Sarcoma granulocítico del sistema nervioso central: reporte de 2 casos y revisión de la literatura / Central nervous system granulocytic sarcoma: Report of 2 cases and review of the literatura

Los sarcomas granulocíticos son neoplasias sólidas compuestas de células mieloides inmaduras, de localización extramedular, asociadas a síndromes mieloproliferativos. La afectación del sistema nervioso central es muy infrecuente y puede desarrollarse tras un periodo de remisión completa, coexistir con o preceder a la enfermedad sistémica, siendo esta el elemento fundamental que orienta el diagnóstico radiológico y marca el pronóstico. En este trabajo, presentamos 2 casos de sarcoma granulocítico intracraneal, verificados desde el punto de vista patológico tras ser tratados mediante cirugía, y discutimos sus características clínicas, diagnósticas, terapéuticas y pronósticas tras realizar una revisión bibliográfica de la literatura científica destacada publicada hasta la fecha

Granulocytic sarcomas are solid, extramedullary-located neoplasms composed of immature myeloid cells, associated with myeloproliferative syndromes. Central nervous system involvement is very rare and may develop either after complete remission, coexist with or precede the systemic disease, being the last one that guides the radiological diagnosis and marks the prognosis. In this work, we report 2 pathologically-verified cases of intracranial granulocytic sarcoma treated by surgical means. Their clinical, diagnostic, therapeutic and prognostic features are discussed in the light of the most relevant scientific literature published to date

Central nervous system granulocytic sarcoma: Report of 2 cases and review of the literature. / Sarcoma granulocítico del sistema nervioso central: reporte de 2 casos y revisión de la literatura.

Granulocytic sarcomas are solid, extramedullary-located neoplasms composed of immature myeloid cells, associated with myeloproliferative syndromes. Central nervous system involvement is very rare and may develop either after complete remission, coexist with or precede the systemic disease, being the last one that guides the radiological diagnosis and marks the prognosis. In this work, we report 2 pathologically-verified cases of intracranial granulocytic sarcoma treated by surgical means. Their clinical, diagnostic, therapeutic and prognostic features are discussed in the light of the most relevant scientific literature published to date.

Medium term effects of physical conditioning on breath-hold diving performance.

The current study aimed to analyze the effects of physical conditioning inclusion on apnea performance after a 22-week structured apnea training program. Twenty-nine male breath-hold divers participated and were allocated into: (1) cross-training in apnea and physical activity (CT; n = 10); (2) apnea training only (AT; n = 10); and control group (CG; n = 9). Measures were static apnea (STA), dynamic with fins (DYN) and dynamic no fins (DNF) performance, body composition, hemoglobin, vital capacity (VC), maximal aerobic capacity (VO2max), resting metabolic rate, oxygen saturation, and pulse during a static apnea in dry conditions at baseline and after the intervention. Total performance, referred as POINTS (constructed from the variables STA, DNF and DYN) was used as a global performance variable on apnea indoor diving. + 30, +26 vs. + 4 average POINTS of difference after-before training for CT, AT and CG respectively were found. After a discriminant analysis, CT appears to be the most appropriate for DNF performance. The post-hoc analysis determined that the CT was the only group in which the difference of means was significant before and after training for the VC (p < 0.01) and VO2max (p < 0.05) variables. Inclusion of physical activity in apnea training increased VC and VO2max in breath hold divers; divers who followed a mixed training, physical training and hypoxic training, achieved increased DNF performance.

Development of a Novel Virus-Like Particle Vaccine Platform That Mimics the Immature Form of Alphavirus.

