 10-fold adhesion improvement compared to smooth Pt substrates by simply altering the morphology of Pt. This layer can be realized in a very simple process that is compatible with any electrode design, turning nanostructured Pt into a universal adhesion layer for CP coatings. By the introduction of these adhesion-promoting strategies, the weakness of CP-based neural probes can ultimately be eliminated and true long-term stable use of PEDOT on neural probes will be possible in future electrode generations

Differential effects of sustained and transient effort triggered by reward : a combined EEG and pupillometry study

In instrumental task contexts, incentive manipulations such as posting reward on successful performance usually trigger increased effort, which is signified by effort markers like increased pupil size. Yet, it is not fully clear under which circumstances incentives really promote performance, and which role effort plays therein. In the present study, we compared two schemes of associating reward with a Flanker task, while simultaneously acquiring electroencephalography (EEG) and pupillometry data in order to explore the contribution of effort-related processes. In Experiment 1, reward was administered in a block-based fashion, with series of targets in pure reward and no-reward blocks. The results imply increased sustained effort in the reward blocks, as reflected in particular in sustained increased pupil size. Yet, this was not accompanied by a behavioral benefit, suggesting a failure of translating increased effort into a behavioral pay-off. In Experiment 2, we introduced trial-based cues in order to also promote transient preparatory effort application, which indeed led to a behavioral benefit. Again, we observed a sustained pupil-size increase, but also transient ones. Consistent with this, the EEG data of Experiment 2 indicated increased transient preparatory effort preceding target onset, as well as reward modulations of target processing that arose earlier than in Experiment 1. Jointly, our results indicate that incentive-triggered effort can operate on different time-scales, and that, at least for the current task, its transient (and largely preparatory) form is critical for achieving a behavioral benefit, which may relate to the temporal dynamics of the catecholaminergic systems

Substantia nigra activity level predicts trial-to-trial adjustments in cognitive control

Effective adaptation to the demands of a changing environment requires flexible cognitive control. The medial and the lateral frontal cortices are involved in such control processes, putatively in close interplay with the BG. In particular, dopaminergic projections from the midbrain (i.e., from the substantia nigra [SN] and the ventral tegmental area) have been proposed to play a pivotal role in modulating the activity in these areas for cognitive control purposes. In that dopaminergic involvement has been strongly implicated in reinforcement learning, these ideas suggest functional links between reinforcement learning, where the outcome of actions shapes behavior over time, and cognitive control in a more general context, where no direct reward is involved. Here, we provide evidence from functional MRI in humans that activity in the SN predicts systematic subsequent trial-to-trial RT prolongations that are thought to reflect cognitive control in a stop-signal paradigm. In particular, variations in the activity level of the SN in one trial predicted the degree of RT prolongation on the subsequent trial, consistent with a modulating output signal from the SN being involved in enhancing cognitive control. This link between SN activity and subsequent behavioral adjustments lends support to theoretical accounts that propose dopaminergic control signals that shape behavior both in the presence and in the absence of direct reward. This SN-based modulatory mechanism is presumably mediated via a wider network that determines response speed in this task, including frontal and parietal control regions, along with the BG and the associated subthalamic nucleus

Activation and maturation of peripheral blood T cells in HIV-1-infected and HIV-1-uninfected adults in Burkina Faso: a cross-sectional study

Background: We wanted to explore to what extent environmental exposure to immune stimulants, which is expected to be more present in rural than in urban settings, influences T cell activation and maturation in healthy and in HIV-1-infected individuals in Burkina Faso in west Africa. Methods: The proportion of circulating naïve T cells and the expression of the T cell activation markers, CD95 and CD38, were analyzed by immunophenotyping and three-colour flow cytometry in 63 healthy individuals and 137 treatment-naïve HIV-1-infected subjects from Ouagadougou (urban setting) and 26 healthy adults and 61 treatment-naïve patients from Nouna (rural). Results: A slightly higher activation level of CD4+ and CD8+ peripheral blood T cells was seen in healthy adults living in Nouna than in those living in Ouagadougou. The percentages of naïve CD45RAbright CCR7+ T cells were not significantly different between both study sites. Taking into consideration that relatively more HIV-1-infected patients in Nouna were in an advanced disease stage, no relevant differences were seen in T cell activation and maturation between patients at both study sites. As expected, the percentage of CD95+ CD4+ and CD38+ CD8+ T cells and the respective antigen density on these cells was significantly higher in patients than in controls in both settings. The percentage of naïve CD8+ T cells was lower in HIV-1-infected subjects than in healthy controls irrespective of the study site, while a lower proportion of naïve CD4+ T cells in patients compared with controls was seen only in Nouna. Conclusions: Environmentally triggered immune activation may contribute to the increased expression of the activation markers CD95 and CD38 on peripheral blood T cells from healthy adults living in rural versus urban settings in Burkina Faso. T cell activation is further increased in HIV-1-infected individuals due to T cell loss and high plasma viral load levels. The observed variations in T cell activation levels or the proportion of naïve T cells in our study patients, however, are not explained by differences in CD4+ T cell counts or HIV-1 plasma viral load levels alone

