On staying grounded and avoiding Quixotic dead ends

The 15 articles in this special issue on The Representation of Concepts illustrate the rich variety of theoretical positions and supporting research that characterize the area. Although much agreement exists among contributors, much disagreement exists as well, especially about the roles of grounding and abstraction in conceptual processing. I first review theoretical approaches raised in these articles that I believe are Quixotic dead ends, namely, approaches that are principled and inspired but likely to fail. In the process, I review various theories of amodal symbols, their distortions of grounded theories, and fallacies in the evidence used to support them. Incorporating further contributions across articles, I then sketch a theoretical approach that I believe is likely to be successful, which includes grounding, abstraction, flexibility, explaining classic conceptual phenomena, and making contact with real-world situations. This account further proposes that (1) a key element of grounding is neural reuse, (2) abstraction takes the forms of multimodal compression, distilled abstraction, and distributed linguistic representation (but not amodal symbols), and (3) flexible context-dependent representations are a hallmark of conceptual processing

The role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats

To study the role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats. Rats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 6), a group in which LPS administration was followed by immediate fluid resuscitation which prevented the drop of renal blood flow (EARLY group) (n = 6), and a group in which LPS administration was followed by delayed (i.e., a 2-h delay) fluid resuscitation (LATE group) (n = 6). Renal blood flow was measured using a transit-time ultrasound flow probe. Microvascular perfusion and oxygenation distributions in the renal cortex were assessed using laser speckle imaging and phosphorimetry, respectively. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α were measured as markers of systemic inflammation. Furthermore, renal tissue samples were stained for leukocyte infiltration and inducible nitric oxide synthase (iNOS) expression in the kidney. LPS infusion worsened both microvascular perfusion and oxygenation distributions. Fluid resuscitation improved perfusion histograms but not oxygenation histograms. Improvement of microvascular perfusion was more pronounced in the EARLY group compared with the LATE group. Serum cytokine levels decreased in the resuscitated groups, with no difference between the EARLY and LATE groups. However, iNOS expression and leukocyte infiltration in glomeruli were lower in the EARLY group compared with the LATE group. In our model, prevention of endotoxemia-induced systemic hypotension by immediate fluid resuscitation (EARLY group) did not prevent systemic inflammatory activation (IL-6, IL-10, TNF-α) but did reduce renal inflammation (iNOS expression and glomerular leukocyte infiltration). However, it could not prevent reduced renal microvascular oxygenatio

Nucleolin, a Shuttle Protein Promoting Infection of Human Monocytes by Francisella tularensis

International audienceWe herein confirm the importance of nucleolin expression for LVS binding and its specificity as nucleolin is not involved in binding of another intracellular pathogen as L. monocytogenes or an inert particle. Association of nucleolin with F. tularensis during infection continues intracellularly after endocytosis of the bacteria. The present work therefore unravels for the first time the presence of nucleolin in the phagosomal compartment of macrophages

Core mutations, IL28B polymorphisms and response to peginterferon/ribavirin treatment in Swedish patients with hepatitis C virus genotype 1 infection

<p>Abstract</p> <p>Background</p> <p>Patients infected with hepatitis C virus (HCV) genotype 1 respond poorly to standard treatment with 50% or less achieving sustained virologic response. Predicting outcome is essential and could help avoid unnecessary treatment and reduce health cost. Recently, an association of amino acid substitutions in the core region and treatment outcome was observed in Japanese patients. In the present study, the impact of these mutations on response kinetics and treatment outcome was explored in Caucasian patients.</p> <p>Methods</p> <p>The core region of HCV pre-treatment samples obtained from 50 patients treated with peginterferon/ribavirin in a previous Swedish clinical trial with genotype 1 infection were sequenced. The alleles at rs12979860, a single nucleotide polymorphism (SNP), were assessed in order to identify any co-association with this strong response predictor.</p> <p>Results</p> <p>No association between treatment response and substitutions of core residue 91 was found. In contrast, substitutions of core residue 70 were observed in 6/21 (29%) non-responders, but only in one of 29 responders (p = 0.03), and were more common in subgenotype 1b (R70Q in 6 of 13 strains) than in 1a (R70P in 1 of 37 strains, p = 0.004). The rs12979860 SNP upstream of the IL28B gene was overall the strongest response predictor (p = 0.0001). Core 70 substitutions were associated with poorer response kinetics in patients carrying the CT genotype at rs12979860.</p> <p>Conclusions</p> <p>The results indicate that substitutions of core residue 70 are related to treatment response in Caucasian patients with HCV-1b infection, but are of less importance than IL28B polymorphism.</p