Virus-like particles (VLPs) are noninfectious multiprotein structures that are engineered to self-assemble from viral structural proteins. Here, we developed a novel VLP-based vaccine platform utilizing VLPs from the chikungunya virus. We identified two regions within the envelope protein, a structural component of chikungunya, where foreign antigens can be inserted without compromising VLP structure. Our VLP displays 480 copious copies of an inserted antigen on the VLP surface in a highly symmetric manner and is thus capable of inducing strong immune responses against any inserted antigen. Furthermore, by mimicking the structure of the immature form of the virus, we altered our VLP's in vivo dynamics and enhanced its immunogenicity. We used the circumsporozoite protein (CSP) of the Plasmodium falciparum malaria parasite as an antigen and demonstrated that our VLP-based vaccine elicits strong immune responses against CSP in animals. The sera from immunized monkeys protected mice from malaria infection. Likewise, mice vaccinated with P. yoelii CSP-containing VLPs were protected from an infectious sporozoite challenge. Hence, our uniquely engineered VLP platform can serve as a blueprint for the development of vaccines against other pathogens and diseases.

Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis.

Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of ≤0.015 and MIC90 of 0.12 µg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 µg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P < 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 µg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 µg/ml) and moderately resistant to fluconazole (MIC of 8 µg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 µg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC.

P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections.

In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer >1x10(6)) and provided 80-100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P. falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine.

Lymph-node resident CD8α+ dendritic cells capture antigens from migratory malaria sporozoites and induce CD8+ T cell responses.

Malaria infection begins when a female Anopheles mosquito injects Plasmodium sporozoites into the skin of its host during blood feeding. Skin-deposited sporozoites may enter the bloodstream and infect the liver, reside and develop in the skin, or migrate to the draining lymph nodes (DLNs). Importantly, the DLN is where protective CD8(+) T cell responses against malaria liver stages are induced after a dermal route of infection. However, the significance of parasites in the skin and DLN to CD8(+) T cell activation is largely unknown. In this study, we used genetically modified parasites, as well as antibody-mediated immobilization of sporozoites, to determine that active sporozoite migration to the DLNs is required for robust CD8(+) T cell responses. Through dynamic in vivo and static imaging, we show the direct uptake of parasites by lymph-node resident DCs followed by CD8(+) T cell-DC cluster formation, a surrogate for antigen presentation, in the DLNs. A few hours after sporozoite arrival to the DLNs, CD8(+) T cells are primed by resident CD8α(+) DCs with no apparent role for skin-derived DCs. Together, these results establish a critical role for lymph node resident CD8α(+) DCs in CD8(+) T cell priming to sporozoite antigens while emphasizing a requirement for motile sporozoites in the induction of CD8(+) T cell-mediated immunity.

CD8 T cells and E-cadherin in host responses against oropharyngeal candidiasis.

BACKGROUND: Oropharyngeal candidiasis (OPC) is the most common oral infection in HIV(+) persons. Previous studies suggest a role for CD8(+) T cells against OPC when CD4(+) T cells are lost, but enhanced susceptibility to infection occurs when CD8(+) T-cell migration is inhibited by reduced tissue E-cadherin. OBJECTIVE: To conduct a longitudinal study of tissue CD8(+) T-cells and E-cadherin expression before, during, and after the episodes of OPC. METHODS: Oral fungal burden was monitored and tissue was evaluated for CD8(+) T cells and E-cadherin over a 1-year period in HIV(+) persons with a history of, or an acute episode of, OPC. RESULTS: While longitudinal analyses precluded formal interpretations, point prevalence analyses of the data set revealed that when patients experiencing OPC were successfully treated, tissue E-cadherin expression was similar to that in patients who had not experienced OPC, and higher numbers of CD8(+) T cells were distributed throughout OPC(-) tissue under normal expression of E-cadherin. CONCLUSION: These results suggest that (1) reduction in tissue E-cadherin expression in patients with OPC(+) is not permanent, and (2) high numbers of CD8(+) T cells can be distributed throughout OPC(-) tissue under normal E-cadherin expression. Together, these results extend our previous studies and continue to support a role for CD8(+) T cells in host defense against OPC.