Immune Reconstitution During the First Year of Antiretroviral Therapy of HIV-1-Infected Adults in Rural Burkina Faso

There are no data on the outcome of highly active antiretroviral therapy (HAART) in HIV-infected adults in rural Burkina Faso. We therefore assessed CD4+ T-cell counts and HIV-1 plasma viral load (VL), the proportion of naive T-cells (co-expressing CCR7 and CD45RA) and T-cell activation (expression of CD95 or CD38) in 61 previously untreated adult patients from Nouna, Burkina Faso, at baseline and 2 weeks, 1, 3, 6, 9 and 12 months after starting therapy. Median CD4+ T-cell counts increased from 174 (10th-90th percentile: 33-314) cells/µl at baseline to 300 (114- 505) cells/µl after 3 months and 360 (169-562) cells/µl after 12 months of HAART. Median VL decreased from 5.8 (4.6- 6.6) log10 copies/ml at baseline to 1.6 (1.6-2.3) log10 copies/ml after 12 months. Early CD4+ T-cell recovery was accompanied by a reduction of the expression levels of CD95 and CD38 on T-cells. Out of 42 patients with complete virological follow-up under HAART, 19 (45%) achieved concordant good immunological (gain of ≥100 CD4+ T-cells/µl above baseline) and virological (undetectable VL) responses after 12 months of treatment (intention-to-treat analysis). Neither a decreased expression of the T-cell activation markers CD38 and CD95, nor an increase in the percentage of naive T-cells reliably predicted good virological treatment responses in patients with good CD4+ T-cell reconstitution. Repeated measurement of CD4+ T-cell counts during HAART remains the most important parameter for immunologic monitoring. Substitution of repeated VL testing by determination of T-cell activation levels (e.g., CD38 expression on CD8+ T-cells) should be applied with caution

Cross-Clade Recognition of HIV-1 CAp24 by CD4+ T Cells in HIV-1-Infected Individuals in Burkina Faso and Germany

The presence of antigen-specific cellular immune responses may be an indicator of long-term asymptomatic HIV-1-disease. The detection of cellular immune responses to infection with different subtypes of HIV-1 may be hampered by genetic differences of immunodominant antigens such as the capsid protein CAp24. In Nouna, Burkina Faso, HIV-1 circulating recombinant forms CRF02_AG and CRF06_cpx are the 2 major strains detectable in HIV-1-infected individuals, while subtype B strains prevail in Europe and North America. Amino acid sequences of CAp24 were assessed in blood samples from 10 HIV-1-infected patients in Nouna, Burkina Faso. Production of interferon-gamma (IFN-γ) in peripheral blood CD4+ lymphocytes in response to recombinant HIV-1 proteins derived from clade B (including CAp24NL4-3) was measured using a modified flow-cytometry-based whole blood short term activation assay (FASTimmune, BDBiosciences). IFN-γ production following stimulation with a whole length CAp24 protein derived from clade B (CAp24NL4-3) was additionally quantified in comparison to a CAp24 protein derived from CRF02_AG (CAp24BD6-15) in 16 HIV-1-infected patients in Heidelberg, Germany. Amino acid sequence identity of CAp24 obtained from patients in Nouna ranged between 86 and 89% when compared to the clade B CAp24NL4-3 consensus sequence, between 90 and 95% when compared to the circulating recombinant form CRF06_CPX consensus sequence, and between 92 and 96% when compared to the CAp24BD6-15 consensus sequence. Significant numbers of HIV-1-specific CD4+ lymphocytes producing IFN-γ were detected in 4 of 10 HIV-1-infected patients. In 7 of 16 patients in Heidelberg, recombinant CAp24BD6-15 stimulated IFN-γ-production in CD4+ lymphocytes to a similar extent as the clade B-derived CAp24NL4-3. Thus, antigen-specific CD4+ lymphocytes from both West African and European patients infected with different strains of HIV-1 show relevant cross-clade recognition of HIV-1 CAp24 in a flow-cytometry-based whole blood short term activation assay

