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Concentrations of certain white blood cells in the peripheral circulation remain decreased during C. albicans infection after irradiation. Adult hairless mice were treated as in the acute infection model. At day 11 postirradiation, mice were sacrificed and blood samples collected and used for complete blood counts for both infected and noninfected animals. Values were pooled from four nonirradiated or five irradiated animals. Error bars are SD. *P , 0.05.
Source publication
Exposure to radiation, particularly a large or total-body dose, weakens the immune system through loss of bone marrow precursor cells, as well as diminished populations of circulating and tissue-resident immune cells. One such population is the skin-resident immune cells. Changes in the skin environment can be of particular importance as the skin i...
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... blood samples were used to determine leukocyte counts. Noninfected control mice received 6 Gy TBI then sacrificed 11 days later and blood samples collected and analyzed. As expected, total leukocyte counts, as well as the individual subpopulations of lymphocytes, monocytes and granulocytes, were all significantly reduced at day 11 postirradiation (Fig. 3), similar to what we had previously observed at earlier time points after irradiation (data not shown). Blood samples were also collected from mice infected (see Fig. 1A) at day 11 post-TBI. As with the noninfected mice, the irradiated/infected mice demonstrated a significant decrease in circulating monocytes and granulocytes, as well ...
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... observed at earlier time points after irradiation (data not shown). Blood samples were also collected from mice infected (see Fig. 1A) at day 11 post-TBI. As with the noninfected mice, the irradiated/infected mice demonstrated a significant decrease in circulating monocytes and granulocytes, as well as decreased white blood cells collectively (Fig. 3). Unlike the noninfected mice, there was not a significant decrease in circulating ...
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... decrease of CD4 þ and CD8 þ lymphocytes in the irradiated/infected ears correlates with irradiated mice having increased dissemination. Additionally, there were no observable changes in noninfected mice (Supplementary Fig. S3). ...
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... essence, it is possible that radiation exposure results in a cutaneous environment with fewer cells capable of responding to and eliminating the fungus. Of note, a significant reduction of DCs was not observed after irradiation only (Supplementary Fig. S3; http://dx.doi. org/10.1667/RR14295.1.S1), unlike in our previous study (27). ...
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... T-cell chemotaxis. Therefore, we hypothesize that the decrease of CXCL9 and CXCL10 could be one reason for fewer CD4 þ and CD8 þ T cells seen in irradiated/infected skin. This may have also been compounded by the decrease in circulating lymphocytes in irradiated mice, resulting in the ability of fewer lymphocytes to respond to the infection site (Fig. 3). In addition, notably, both CXCL9 and CXCL10 have shown some antimicrobial properties (43,44). While CXCL9 has antibacterial properties, CXCL10 has shown some antifungal properties (43). The reduction of these chemokines, and IFN-c, may also indicate that the cutaneous environment's innate defenses are impaired. This could have ...
Citations
... As expected, radiation exposure led to increased susceptibility of immunocompetent mice to OPC (Figure 1) [45][46][47]. The condition of HNI + OPC led to elevated levels of Il17a transcript expression in the oral mucosa compared to just HNI or OPC alone. ...
Fungal infections caused by Candida albicans are a serious problem for immunocompromised individuals, including those undergoing radiotherapy for head and neck cancers. Targeted irradiation causes inflammatory dysregulation and damage to the oral mucosa that can be exacerbated by candidiasis. Post-irradiation the cytokine interleukin-17 (IL-17) protects the oral mucosae by promoting oral epithelial regeneration and balancing the oral immune cell populations, which leads to the eventual healing of the tissue. IL-17 signaling is also critical for the antifungal response during oropharyngeal candidiasis (OPC). Yet, the benefit of IL-17 during other forms of candidiasis, such as vulvovaginal candidiasis, is not straightforward. Therefore, it was important to determine the role of IL-17 during OPC associated with radiation-induced inflammatory damage. To answer this question, we exposed Il17ra−/− and wild-type mice to head-neck irradiation (HNI) and OPC to determine if the IL-17 signaling pathway was still protective against C. albicans. HNI increased susceptibility to OPC, and in Il17ra−/− mice, the mucosal damage and fungal burden were elevated compared to control mice. Intriguingly, neutrophil influx was increased in Il17ra−/− mice, yet these cells had reduced capacity to phagocytose C. albicans and failed to clear OPC compared to immunocompetent mice. These findings suggest that radiotherapy not only causes physical damage to the oral cavity but also skews immune mediators, leading to increased susceptibility to oropharyngeal candidiasis.
... However, it must be taken into account that in such conditions of skin damage the defense functions of the epithelial surfaces of the body are particularly vulnerable or depleted (keratin of the stratum corneum, acid mantle and lysozymes of sweat in the skin, enzymes of vaginal secretions or lysozymes of saliva in buccal cavity). Thus the occurrence of opportunistic infections by organisms belonging to the resident flora is quite possible [6]. Indeed, candidiasis is the most common fungal infection after radiation or high thermal exposure that could lead to serious complications, or even death. ...
Clotrimazole (CLT) was formulated in a multiple W/O/W emulsion (ME) with the aim of evaluating its potential as topical anticandidal agent and comparing with marketed products. A previously evaluated CLT-ME was selected and physicochemically characterized. The in vitro release behavior and the ex vivo permeation profiles were assessed using Franz diffusion cells using three different types of biological membranes: human skin and porcine buccal, sublingual and vaginal mucosae. The antifungal activity against Candida strains was also tested. Results showed CLT-MEs sizes of 29.206 and 47.678 μm with skin compatible pH values of 6.47 and 6.42 exhibiting high zeta potential values of -55.13 and -55.59 mV with dependence on the pH variation. The physicochemical stability was kept for a period of 180 days of storage at room temperature. CLT-MEs exhibited pseudoplastic behavior with hysteresis areas and viscosities of 286 and 331 mPa⋅s showing higher spreadability properties than commercial counterparts. An improved CLT release pattern was supplied by the ME system following a hyperbolic model. Likewise, ME system gave higher skin permeation flux of CLT than commercial reference. CLT amounts retained in the skin and mucosae were also higher than commercial references, which coupled with the higher antimycotic efficacy make CLT-MEs a great tool for clinical investigation of topical candidiasis treatments.
