Oxidative Stress Predicts All-Cause Mortality in HIV-Infected Patients

ObjectiveWe aimed to assess whether oxidative stress is a predictor of mortality in HIV-infected patients.MethodsWe conducted a nested case-control study in CoRIS, a contemporary, multicentre cohort of HIV-infected patients, antiretroviral-naïve at entry, launched in 2004. Cases were patients who died with available stored plasma samples collected. Two age and sex-matched controls for each case were selected. We measured F2-isoprostanes (F₂-IsoPs) and malondialdehyde (MDA) plasma levels in the first blood sample obtained after cohort engagement.Results54 cases and 93 controls were included. Median F₂-IsoPs and MDA levels were significantly higher in cases than in controls. When adjustment was performed for age, HIV-transmission category, CD4 cell count and HIV viral load at cohort entry, and subclinical inflammation measured with highly-sensitive C-reactive protein (hsCRP), the association of F₂-IsoPs with mortality remained significant (adjusted OR per 1 log₁₀ increase, 2.34 [1.23–4.47], P = 0.009). The association of MDA with mortality was attenuated after adjustment: adjusted OR (95% CI) per 1 log₁₀ increase, 2.05 [0.91–4.59], P = 0.080. Median hsCRP was also higher in cases, and it also proved to be an independent predictor of mortality in the adjusted analysis: OR (95% CI) per 1 log₁₀ increase, 1.39 (1.01–1.91), P = 0.043; and OR (95% CI) per 1 log₁₀ increase, 1.46 (1.07–1.99), P = 0.014, respectively, when adjustment included F₂-IsoPs and MDA.ConclusionOxidative stress is a predictor of all-cause mortality in HIV-infected patients. For plasma F₂-IsoPs, this association is independent of HIV-related factors and subclinical inflammation.     

Modeling Staphylococcus epidermidis-Induced Non-Unions: Subclinical and Clinical Evidence in Rats

S. epidermidis is one of the leading causes of orthopaedic infections associated with biofilm formation on implant devices. Open fractures are at risk of S. epidermidis transcutaneous contamination leading to higher non-union development compared to closed fractures. Although the role of infection in delaying fracture healing is well recognized, no in vivo models investigated the impact of subclinical low-grade infections on bone repair and non-union. We hypothesized that the non-union rate is directly related to the load of this commonly retrieved pathogen and that a low-grade contamination delays the fracture healing without clinically detectable infection. Rat femurs were osteotomized and stabilized with plates. Fractures were infected with a characterized clinical-derived methicillin-resistant S. epidermidis (10³, 10⁵, 10⁸ colony forming units) and compared to uninfected controls. After 56 days, bone healing and osteomyelitis were clinically assessed and further evaluated by micro-CT, microbiological and histological analyses. The biofilm formation was visualized by scanning electron microscopy. The control group showed no signs of infection and a complete bone healing. The 10³ group displayed variable response to infection with a 67% of altered bone healing and positive bacterial cultures, despite no clinical signs of infection present. The 10⁵ and 10⁸ groups showed severe signs of osteomyelitis and a non-union rate of 83–100%, respectively. The cortical bone reaction related to the periosteal elevation in the control group and the metal scattering detected by micro-CT represented limitations of this study. Our model showed that an intra-operative low-grade S. epidermidis contamination might prevent the bone healing, even in the absence of infectious signs. Our findings also pointed out a dose-dependent effect between the S. epidermidis inoculum and non-union rate. This pilot study identifies a relevant preclinical model to assess the role of subclinical infections in orthopaedic and trauma surgery and to test specifically designed diagnostic, prevention and therapeutic strategies.     

Oral Administration of Polymyxin B Modulates the Activity of Lipooligosaccharide E. coli B against Lung Metastases in Murine Tumor Models

Introduction

Polymyxin B (PmB) belongs to the group of cyclic peptide antibiotics, which neutralize the activity of LPS by binding to lipid A. The aim of this study was to analyze the effect of PmB on the biological activity of lipooligosaccharide (LOS E. coli B,rough form of LPS) in vitro and in experimental metastasis models.

Results

Cultures of murine macrophage J774A.1 cells and murine bone marrow-derived dendritic cells (BM-DC) stimulated in vitro with LOS and supplemented with PmB demonstrated a decrease in inflammatory cytokine production (IL-6, IL-10, TNF-α) and down-regulation of CD40, CD80, CD86 and MHC class II molecule expression. Additionally, PmB suspended in drinking water was given to the C57BL/6 mice seven or five days prior to the intravenous injection of B16 or LLC cells and intraperitoneal application of LOS. This strategy of PmB administration was continued throughout the duration of the experiments (29 or 21 days). In B16 model, statistically significant decrease in the number of metastases in mice treated with PmB and LOS (p<0.01) was found on the 14th day of the experiments, whereas the most intensive changes in surface-antigen expression and ex vivo production of IL-6, IL-1β and TNF-α by peritoneal cells were observed 7 days earlier. By contrast, antigen expression and ex vivo production of IL-6, IL-10, IFN-γ by splenocytes remained relatively high and stable. Statistically significant decrease in LLC metastases number was observed after the application of LOS (p<0.01) and in the group of mice preconditioned by PmB and subsequently treated with LOS (LOS + PmB, p<0.01).

Conclusions

In conclusion, prolonged in vivo application of PmB was not able to neutralize the LOS-induced immune cell activity but its presence in the organism of treated mice was important in modulation of the LOS-mediated response against the development of metastases.     

Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model

B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-X_L and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.     

