The blind monks and the elephant : contrasting narratives of financial crisis

Three persuasive narratives of the US subprime crisis are explored with reference both to theory and to emergency acts of public policy undertaken. First the role of pecuniary externalities that amplify any shocks to the quality of risk-assets held by Investment Banks and others. Second is adverse selection in marketing these assets; and third the role of financial panic in making investment-banking disaster-prone. How relevant these differing perspectives proved is attested by the nature of state support and by subsequent findings in courts of law. As Chair of the US Federal Reserve, Janet Yellen argued that vulnerabilities within the US financial system in the mid-2000s were “numerous and familiar from past financial panics”. That the varied threats to stability featuring in these narratives should be complements and not substitutes is of more than technical interest: it helps to explain why the US financial system was so exposed to radical failure

Intestinal Inflammation Responds to Microbial Tissue Load Independent of Pathogen/Non-Pathogen Discrimination

The intestinal immune system mounts inflammatory responses to pathogens but tolerates harmless commensal microbiota. Various mechanisms for pathogen/non-pathogen discrimination have been proposed but their general relevance for inflammation control is unclear. Here, we compared intestinal responses to pathogenic Salmonella and non-pathogenic E. coli. Both microbes entered intestinal Peyer’s patches and, surprisingly, induced qualitatively and quantitatively similar initial inflammatory responses revealing a striking discrimination failure. Diverging inflammatory responses only occurred when Salmonella subsequently proliferated and induced escalating neutrophil infiltration, while harmless E. coli was rapidly cleared from the tissue and inflammation resolved. Transient intestinal inflammation induced by harmless E. coli tolerized against subsequent exposure thereby preventing chronic inflammation during repeated exposure. These data revealed a striking failure of the intestinal immune system to discriminate pathogens from harmless microbes based on distinct molecular signatures. Instead, appropriate intestinal responses to gut microbiota might be ensured by immediate inflammatory responses to any rise in microbial tissue loads, and desensitization after bacterial clearance

T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection

Human endogenous retroviruses (HERVs) are remnants of ancient infectious agents that have integrated into the human genome. Under normal circumstances, HERVs are functionally defective or controlled by host factors. In HIV-1-infected individuals, intracellular defense mechanisms are compromised. We hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. We determined that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, we examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. We report T cell responses to peptides derived from regions of HERV detected by ELISPOT analysis in the HIV-1-positive study participants. We show an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, we demonstrate that HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design

Clinical Safety-in-Use Study of a New Tampon Design

Objective: To confirm the safety of a new experimental Tampax(®) tampon and applicator compared with that of a currently marketed Tampax(®) tampon and applicator using comprehensive gynecological and microbiological assessments. Methods: A 2-month, single-blind, randomized, crossover study was conducted in which each subject served as her own control. Safety was evaluated by comparing potential product-related irritation (using colposcopic examination and subject diary data), assessment of vaginal discharge, vaginal pH, and effects on selected microorganisms (yeast, Escherichia coli ,Staphylococcus aureus and group B streptococci) obtained by vaginal swab cultures after normal menstrual use in the experimental and control groups. Results: In total, 110 women completed the study. There were no significant differences between the groups that used either the experimental or control tampon with regard to prevalence or mean cell density for the selected microorganisms. No differences were observed in the incidence or severity of erythema, in abrasion or ulceration of the cervix, vagina, introitus, vulva or perineum, or in mean vaginal pH and discharge assessments. There were equivalent low incidences of reported symptoms such as discomfort during insertion, wear or removal, and a similar low incidence of burning, stinging or itching during use of either the control or experimental tampon. There was a more favorable overall product rating for the experimental tampon (p = 0.003). Conclusions: This approach provides a combination of gynecological, microbiological and self-reported (diary recall) methodologies in order to assess tampon safety during use more thoroughly than has previously been reported, and it supports a comparable safety profile for the experimental tampon and a currently marketed tampon

Microbial Patterns Signaling via Toll-Like Receptors 2 and 5 Contribute to Epithelial Repair, Growth and Survival