EphB2-dependent signaling promotes neuronal excitotoxicity and inflammation in the acute phase of ischemic stroke

Local cerebral hypoperfusion causes ischemic stroke while driving multiple cell-specific responses including inflammation, glutamate-induced neurotoxicity mediated via NMDAR, edema formation and angiogenesis. Despite the relevance of these pathophysiological mechanisms for disease progression and outcome, molecular determinants controlling the onset of these processes are only partially understood. In this context, our study intended to investigate the functional role of EphB2, a receptor tyrosine kinase that is crucial for synapse function and binds to membrane-associated ephrin-B ligands. Cerebral ischemia was induced in Ephb2−/− mice by transient middle cerebral artery occlusion followed by different times (6, 12, 24 and 48 h) of reperfusion. Histological, neurofunctional and transcriptome analyses indicated an increase in EphB2 phosphorylation under these conditions and attenuated progression of stroke in Ephb2−/− mice. Moreover, while infiltration of microglia/macrophages and astrocytes into the peri-infarct region was not altered, expression of the pro-inflammatory mediators MCP-1 and IL-6 was decreased in these mice. In vitro analyses indicated that binding of EphB2 to astrocytic ephrin-B ligands stimulates NF-κB-mediated cytokine expression via the MAPK pathway. Further magnetic resonance imaging of the Ephb2−/− ischemic brain revealed a lower level of cytotoxic edema formation within 6 h upon onset of reperfusion. On the mechanistic level, absence of neuronal EphB2 decreased the mitochondrial Ca2+ load upon specific activation of NMDAR but not during synaptic activity. Furthermore, neuron-specific loss of ephrin-B2 reduced the extent of cerebral tissue damage in the acute phase of ischemic stroke. Collectively, EphB2 may promote the immediate response to an ischemia-reperfusion event in the central nervous system by (i) pro-inflammatory activation of astrocytes via ephrin-B-dependent signaling and (ii) amplification of NMDA-evoked neuronal excitotoxicity

A qualitative investigation into knowledge, beliefs, and practices surrounding mastitis in sub-Saharan Africa: what implications for vertical transmission of HIV?

BACKGROUND: Mastitis constitutes an important risk factor in HIV vertical transmission. Very little, however, is known on how women in sub-Saharan Africa conceptualise health problems related to breastfeeding, such as mastitis, and how they act when sick. We aimed at filling this gap in knowledge, by documenting the indigenous nosography of mastitis, health seeking behaviour, and remedies for prophylaxis and treatment in rural sub-Saharan Africa. METHODS: The study was conducted in the Nouna Health District, rural Burkina Faso. We employed a combination of in-depth individual interviews and focus group discussions reaching both women and guérisseuers. All material was transcribed, translated, and analysed inductively, applying data and analyst triangulation. RESULTS: Respondents perceived breast problems related to lactation to be highly prevalent and described a sequence of symptoms which resembles the biomedical understanding of pathologies related to breastfeeding, ranging from breast engorgement (stasis) to inflammation (mastitis) and infection (breast abscess). The aetiology of disease, however, differed from biomedical notions as both women and guerisseurs distinguished between "natural" and "unnatural" causes of health problems related to breastfeeding. To prevent and treat such pathologies, women used a combination of traditional and biomedical therapies, depending on the perceived cause of illness. In general, however, a marked preference for traditional systems of care was observed. CONCLUSION: Health problems related to breastfeeding are perceived to be very common in rural Burkina Faso. Further epidemiological research to assess the actual prevalence of such pathologies is urgently needed to inform the design of adequate control measures, especially given the impact of mastitis on HIV vertical transmission. Our investigation into local illness concepts and health care seeking behaviour is useful to ensure that such measures be culturally sensitive. Further research into the efficacy of local customs and traditional healing methods and their effect on viral load in breast milk is also urgently needed