IL-10 Mediates Rosiglitazone-Induced Kidney Protection in Cisplatin Nephrotoxicity

Cisplatin, a major anti-neoplastic drug, is known to be nephrotoxic and inflammation-inducing. A peroxisome proliferator-activated receptor gamma agonist, regulating lipid metabolism, has known to have anti-inflammatory effect, but the protection mechanisms in various kidney injuries are not fully understood. The purpose of this study was to examine the reno-protective effect of rosiglitazone on cisplatin nephrotoxicity in mice focusing on inflammation and apoptosis. Male BALB/c mice were pretreated with rosiglitazone (10 mg/kg) or vehicle through daily intraperitoneal injection for 3 days and then were given a single injection of cisplatin (20 mg/kg). Cisplatin induced a significant rise in blood urea nitrogen and creatinine levels, and tubular cell damage with marked tissue inflammation. Tissue cytokines and chemokines measured by a cytometric bead array showed increased TNF-α, IL-6, MCP-1, and IFN-γ levels, while IL-10, an anti-inflammatory cytokine, was significantly decreased by cisplatin treatment. However, rosiglitazone pretreatment substantially reversed the depressed IL-10 level with simultaneous suppression of proinflammatory cytokines and chemokines. This tissue cytokine and chemokine milieu was associated with marked attenuation of kidney injury elicited by cisplatin. These findings suggest that the rosiglitazone-mediated renoprotective effect in cisplatin nephrotoxicity of mice is partially mediated by upregulation of anti-inflammatory IL-10 production

Computers in the Exam Room: Differences in Physician–Patient Interaction May Be Due to Physician Experience

BACKGROUND: The use of electronic medical records can improve the technical quality of care, but requires a computer in the exam room. This could adversely affect interpersonal aspects of care, particularly when physicians are inexperienced users of exam room computers. OBJECTIVE: To determine whether physician experience modifies the impact of exam room computers on the physician–patient interaction. DESIGN: Cross-sectional surveys of patients and physicians. SETTING AND PARTICIPANTS: One hundred fifty five adults seen for scheduled visits by 11 faculty internists and 12 internal medicine residents in a VA primary care clinic. MEASUREMENTS: Physician and patient assessment of the effect of the computer on the clinical encounter. MAIN RESULTS: Patients seeing residents, compared to those seeing faculty, were more likely to agree that the computer adversely affected the amount of time the physician spent talking to (34% vs 15%, P = 0.01), looking at (45% vs 24%, P = 0.02), and examining them (32% vs 13%, P = 0.009). Moreover, they were more likely to agree that the computer made the visit feel less personal (20% vs 5%, P = 0.017). Few patients thought the computer interfered with their relationship with their physicians (8% vs 8%). Residents were more likely than faculty to report these same adverse effects, but these differences were smaller and not statistically significant. CONCLUSION: Patients seen by residents more often agreed that exam room computers decreased the amount of interpersonal contact. More research is needed to elucidate key tasks and behaviors that facilitate doctor–patient communication in such a setting

Brugia malayi Excreted/Secreted Proteins at the Host/Parasite Interface: Stage- and Gender-Specific Proteomic Profiling

Relatively little is known about the filarial proteins that interact with the human host. Although the filarial genome has recently been completed, protein profiles have been limited to only a few recombinants or purified proteins of interest. Here, we describe a large-scale proteomic analysis using microcapillary reverse-phase liquid chromatography-tandem-mass spectrometry to identify the excretory-secretory (ES) products of the L3, L3 to L4 molting ES, adult male, adult female, and microfilarial stages of the filarial parasite Brugia malayi. The analysis of the ES products from adult male, adult female, microfilariae (Mf), L3, and molting L3 larvae identified 852 proteins. Annotation suggests that the functional and component distribution was very similar across each of the stages studied; however, the Mf contributed a higher proportion to the total number of identified proteins than the other stages. Of the 852 proteins identified in the ES, only 229 had previous confirmatory expressed sequence tags (ESTs) in the available databases. Moreover, this analysis was able to confirm the presence of 274 “hypothetical” proteins inferred from gene prediction algorithms applied to the B. malayi (Bm) genome. Not surprisingly, the majority (160/274) of these “hypothetical” proteins were predicted to be secreted by Signal IP and/or SecretomeP 2.0 analysis. Of major interest is the abundance of previously characterized immunomodulatory proteins such as ES-62 (leucyl aminopeptidase), MIF-1, SERPIN, glutathione peroxidase, and galectin in the ES of microfilariae (and Mf-containing adult females) compared to the adult males. In addition, searching the ES protein spectra against the Wolbachia database resulted in the identification of 90 Wolbachia-specific proteins, most of which were metabolic enzymes that have not been shown to be immunogenic. This proteomic analysis extends our knowledge of the ES and provides insight into the host–parasite interaction