Candida-host interactions in HIV disease: implications for oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC), caused primarily by Candida albicans, is the most common oral infection in HIV(+) persons. Although Th1-type CD4(+) T cells are the predominant host defense mechanism against OPC, CD8(+) T cells and epithelial cells become important when blood CD4(+) T cells are reduced below a protective threshold during progression to AIDS. In an early cross-sectional study, OPC(+) tissue biopsied from HIV(+) persons had an accumulation of activated memory CD8(+) T cells at the oral epithelial-lamina propria interface, with reduced expression of the adhesion molecule E-cadherin, suggesting a protective role for CD8(+) T cells but a dysfunction in the mucosal migration of the cells. In a subsequent 1-year longitudinal study, OPC(-) patients with high oral Candida colonization (indicative of a preclinical OPC condition), had higher numbers of CD8(+) T cells distributed throughout the tissue, with normal E-cadherin expression. In OPC(+) patients, where lack of CD8(+) T cell migration was associated with reduced E-cadherin, subsequent evaluations following successful treatment of infection revealed normal E-cadherin expression and cellular distribution. Regarding epithelial cell responses, intact oral epithelial cells exhibit fungistatic activity via an acid-labile protein moiety. A proteomic analysis revealed that annexin A1 is a strong candidate for the effector moiety. The current hypothesis is that under reduced CD4(+) T cells, HIV(+) persons protected from OPC have CD8(+) T cells that migrate to the site of a preclinical infection under normal expression of E-cadherin, whereas those with OPC have a transient reduction in E-cadherin that prohibits CD8(+) T cells from migrating for effector function. Oral epithelial cells concomitantly function through annexin A1 to keep Candida in a commensal state but can easily be overwhelmed, thereby contributing to susceptibility to OPC.

Innate immunity including epithelial and nonspecific host factors: workshop 1B.

The majority of HIV infections are initiated at mucosal sites. The oral mucosal tissue has been shown to be a potential route of entry in humans and primates. Whereas HIV RNA, proviral DNA, and infected cells are detected in the oral mucosa and saliva of infected individuals, it appears that the oral mucosa is not permissive for efficient HIV replication and therefore may differ in susceptibility to infection when compared to other mucosal sites. Since there is no definitive information regarding the fate of the HIV virion in mucosal epithelium, there is a pressing need to understand what occurs when the virus is in contact with this tissue, what mechanisms are in play to determine the outcome, and to what degree the mechanisms and outcomes differ between mucosal sites. Workshop 1B tackled 5 important questions to define current knowledge about epithelial cell-derived innate immune agents, commensal and endogenous pathogens, and epithelial cells and cells of the adaptive immune system and how they contribute to dissemination or resistance to HIV infection. Discovering factors that explain the differential susceptibility and resistance to HIV infection in mucosal sites will allow for the identification and development of novel protective strategies.

HIV infection and specific mucosal immunity: workshop 4B.

Most HIV infections are transmitted across mucosal epithelium. An area of fundamental importance is understanding the role of innate and specific mucosal immunity in susceptibility or protection against HIV infection, as well as the effect of HIV infection on mucosal immunity, which leads to increased susceptibility to bacterial, fungal, and viral infections of oral and other mucosae. This workshop attempted to address 5 basic issues-namely, HIV acquisition across mucosal surfaces, innate and adaptive immunity in HIV resistance, antiviral activity of breast milk as a model mucosal fluid, neutralizing immunoglobulin A antibodies against HIV, and progress toward a mucosal vaccine against HIV. The workshop attendants agreed that progress had been made in each area covered, with much recent information. However, these advances revealed how little work had been performed on stratified squamous epithelium compared with columnar epithelium, and the attendants identified several important biological questions that had not been addressed. It is increasingly clear that innate immunity has an important biological role, although basic understanding of the mechanisms of normal homeostasis is still being investigated. Application of the emerging knowledge was lacking with regard to homeostatic mucosal immunity to HIV and its role in changing this homeostasis. With regard to breast milk, a series of studies have demonstrated the differences between transmitters and nontransmitters, although whether these findings could be generalized to other secretions such as saliva was less clear. Important progress toward an oral mucosal HIV vaccine has been made, demonstrating proof of principle for administering vaccine candidates into oral lymphoid tissues to trigger anti-HIV local and systemic immune responses. Similarly, experimental data emphasized the central role of neutralizing antibodies to prevent HIV infection via mucosal routes.

New approaches to Candida and oral mycotic infections: Workshop 2A.