... Studies with cancer patients have shown that opportunistic yeasts can colonize sites where radiation is applied, such as oral mucosa and therefore could be a start of local or systemic infections in weakness host [5][6][7][8]. Patients with head and neck cancer submitted to radiotherapy can display a higher risk of oral colonization by Candida species [9][10][11]. However, there are few studies addressing the impact of γ-radiation directly on yeast cells. ...
Aim:
To evaluate if radiation used in radiotherapy can cause changes in the virulence potential of Candida tropicalis ATCC 750.
Materials & methods:
C. tropicalis was exposed in vitro to identical dose and scheme of irradiation would be used in patients with head and neck cancer. Some virulence parameters were analyzed before and after irradiation.
Results:
Colony morphologies were irreversibly affected by irradiation. Increase in growth rate, filamentation, adhesion on cell lines and phagocytosis process were also observed. Overall the irradiated C. tropicalis cells became more efficient at causing systemic infection in mice.
Conclusion:
γ-radiation induced important changes in C. tropicalis increasing its virulence profile, which could directly affect the relationship between yeasts and hosts.
Clotrimazole (CLT) was formulated in a nanoemulsion (NE) for the topical treatment of candidiasis consisting of 10% labrafac® lipophile, 60% labrasol®:capryol® 90 mixture (ratio 4:1) and 30% propylene glycol. Physicochemical properties, stability, rheology, in vitro drug release, ex vivo drug permeation through human skin and porcine buccal, sublingual and vaginal mucosae, antifungal efficacy, as well as in vivo skin tolerance were evaluated. 1% CLT-NE (CLT-NE1) and 2% CLT-NE (CLT-NE2) exhibited 153 ± 17.25 and 186 ± 15.38 nm droplet sizes, low polydispersity indexes, negative zeta potentials and biocompatible pH values. The CLT-NEs exhibited typical Newtonian profiles with viscosities of 42.14 ± 0.037 mPa·s and 41.35 ± 0.041 mPa·s, respectively and higher extensibility properties than commercial counterparts retaining their physicochemical properties for 180 days. NEs provided a sustained release of drug according to the first order model. Similar skin permeation properties were observed between CLT-NE1 and commercial reference. However, significant higher CLT amounts retained in mucosae were provided by CLT-NE2 when compared with references. Antifungal efficacies were also higher than commercial references, and the in vivo tolerance study confirmed the suitability for topical application, making CLT-NEs a great tool for clinical investigation of topical candidiasis treatments.
Several investigators performing bone marrow transplantation studies have previously reported sporadic increases in mortality that were associated with pronounced swelling in the face, head and neck of mice. Over the past few years, we and others have noted an increasing number of experiments in which mice that have received total-body irradiation (TBI) or partial-body irradiation (PBI) develop swollen muzzles, drastic thickening of the upper lip and redness, bruising and/or swelling around the nose and muzzle and sometimes over the top of the head. We refer to this rapid and extreme swelling after irradiation as swollen muzzle syndrome (SMS). The development of SMS postirradiation is associated with morbidity that occurs earlier than would be expected from the traditional hematopoietic acute radiation syndrome (H-ARS), and has impeded studies in several laboratories attempting to evaluate medical countermeasures (MCM) against radiation. However, little has been done to characterize this somewhat unpredictable radiation effect. To investigate the cause and etiology of SMS, data from three different laboratories collected over a seven-year period from 100 MCM 30-day survival studies using mice from different vendors were retrospectively analyzed to determine the time of onset, progression and incidence of SMS in male and female mice exposed to various doses of ionizing radiation An additional study compared incidence and etiology of SMS in mice from two different vendors (identified as vendors A and B) after exposure to the LD50/30 (X rays). Mice presenting with SMS, as well as non-SMS (irradiated) control mice, were necropsied to determine microbial status of the blood, heart, spleen, liver, kidney and muzzle tissue. Only mice from vendor A (20%) developed SMS. While the number of bacterial species isolated from various tissues of SMS and non-SMS mice was not different, the number of tissues positive for bacteria was significantly greater in SMS mice. At least one tissue in 83% of SMS mice from vendor A tested positive for Streptococcus agalactiae [group B beta Streptococcus (GBS)], compared to 25% of non-SMS mice from vendor A, and 0% of non-SMS mice from vendor B. In addition, all mice from vendor A with SMS had at least one tissue with >104 CFU/g, with GBS as the predominant bacterium, compared to only 25% of non-SMS mice from vendor A, and 0% of non-SMS mice from vendor B. The incidence and magnitude of GBS growth in cultures correlated with the onset of SMS; the earliest and heaviest infections occurred in mice presenting with SMS on days 5-6 postirradiation. The majority of SMS mice (5 out of 6) had positive blood cultures, with the same bacterial strain isolated from other tissues, suggesting systemic translocation via the bloodstream. We propose that testing of mice and the identification of the microorganisms frequently associated with SMS may provide guidance for selection of antimicrobials for use by other investigators in studies evaluating potential MCM, and for the ordering, handling and care of immunodeficient mice or mice that are to be rendered immunodeficient after acute irradiation.