The Stress-Response Factor SigH Modulates the Interaction between Mycobacterium tuberculosis and Host Phagocytes

The Mycobacterium tuberculosis stress response factor SigH plays a crucial role in modulating the pathogen's response to heat, oxidative-stress, envelope damage and hypoxia. We hypothesized that the lack of this key stress response factor would alter the interaction between the pathogen and its host cells. We compared the interaction of Mtb, Mtb:Δ-sigH and a strain where the mutation had been genetically complemented (Mtb: Δ-sigH:CO) with primary rhesus macaque bone marrow derived macrophages (Rh-BMDMs). The expression of numerous inducible and homeostatic (CCL) β-chemokines and several apoptotic markers was induced to higher levels in the cells infected with Mtb:Δ-sigH, relative to Mtb or the complemented strain. The differential expression of these genes manifested into functional differences in chemotaxis and apoptosis in cells infected with these two strains. The mutant strain also exhibited reduced late-stage survival in Rh-BMDMs. We hypothesize that the product of one or more SigH-dependent genes may modulate the innate interaction of Mtb with host cells, effectively reducing the chemokine-mediated recruitment of immune effector cells, apoptosis of infected monocytes and enhancing the long-term survival and replication of the pathogen in this milieu The significantly higher induction of Prostaglandin Synthetase 2 (PTGS2 or COX2) in Rh-BMDMs infected with Mtb relative to Mtb: Δ-sigH may explain reduced apoptosis in Mtb-infected cells, as PTGS2 is known to inhibit p53-dependent apoptosis.The SigH-regulon modulates the innate interaction of Mtb with host phagocytes, perhaps as part of a strategy to limit its clearance and prolong its survival. The SigH regulon appears to be required to modulate innate immune responses directed against Mtb

Bovine Lactoferrin Counteracts Toll-Like Receptor Mediated Activation Signals in Antigen Presenting Cells

Lactoferrin (LF), a key element in mammalian immune system, plays pivotal roles in host defence against infection and excessive inflammation. Its protective effects range from direct antimicrobial activities against a large panel of microbes, including bacteria, viruses, fungi and parasites, to antinflammatory and anticancer activities. In this study, we show that monocyte-derived dendritic cells (MD-DCs) generated in the presence of bovine LF (bLF) fail to undergo activation by up-modulating CD83, co-stimulatory and major histocompatibility complex molecules, and cytokine/chemokine secretion. Moreover, these cells are weak activators of T cell proliferation and retain antigen uptake activity. Consistent with an impaired maturation, bLF-MD-DC primed T lymphocytes exhibit a functional unresponsiveness characterized by reduced expression of CD154 and impaired expression of IFN-γ and IL-2. The observed imunosuppressive effects correlate with an increased expression of molecules with negative regulatory functions (i.e. immunoglobulin-like transcript 3 and programmed death ligand 1), indoleamine 2,3-dioxygenase, and suppressor of cytokine signaling-3. Interestingly, bLF-MD-DCs produce IL-6 and exhibit constitutive signal transducer and activator of transcription 3 activation. Conversely, bLF exposure of already differentiated MD-DCs completely fails to induce IL-6, and partially inhibits Toll-like receptor (TLR) agonist-induced activation. Cell-specific differences in bLF internalization likely account for the distinct response elicited by bLF in monocytes versus immature DCs, providing a mechanistic base for its multiple effects. These results indicate that bLF exerts a potent anti-inflammatory activity by skewing monocyte differentiation into DCs with impaired capacity to undergo activation and to promote Th1 responses. Overall, these bLF-mediated effects may represent a strategy to block excessive DC activation upon TLR-induced inflammation, adding further evidence for a critical role of bLF in directing host immune function

Stage- and Gender-Specific Proteomic Analysis of Brugia malayi Excretory-Secretory Products

To succeed in infection, parasites must have ways to reach the host, penetrate its tissues and escape its defense systems. As they are not necessarily fatal, most helminth parasites remain viable within their host for many years, exerting a strong influence over the host immune function. Many of these functions are performed by products that are released from the parasite. We exploited the remarkable sensitivity of modern proteomics tools together with the availability of a sequenced genome to identify and compare the proteins released in vitro by adult males, adult females and the microfilariae of the filarial nematode Brugia malayi. This parasite is one of the etiological agents of lymphatic filariasis, a disease that poses continuing and significant threats to human health. The different forms of the parasite inhabit different compartments in the mammalian host. We found that the set of proteins released by each form is unique; they must reflect particular developmental processes and different strategies for evasion of host responses. The identification of these proteins will allow us to illuminate the biology of secretory processes in this organism and to establish a path for developing an understanding of how these parasite proteins function in immune evasion events