This workshop reviewed aspects of the following: oral fungal disease in HIV-infected patients and the predictive value of oral mucosal disease in HIV progression; the role of the oral biofilms in mucosal disease; microbial virulence factors and the pseudomembranous oral mucosal disease process; the role that oral mucosal disease may have in HIV transmission; and the available topical antifungal treatment. This article summarizes the ensuing discussions and raises pertinent problems and potential research directions associated with oral fungal disease in HIV-infected patients, including the frequency of oral candidosis, the role of the intraoral biofilm in the development of oral mucosal disease, and host-pathogen interactions, as well as the development of the fetal oral mucosa, neonatal nutrition, and the role of oral candidosis in this setting. Finally, discussions are summarized on the use of inexpensive effective antifungal mouthwashes in resource-poor countries, the potential stigmata that may be associated with their use, as well as novel topical medications that may have clinical applicability in managing oral candidal infections in HIV-infected patients.

Fabrication of a multi-applicable removable intraoral denture system for rodent research.

The objective was to engineer an inexpensive intraoral removable denture system for rodents that can be utilised in numerous oral health research applications. At the forefront is biofilm research related to Candida-associated denture stomatitis. Previously described intraoral devices are primitive and inadequate. The denture system was engineered consisting of a fixed part that is anchored to the posterior palate by orthodontic wires and acrylic resin and a removable part fitted to the anterior palate that is retained by magnets embedded in the fixed part. Both parts are custom fitted to the rodent palate by impression making and cast fabrication. Rats fitted with the intraoral denture system maintained body weight and normal activity with the device maintaining integrity and durability for upwards of 8 weeks. The denture system was used successfully to establish a working model of denture stomatitis. This newly engineered inexpensive intraoral removable denture system for rodents can be utilised in numerous oral health research applications, including denture-associated infections, biofilms and a variety of biomaterial applications. The removable portion is advantageous for longitudinal analyses and charging/discharging of biomaterials.

Candida albicans forms biofilms on the vaginal mucosa.

Current understanding of resistance and susceptibility to vulvovaginal candidiasis challenges existing paradigms of host defence against fungal infection. While abiotic biofilm formation has a clearly established role during systemic Candida infections, it is not known whether C. albicans forms biofilms on the vaginal mucosa and the possible role of biofilms in disease. In vivo and ex vivo murine vaginitis models were employed to examine biofilm formation by scanning electron and confocal microscopy. C. albicans strains included 3153A (lab strain), DAY185 (parental control strain), and mutants defective in morphogenesis and/or biofilm formation in vitro (efg1/efg1 and bcr1/bcr1). Both 3153A and DAY815 formed biofilms on the vaginal mucosa in vivo and ex vivo as indicated by high fungal burden and microscopic analysis demonstrating typical biofilm architecture and presence of extracellular matrix (ECM) co-localized with the presence of fungi. In contrast, efg1/efg1 and bcr1/bcr1 mutant strains exhibited weak or no biofilm formation/ECM production in both models compared to wild-type strains and complemented mutants despite comparable colonization levels. These data show for the first time that C. albicans forms biofilms in vivo on vaginal epithelium, and that in vivo biotic biofilm formation requires regulators of biofilm formation (BCR1) and morphogenesis (EFG1).

Annexin-A1 identified as the oral epithelial cell anti-Candida effector moiety.

Innate and adaptive immunity are considered critical to protection against mucosal candidal infections. Among innate anti-Candida mechanisms, oral and vaginal epithelial cells have antifungal activity. The mechanism is fungistatic, acid-labile and includes a requirement for cell contact by intact, but not necessarily live, epithelial cells. The purpose of this study was to use the acid-labile property to further characterize the effector moiety. Surface material extracted from phosphate-buffered saline (PBS) -treated, but not acid-treated, epithelial cells significantly inhibited the growth of Candida blastoconidia in a dose-dependent manner which was abrogated by prior heat and protease treatment. Proteins extracted from PBS-treated cells bound blastoconidia and hyphae more intensely than those from acid-treated cells. Proteins from PBS-treated cells eluted from Candida revealed two unique bands of approximately 33 and 45 kDa compared with acid-treated cells. Mass spectrometry identified these proteins as Annexin-A1 and actin, respectively. Oral epithelial cells stained positive for Annexin-A1, but not actin. Western blots showed reduced Annexin-A1 in proteins from acid-treated epithelial cells compared with those from PBS-treated epithelial cells. Lastly, it was demonstrated that immunoprecipitation of Annexin-A1 from proteins extracted from PBS-treated oral epithelial cells resulted in abrogation of inhibitory activity. Taken together, these results indicate that Annexin-A1 is a strong candidate for the epithelial cell anti-Candida effector protein.