Epithelial cells (ECs) continuously interact with microorganisms and detect their presence via different pattern-recognition receptors (PRRs) including Toll-like receptors (TLRs). Ligation of epithelial TLRs by pathogens is usually associated with the induction of pro-inflammatory mediators and antimicrobial factors. In this study, using human airway ECs as a model, we found that detection of microbial patterns via epithelial TLRs directly regulates tissue homeostasis. Staphylococcus aureus (S. aureus) and microbial patterns signaling via TLR2 and TLR5 induce a set of non-immune epithelial responses including cell migration, wound repair, proliferation, and survival of primary and cancerous ECs. Using small interfering RNA (siRNA) gene targeting, receptor-tyrosine kinase microarray and inhibition studies, we determined that TLR and the epidermal growth factor receptor (EGFR) mediate the stimulating effect of microbial patterns on epithelial repair. Microbial patterns signaling via Toll-like receptors 2 and 5 contribute to epithelial repair, growth and survival. This effect is independent of hematopoietic and other cells as well as inflammatory cytokines suggesting that epithelia are able to regulate their integrity in an autonomous non-inflammatory manner by sensing microbes directly via TLRs

Human oral isolate Lactobacillus fermentum AGR1487 induces a proinflammatory response in germ-free rat colons

Lactobacilli are thought to be beneficial for human health, with lactobacilli-associated infections being confined to immune-compromised individuals. However, Lactobacillus fermentum AGR1487 negatively affects barrier integrity in vitro so we hypothesized that it caused a pro-inflammatory response in the host. We compared germ-free rats inoculated with AGR1487 to those inoculated with another L. fermentum strain, AGR1485, which does not affect in vitro barrier integrity. We showed that rats inoculated with AGR1487 had more inflammatory cells in their colon, higher levels of inflammatory biomarkers, and increased colonic gene expression of pro-inflammatory pathways. In addition, our in vitro studies showed that AGR1487 had a greater capacity to activate TLR signaling and induce pro-inflammatory cytokines in immune cells. This study indicates the potential of strains of the same species to differentially elicit inflammatory responses in the host and highlights the importance of strain characterization in probiotic approaches to treat inflammatory disorders

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Improving Appropriate Use of Antifungal Medications: The Role of an Over-the-Counter Vaginal pH Self-Test Device

Objectives: To determine whether patients can understand and use the vaginal pH device in the diagnosis of vaginitis. To compare whether vaginal pH readings determined by patients and healthcare providers are similar. To determine whether vaginalpHcan reduce inappropriate over-the-counter (OTC) antifungal medication use and improve the correct diagnosis of vaginitis. Methods: One hundred and fifty-one women indicated their belief about the cause of their vaginal infection, read the instructions of the vaginal pH device package insert, used the device and interpreted the findings. The patient interpretations were compared with results obtained by healthcare providers, blinded to patient findings. Results: Over 96% of patients stated that they could easily read the instructions, use the vaginal pH device and interpret the readings. They obtained the same readings as healthcare professionals (Kappa = 0.9). Restricting the use of OTC antifungal medications to those individuals with vaginitis symptoms and vaginal pH ≤ 4.5 significantly reduced inappropriate use by approximately 50%, Fisher's exact test,p-value = 0.018. Conversely, seeking healthcare provider assessment with vaginal pH > 4.5, leads to correct diagnosis of vaginitis. Conclusions: The vaginal pH device can be used as an OTC diagnostic tool by consumers when a vaginal infection is suspected. Vaginal pH readings would direct patients whether to purchase an antifungal medication or seek professional diagnosis from a healthcare provider. Understanding and use of this vaginal pH device could reduce inappropriate use of OTC antifungal medications by approximately 50% and improve the correct diagnosis of vaginitis

O-Antigen Delays Lipopolysaccharide Recognition and Impairs Antibacterial Host Defense in Murine Intestinal Epithelial Cells

Although Toll-like receptor (TLR) 4 signals from the cell surface of myeloid cells, it is restricted to an intracellular compartment and requires ligand internalization in intestinal epithelial cells (IECs). Yet, the functional consequence of cell-type specific receptor localization and uptake-dependent lipopolysaccharide (LPS) recognition is unknown. Here, we demonstrate a strikingly delayed activation of IECs but not macrophages by wildtype Salmonella enterica subsp. enterica sv. (S.) Typhimurium as compared to isogenic O-antigen deficient mutants. Delayed epithelial activation is associated with impaired LPS internalization and retarded TLR4-mediated immune recognition. The O-antigen-mediated evasion from early epithelial innate immune activation significantly enhances intraepithelial bacterial survival in vitro and in vivo following oral challenge. These data identify O-antigen expression as an innate immune evasion mechanism during apical intestinal epithelial invasion and illustrate the importance of early innate immune recognition for efficient host defense against invading Salmonella