Influence of GB virus C on IFN-γ and IL-2 production and CD38 expression in T lymphocytes from chronically HIV-infected and HIV-HCV-co-infected patients

This study was designed to assess the effect of GB virus (GBV)-C on the immune response to human immunodeficiency virus (HIV) in chronically HIV-infected and HIV- hepatitis C virus (HCV)-co-infected patients undergoing antiretroviral therapy. A cohort of 159 HIV-seropositive patients, of whom 52 were HCV-co-infected, was included. Epidemiological data were collected and virological and immunological markers, including the production of interferon gamma (IFN-γ) and interleukin (IL)-2 by CD4, CD8 and Tγδ cells and the expression of the activation marker, CD38, were assessed. A total of 65 patients (40.8%) presented markers of GBV-C infection. The presence of GBV-C did not influence HIV and HCV replication or TCD4 and TCD8 cell counts. Immune responses, defined by IFN-γ and IL-2 production and CD38 expression did not differ among the groups. Our results suggest that neither GBV-C viremia nor the presence of E2 antibodies influence HIV and HCV viral replication or CD4 T cell counts in chronically infected patients. Furthermore, GBV-C did not influence cytokine production or CD38-driven immune activation among these patients. Although our results do not exclude a protective effect of GBV-C in early HIV disease, they demonstrate that this effect may not be present in chronically infected patients, who represent the majority of patients in outpatient clinics.Universidade Federal de São Paulo (UNIFESP) Laboratório de Virologia e Imunologia Disciplina de InfectologiaFleury Medicina DiagnósticaUNIFESP, Laboratório de Virologia e Imunologia Disciplina de InfectologiaSciEL

Adolescent and adult first time mothers' health seeking practices during pregnancy and early motherhood in Wakiso district, central Uganda

<p>Abstract</p> <p>Background</p> <p>Maternal health services have a potentially critical role in the improvement of reproductive health. In order to get a better understanding of adolescent mothers'needs we compared health seeking practices of first time adolescent and adult mothers during pregnancy and early motherhood in Wakiso district, Uganda.</p> <p>Methods</p> <p>This was a cross-sectional study conducted between May and August, 2007 in Wakiso district. A total of 762 women (442 adolescents and 320 adult) were interviewed using a structured questionnaire. We calculated odds ratios with their 95% CI for antenatal and postnatal health care seeking, stigmatisation and violence experienced from parents comparing adolescents to adult first time mothers. STATA V.8 was used for data analysis.</p> <p>Results</p> <p>Adolescent mothers were significantly more disadvantaged in terms of health care seeking for reproductive health services and faced more challenges during pregnancy and early motherhood compared to adult mothers. Adolescent mothers were more likely to have dropped out of school due to pregnancy (OR = 3.61, 95% CI: 2.40–5.44), less likely to earn a salary (OR = 0.43, 95%CI: 0.24–0.76), and more likely to attend antenatal care visits less than four times compared to adult mothers (OR = 1.52, 95%CI: 1.12–2.07). Adolescents were also more likely to experience violence from parents (OR = 2.07, 95%CI: 1.39–3.08) and to be stigmatized by the community (CI = 1.58, 95%CI: 1.09–2.59). In early motherhood, adolescent mothers were less likely to seek for second and third vaccine doses for their infants [Polio2 (OR = 0.73, 95% CI: 0.55–0.98), Polio3 (OR = 0.70: 95% CI: 0.51–0.95), DPT2 (OR = 0.71, 95% CI: 0.53–0.96), DPT3 (OR = 0.68, 95% CI: 0.50–0.92)] compared to adult mothers. These results are compelling and call for urgent adolescent focused interventions.</p> <p>Conclusion</p> <p>Adolescents showed poorer health care seeking behaviour for themselves and their children, and experienced increased community stigmatization and violence, suggesting bigger challenges to the adolescent mothers in terms of social support. Adolescent friendly interventions such as pregnancy groups targeting to empower pregnant adolescents providing information on pregnancy, delivery and early childhood care need to be introduced and implemented.</p

Skewed Exposure to Environmental Antigens Complements Hygiene Hypothesis in Explaining the Rise of Allergy