Chemokine receptor expression in HIV-positive persons with oropharyngeal candidiasis.

OBJECTIVE: In HIV+ persons with reduced CD4+ T cells, oropharyngeal candidiasis (OPC) is often associated with the accumulation of CD8+ T cells at the epithelial/lamina propria interface within the lesion together with increased tissue-associated cytokines and chemokines. Despite this reactivity, a dysfunction in the ability of the CD8+ cells to reach the organism at the outer epithelium is postulated. The purpose of this study was to examine chemokine receptors present in the OPC lesions for a potential role in susceptibility to infection. METHODS: Biopsies taken from buccal mucosa of HIV- persons, healthy mucosa of HIV+ OPC- persons, and OPC lesions were processed for protein immunohistochemical staining or RNA analysis by real-time PCR and Superarray. RESULTS: There was little change in expression of chemokine receptors at the protein or RNA level between OPC+ and OPC- tissue. At the protein level, increases occurred in OPC+ persons only if associated with CD8 cells. In the Superarray, of the 22 chemokine receptor mRNAs expressed, c. 90% remained unchanged (< 1.0-fold change) between HIV- and HIV+ tissue and between HIV+ OPC- and HIV+ OPC+ tissue. CONCLUSION: Tissue-associated chemokine receptor expression does not appear to contribute to the dysfunction in cellular migration associated with susceptibility to OPC.

Candida-induced oral epithelial cell responses.

OBJECTIVE: Oropharyngeal candidiasis (OPC), caused by Candida albicans, is the most common oral infection in HIV(+) persons. Oral epithelial cells are considered important for innate host defense against OPC with production of cytokines in response to C. albicans and the ability to inhibit Candida growth in vitro. The purpose of this study was to determine if Candida similarly induces cytokines by oral epithelial cells from HIV(+) persons, including those with OPC, as well as to determine if cytokines can influence the oral epithelial cell anti-Candida activity. METHODS: Supernatants from oral epithelial cells from HIV(+) persons with and without OPC cultured with Candida were evaluated for cytokines by ELISA, or cytokines were added to the standard growth inhibition assay using epithelial cells from HIV(-) persons. RESULTS: Results showed low Candida-induced epithelial cell cytokine production from HIV(+) persons, but with some elevated proinflammatory cytokines (TNF-alpha, IL-6) in those with OPC compared to those without OPC. The addition of specific proinflammatory or Th cytokines had no effect on oral epithelial cell anti-Candida activity in healthy HIV(-) persons. CONCLUSION: These results suggest that oral epithelial cells from HIV(+) persons can contribute at some level to the oral cytokine milieu in response to Candida during OPC, but that cytokines do not appear to influence oral epithelial cell anti-Candida activity.

Candida-host interactions in HIV disease: relationships in oropharyngeal candidiasis.