Clinical Focus on Malassezia Folliculitis

Malassezia spp. folliculitis is a variant quite frequent at the tropics. The clinical aspect of perifollicular pustules on an erythematous base with a central hair is the clue for the diagnosis, especially on hairy surfaces. We describe this clinical form caused by Malassezia sp., with background, direct examination findings, and histopathology.     

Epidemiology and Management of Candidiasis in Solid Organ Transplant Recipients

Purpose of Review

Invasive candidiasis (IC) is the leading cause of fungal infections in solid organ transplant recipients (SOT). In this article, we aim to review the epidemiology, risk factors, presentation, and management of IC in this population.

Recent Findings

Certain risk factors have been associated with IC in SOT recipients. Targeted antifungal prophylaxis for SOT recipients at the highest risk of infection is currently recommended although the choice and duration of antifungal agents remain controversial. Early diagnosis and monitoring of IC in SOT recipients are critical to achieve better outcomes and prevent serious complications. Non-culture-based diagnostic modalities have been introduced to aid in earlier and more accurate diagnosis.

Summary

The use of azoles for prophylaxis or treatment in SOT recipients allowed for selection of resistance and increased the incidence of non-albicans Candida. Drug–drug interactions, cost, and risk of resistance are to be considered when using more potent or newer antifungal agents.

     

Evaluation of QTLs for Shoot Fly (<Emphasis Type="Italic">Atherigona soccata</Emphasis>) Resistance Component Traits of Seedling Leaf Blade Glossiness and Trichome Density on Sorghum (<Emphasis Type="Italic">Sorghum bicolor</Emphasis>) Chromosome SBI-10L

Shoot fly is a major insect pest of sorghum damaging early crop growth, establishment and productivity. Host plant resistance is an efficient approach to minimize yield losses due to shoot fly infestation. Seedling leaf blade glossiness and trichome density are morphological traits associated with shoot fly resistance. Our objective was to identify and evaluate QTLs for glossiness and trichome density using- i) 1894 F₂s, ii) a sub-set of 369 F₂-recombinants, and iii) their derived 369 F_2:3 progenies, from a cross involving introgression lines RSG04008-6 (susceptible)?×?J2614-11 (resistant). The QTLs were mapped to a 37–72 centimorgan (cM) or 5–15 Mb interval on the long arm of sorghum chromosome 10 (SBI-10L) with flanking markers Xgap001 and Xtxp141. One QTL each for glossiness (QGls10) and trichome density (QTd10) were mapped in marker interval Xgap001-Xnhsbm1044 and Xisep0630-Xtxp141, confirming their loose linkage, for which phenotypic variation accounted for ranged from 2.29 to 11.37 % and LOD values ranged from 2.03 to 24.13, respectively. Average physical map positions for glossiness and trichome density QTLs on SBI-10 from earlier studies were 4 and 2 Mb, which in the present study were reduced to 2 Mb and 800 kb, respectively. Candidate genes Glossy15 (Sb10g025053) and ethylene zinc finger protein (Sb10g027550) falling in support intervals for glossiness and trichome density QTLs, respectively, are discussed. Also we identified a sub-set of recombinant population that will facilitate further fine mapping of the leaf blade glossiness and trichome density QTLs on SBI-10.     

Pathogenesis of Fungal Infections in Cystic Fibrosis

For a long time, the microbiology of cystic fibrosis has been focussed on Pseudomonas aeruginosa and associated Gram-negative pathogens. An increasing body of evidence has been compiled demonstrating an important role for moulds and yeasts within this complex patient group. Whether or not fungi are active participants, spectators or transient passersby remain to be elucidated. However, functionally, they do appear to play a contributory role in pathogenesis, albeit we do not know if this is a direct or indirect effect. The following review examines some of the key evidence for the role of fungi in CF pathogenesis.     

Impact of New Diagnostic Approaches for Invasive Candidiasis on Antifungal Stewardship

Background

Invasive candidiasis (IC) including candidemia and deep-seated candidiasis is associated with up to 50 % overall mortality and up to $80,000 in attributable cost (2015 US$). Rapid diagnostic tests (RDTs) for Candida have been developed. However, whether RDTs along with real-time decision support translate to better attainment of stewardship goals—improve clinical outcomes, minimize unintended consequences of antifungal use, and reduce healthcare costs—is unknown. The purpose of this systematic review was to provide an up-to-date review of recently published studies that have assessed how RDTs for IC impact attainment of these goals.

Methods

Three electronic bibliographic databases were searched using a pre-defined search strategy evaluating the impact of RDTs for IC on attainment of antifungal stewardship goals. Quality assessments were performed by two reviewers using established study methodology metrics.

Results and Conclusions

Eight studies were identified of which five had sufficient information to be included in the review. Despite the limitations of the various studies and the different methodologies employed, the studies all produced similar conclusions. Compared to conventional methods and baseline stewardship activities, the integration of RDTs for IC and real-time decision support, mainly through antifungal stewardship, was associated with decreased mortality, more optimal use of antifungals, and reduced healthcare costs. However, larger clinical studies are needed to confirm these trends.

     

Antifungal Penetration into the Nail and New Topicals for Onychomycosis

Onychomycosis is a common and difficult to treat infection, owing predominately to the limited penetration of topical drugs to the site of infection. Systemic drugs are not an option for all patients due to adverse events and drug-drug interactions. In this article, we review the nail penetration and clinical efficacy data of topical drugs, including older agents such as ciclopirox and amorolfine, as well as the newer agents, efinaconazole and tavaborole. Additionally, we describe some unresolved questions in the management of onychomycosis.