Adverse Drug Reactions in Children—A Systematic Review

Adverse drug reactions in children are an important public health problem. We have undertaken a systematic review of observational studies in children in three settings: causing admission to hospital, occurring during hospital stay and occurring in the community. We were particularly interested in understanding how ADRs might be better detected, assessed and avoided

The Impact of eHealth on the Quality and Safety of Health Care: A Systematic Overview

Aziz Sheikh and colleagues report the findings of their systematic overview that assessed the impact of eHealth solutions on the quality and safety of health care

Reducing the Activity and Secretion of Microbial Antioxidants Enhances the Immunogenicity of BCG

BACKGROUND:In early clinical studies, the live tuberculosis vaccine Mycobacterium bovis BCG exhibited 80% protective efficacy against pulmonary tuberculosis (TB). Although BCG still exhibits reliable protection against TB meningitis and miliary TB in early childhood it has become less reliable in protecting against pulmonary TB. During decades of in vitro cultivation BCG not only lost some genes due to deletions of regions of the chromosome but also underwent gene duplication and other mutations resulting in increased antioxidant production. METHODOLOGY/PRINCIPAL FINDINGS:To determine whether microbial antioxidants influence vaccine immunogenicity, we eliminated duplicated alleles encoding the oxidative stress sigma factor SigH in BCG Tice and reduced the activity and secretion of iron co-factored superoxide dismutase. We then used assays of gene expression and flow cytometry with intracellular cytokine staining to compare BCG-specific immune responses in mice after vaccination with BCG Tice or the modified BCG vaccine. Compared to BCG, the modified vaccine induced greater IL-12p40, RANTES, and IL-21 mRNA in the spleens of mice at three days post-immunization, more cytokine-producing CD8+ lymphocytes at the peak of the primary immune response, and more IL-2-producing CD4+ lymphocytes during the memory phase. The modified vaccine also induced stronger secondary CD4+ lymphocyte responses and greater clearance of challenge bacilli. CONCLUSIONS/SIGNIFICANCE:We conclude that antioxidants produced by BCG suppress host immune responses. These findings challenge the hypothesis that the failure of extensively cultivated BCG vaccines to prevent pulmonary tuberculosis is due to over-attenuation and suggest instead a new model in which BCG evolved to produce more immunity-suppressing antioxidants. By targeting these antioxidants it may be possible to restore BCG's ability to protect against pulmonary TB

Host-Adaptation of Francisella tularensis Alters the Bacterium's Surface-Carbohydrates to Hinder Effectors of Innate and Adaptive Immunity

The gram-negative bacterium Francisella tularensis survives in arthropods, fresh water amoeba, and mammals with both intracellular and extracellular phases and could reasonably be expected to express distinct phenotypes in these environments. The presence of a capsule on this bacterium has been controversial with some groups finding such a structure while other groups report that no capsule could be identified. Previously we reported in vitro culture conditions for this bacterium which, in contrast to typical methods, yielded a bacterial phenotype that mimics that of the bacterium's mammalian, extracellular phase.SDS-PAGE and carbohydrate analysis of differentially-cultivated F. tularensis LVS revealed that bacteria displaying the host-adapted phenotype produce both longer polymers of LPS O-antigen (OAg) and additional HMW carbohydrates/glycoproteins that are reduced/absent in non-host-adapted bacteria. Analysis of wildtype and OAg-mutant bacteria indicated that the induced changes in surface carbohydrates involved both OAg and non-OAg species. To assess the impact of these HMW carbohydrates on the access of outer membrane constituents to antibody we used differentially-cultivated bacteria in vitro to immunoprecipitate antibodies directed against outer membrane moieties. We observed that the surface-carbohydrates induced during host-adaptation shield many outer membrane antigens from binding by antibody. Similar assays with normal mouse serum indicate that the induced HMW carbohydrates also impede complement deposition. Using an in vitro macrophage infection assay, we find that the bacterial HMW carbohydrate impedes TLR2-dependent, pro-inflammatory cytokine production by macrophages. Lastly we show that upon host-adaptation, the human-virulent strain, F. tularensis SchuS4 also induces capsule production with the effect of reducing macrophage-activation and accelerating tularemia pathogenesis in mice.F. tularensis undergoes host-adaptation which includes production of multiple capsular materials. These capsules impede recognition of bacterial outer membrane constituents by antibody, complement, and Toll-Like Receptor 2. These changes in the host-pathogen interface have profound implications for pathogenesis and vaccine development