Oropharyngeal candidiasis (OPC) caused by the commensal organism, Candida albicans, is the most common oral infection in HIV disease. Although cell-mediated immunity (CMI) by Th1-type CD4+ T-cells is considered the predominant host defense mechanism against OPC, other systemic or local immune mechanisms are critical when blood CD4+ T-cells are reduced below a protective threshold. For example, the Th cytokine profile in saliva may influence resistance or susceptibility to OPC. In OPC lesions, CD8+ T-cells become accumulated at the lamina propria-epithelium interface, suggesting some role for CD8+ T-cells against OPC. However, the absence of CD8+ T-cells close to Candida at the outer epithelium indicates that susceptibility to OPC involves a dysfunction in the CD8+ T-cells or in the micro-environment. Further evaluation of the buccal mucosa lesion showed that CD8 T-cell-associated cytokine and chemokine mRNA is increased compared with buccal mucosa from lesion-negative matched controls. The majority of CD8+ T-cells present possess the alphabeta T-cell receptor and several homing receptors (i.e., 4beta7, 4beta1, ebeta7). While several adhesion molecules are similar in OPC+ vs. OPC- persons, E-cadherin is reduced in the tissue of OPC+ persons. These results support evidence for a role for CD8+ T-cells against OPC, but suggest that a putative dysfunction in mucosal T-cell trafficking may be associated with susceptibility to infection. Similar levels of Candida-specific antibodies in persons with and without OPC confirmed a limited role for humoral immunity. Finally, oral epithelial cells inhibit the growth of Candida in vitro in a static rather than a cidal manner. Clinically, oral epithelial cell anti-Candida activity is reduced in HIV+ persons with OPC, compared with controls. The mechanism of action includes a strict requirement for cell contact by an acid-labile moiety on intact, but not necessarily live, epithelial cells, with no role for soluble factors. Taken together, host defense against OPC involves several levels of activity. The status and efficiency of local host defenses when blood CD4+ T-cells are not available appear to play a role in protection against or susceptibility to OPC.

(B1) Candida and mycotic infections.

Oral candidiasis (OC) is the most common mucosal manifestation of HIV infection. This workshop examined OC and other mycoses associated with HIV infection. Historically, blood CD4 cell numbers were the primary prognosticator for the development of OC. However, a study that statistically evaluated the predictive role of HIV viral load vs. CD4 cell counts revealed viral load to be a stronger predictor for OC. The role of biofilms and antifungal resistance in recalcitrant OC is unclear at present. In general, micro-organisms including yeasts in biofilms are more resistant to antifungals than their planktonic counterparts. When the remaining organisms are eliminated, the few resistant organisms may not be problematic, because they are present in low numbers. Unusual exotic mycoses in HIV-infected patients are more common in patients from the developing than the developed world. These infections may be recurrent and recalcitrant to therapy, be present in multiple and uncommon sites, increase with the progression of HIV disease, and may play a role similar to that of the more common mycoses. Typing and subtyping of yeasts are probably not critical to the clinical management of candidiasis caused by Candida albicans and non-albicans strains, including C. dubliniensis, because it is responsive to antifungal therapy. C. glabrata is probably the only exception. The presence of oral thrush in infants younger than 6 months of age is associated with an increased post-natal transmission risk of HIV infection. Thus, perinatal retroviral therapy should be combined with the treatment of oral thrush to prevent the post-natal acquisition of HIV.

The host cytokine responses and protective immunity in oropharyngeal candidiasis.

Over the last three decades, the prevalence of oropharyngeal fungal infections has increased enormously, mainly due to an increasing population of immunocompromised patients, including individuals with HIV infection, transplant recipients, and patients receiving cancer therapy. The vast majority of these infections are caused by Candida species. The presence of cytokines in infected tissues ultimately dictates the host defense processes that are specific to each pathogenic organism. During oral infection with Candida, a large number of pro-inflammatory and immunoregulatory cytokines are generated in the oral mucosa. The main sources of these cytokines are oral epithelial cells, which maintain a central role in the protection against fungal organisms. These cytokines may drive the chemotaxis and effector functions of innate and/or adaptive effector cells, such as infiltrating neutrophils and T-cells in immunocompetent hosts, and CD8(+) T-cells in HIV(+) hosts. Epithelial cells also have direct anti-Candida activity. Several studies have provided a potential link between lower levels of certain pro-inflammatory cytokines and susceptibility to oral C. albicans infection, suggesting that such cytokines may be involved in immune protection. The exact role of these cytokines in immune protection against oropharyngeal candidiasis is still incompletely understood and requires further investigation. Identification of such cytokines with the ability to enhance anti-fungal activities of immune effector cells may have therapeutic implications in the treatment of this oral infection in the severely immunocompromised host.