The Hygiene Hypothesis has been recognized as an important cornerstone to explain the sudden increase in the prevalence of asthma and allergic diseases in modernized culture. The recent epidemic of allergic diseases is in contrast with the gradual implementation of Homo sapiens sapiens to the present-day forms of civilization. This civilization forms a gradual process with cumulative effects on the human immune system, which co-developed with parasitic and commensal Helminths. The clinical manifestation of this epidemic, however, became only visible in the second half of the twentieth century. In order to explain these clinical effects in terms of the underlying IgE-mediated reactions to innocuous environmental antigens, the low biodiversity of antigens in the domestic environment plays a pivotal role. The skewing of antigen exposure as a cumulative effect of reducing biodiversity in the immediate human environment as well as in changing food habits, provides a sufficient and parsimonious explanation for the rise in allergic diseases in a highly developed and helminth-free modernized culture. Socio-economic tendencies that incline towards a further reduction of environmental biodiversity may provide serious concern for future health. This article explains that the “Hygiene Hypothesis”, the “Old Friends Hypothesis”, and the “Skewed Antigen Exposure Hypothesis” are required to more fully explain the rise of allergy in modern societies

Models of epidemics: when contact repetition and clustering should be included

Background The spread of infectious disease is determined by biological factors, e.g. the duration of the infectious period, and social factors, e.g. the arrangement of potentially contagious contacts. Repetitiveness and clustering of contacts are known to be relevant factors influencing the transmission of droplet or contact transmitted diseases. However, we do not yet completely know under what conditions repetitiveness and clustering should be included for realistically modelling disease spread. Methods We compare two different types of individual-based models: One assumes random mixing without repetition of contacts, whereas the other assumes that the same contacts repeat day-by-day. The latter exists in two variants, with and without clustering. We systematically test and compare how the total size of an outbreak differs between these model types depending on the key parameters transmission probability, number of contacts per day, duration of the infectious period, different levels of clustering and varying proportions of repetitive contacts. Results The simulation runs under different parameter constellations provide the following results: The difference between both model types is highest for low numbers of contacts per day and low transmission probabilities. The number of contacts and the transmission probability have a higher influence on this difference than the duration of the infectious period. Even when only minor parts of the daily contacts are repetitive and clustered can there be relevant differences compared to a purely random mixing model. Conclusion We show that random mixing models provide acceptable estimates of the total outbreak size if the number of contacts per day is high or if the per-contact transmission probability is high, as seen in typical childhood diseases such as measles. In the case of very short infectious periods, for instance, as in Norovirus, models assuming repeating contacts will also behave similarly as random mixing models. If the number of daily contacts or the transmission probability is low, as assumed for MRSA or Ebola, particular consideration should be given to the actual structure of potentially contagious contacts when designing the model.ISSN:1742-468

Humanized Rag1−/−γc−/− Mice Support Multilineage Hematopoiesis and Are Susceptible to HIV-1 Infection via Systemic and Vaginal Routes

Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2−/−γc−/−, NOD/SCID, NOD/SCIDγc−/− and NOD/SCIDβ2m−/− strains. Transplantation of these mice with CD34+ human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1−/−γ−/− strain for engraftment by human fetal liver derived CD34+ hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2−/−γc−/− mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1−/−γc−/− mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting

The Hepatitis E Virus Polyproline Region Is Involved in Viral Adaptation

Genomes of hepatitis E virus (HEV), rubivirus and cutthroat virus (CTV) contain a region of high proline density and low amino acid (aa) complexity, named the polyproline region (PPR). In HEV genotypes 1, 3 and 4, it is the only region within the non-structural open reading frame (ORF1) with positive selection (4–10 codons with dN/dS>1). This region has the highest density of sites with homoplasy values >0.5. Genotypes 3 and 4 show ∼3-fold increase in homoplastic density (HD) in the PPR compared to any other region in ORF1, genotype 1 does not exhibit significant HD (p<0.0001). PPR sequence divergence was found to be 2-fold greater for HEV genotypes 3 and 4 than for genotype 1. The data suggest the PPR plays an important role in host-range adaptation. Although the PPR appears to be hypervariable and homoplastic, it retains as much phylogenetic signal as any other similar sized region in the ORF1, indicating that convergent evolution operates within the major HEV phylogenetic lineages. Analyses of sequence-based secondary structure and the tertiary structure identify PPR as an intrinsically disordered region (IDR), implicating its role in regulation of replication. The identified propensity for the disorder-to-order state transitions indicates the PPR is involved in protein-protein interactions. Furthermore, the PPR of all four HEV genotypes contains seven putative linear binding motifs for ligands involved in the regulation of a wide number of cellular signaling processes. Structure-based analysis of possible molecular functions of these motifs showed the PPR is prone to bind a wide variety of ligands. Collectively, these data suggest a role for the PPR in HEV adaptation. Particularly as an IDR, the PPR likely contributes to fine tuning of viral replication through protein-protein interactions and should be considered as a target for development of novel anti-viral drugs