Growth inhibitory effect of selected medicinal plants from Southern Ethiopia on the mycelial phase of Histoplasma capsulatum var. farciminosum.

BACKGROUND: Epizootic lymphangitis is an infectious and chronically debilitating disease of the equines. Histoplasma capsulatum var. farciminosum, a thermally dimorphic fungi, is the causative agent for the disease. In Ethiopia, the disease significantly affects carthorses, posing threats to animal welfare, and resulting in substantial economic losses. Limited availability of widely accessible antifungals in addition to the chronic nature of the disease is the major challenge against management of epizootic lymphangitis. This study aimed to assess the in vitro efficacy of specific local medicinal plant extracts against the mycelial phase development of H. capsulatum var. farciminosum in southern Ethiopia. The leaves of Xanthium strumarium, Kanda (Family Rubiaceae), Croton macrostachyus (Bisana in Amharic), and Centella Asiatica (Echere waye as a local name in Zeyissegna) that are traditionally used for the treatment of different skin ailments were collected and extracted for the in vitro trial. RESULTS: The study revealed that methanol extracts of Xanthium strumarium, Kanda, Croton macrostachyus, and Centella Asiatica, at minimum inhibitory concentrations of 1.25 mg/ml, 2.5 mg/ml, 2.5 mg/ml, and 5 mg/ml, respectively, inhibited the growth of H. capsulatum var. farciminosum. CONCLUSION: This in vitro finding could serve as significant preliminary data in the exploration of effective alternative treatment options for epizootic lymphangitis. This study provides a crucial foundation for further research aimed at determining the chemical components and in vivo effectiveness of these plant extracts against both the mycelial and yeast forms of Histoplasma capsulatum var. farciminosum.

Histoplasma capsulatum Relies on Tryptophan Biosynthesis To Proliferate within the Macrophage Phagosome.

Histoplasma capsulatum yeasts reside and proliferate within the macrophage phagosome during infection. This nutrient-depleted phagosomal environment imposes challenges to Histoplasma yeasts for nutrition acquisition. Histoplasma yeasts require all 20 amino acids, which can be formed by de novo biosynthesis and/or acquired directly from the phagosomal environment. We investigated how Histoplasma obtains aromatic amino acids (i.e., phenylalanine, tyrosine, and tryptophan) within the phagosome during infection of macrophages. Depletion of key enzymes of the phenylalanine or tyrosine biosynthetic pathway neither impaired Histoplasma's ability to proliferate within macrophages nor resulted in attenuated virulence in vivo. However, loss of tryptophan biosynthesis resulted in reduced growth within macrophages and severely attenuated virulence in vivo. Together, these results indicate that phenylalanine and tyrosine, but not tryptophan, are available to Histoplasma within the macrophage phagosome. The herbicide glyphosate, which targets 5-enolpyruvylshikimate-3-phosphate synthase of the aromatic amino acid biosynthetic pathway, inhibited Histoplasma yeast growth, and this growth inhibition was partially reversed by aromatic amino acid supplementation or overexpression of ARO1. These results suggest that the aromatic amino acid biosynthetic pathway is a candidate drug target to develop novel antifungal therapeutics.

In Vitro Evaluation of the Effects of Selected Plants on the Growth of the Mycelial Form of Histoplasma capsulatum Variety farciminosum in Ethiopia.

Epizootic lymphangitis is prevalent in equines in Ethiopia, causing remarkable economic and welfare impacts but often neglected. Lack of effective treatment contributed to its continued occurrence, and hence, search for an effective treatment should be considered a priority area to minimize its impacts. Previous ethnobotanical studies have reported that Curcuma longa, Phytolacca dodecandra, and Datura stramonium were used to treat cutaneous fungal infections and reduce their incidence. The treatment effects of these plants against epizootic lymphangitis should be studied. The in vitro growth inhibitory effects of methanol extracts of the root of C. longa, berry of P. dodecandra, and leaf of D. stramonium were evaluated. Histoplasma capsulatum var farciminosum was isolated from clinical cases of epizootic lymphangitis in carthorses in central Ethiopia. The nested polymerase chain reaction was used to confirm the identity of the isolates. Serial twofold dilutions of the extract of berries of P. dodecandra and leaves of D. stramonium were done in sterile water, whereas dilution of the extract of roots of C. longa was done in dimethylsulphoxide. The effects of the plants on the growth of Histoplasma capsulatum var farciminosum were assessed by agar dilution assay. Culture media with no antifungal agent and media containing ketoconazole served as negative and positive control, respectively. The methanol extract of C. longa showed inhibitory effects at concentrations ranging from 0.07 to 5 mg/mL. Similarly, the methanol extract of P. dodecandra showed growth inhibitory effects at concentrations ranging from 0.156 to 5 mg/mL. That is, the growth inhibitory concentration of C. longa was 0.07 mg/mL, whereas that of P. dodecandra was 0.156 mg/mL. In contrast, D. stramonium showed no inhibitory effect. This preliminary observation showed that methanol extracts of C. longa and P. dodecandra showed inhibitory effects on the growth of Histoplasma capsulatum var farciminosum requiring further repeated in vitro evaluation so as to generate adequate evidence, which would justify in vivo trials.

Disseminated pulmonary histoplasmosis in immunocompetent patients: a common epidemiological exposure.

We describe the initial presentation, diagnostic work-up and treatment of three adult immunocompetent men who presented within a short time frame of each other to an academic medical centre with acute respiratory distress syndrome. Their presentation was found to be secondary to a large inoculum of histoplasmosis from remodelling a building with bat droppings infestation. We discuss the pathophysiology of histoplasmosis and highlight the importance of exposure history in patients with acute respiratory failure and why patients with the occupational risk of exposure to fungal inoculum should wear protective respirator gear.

Paracoccidioides spp. and Histoplasma capsulatum: Current and New Perspectives for Diagnosis and Treatment.

The thermally-dimorphic systemic fungal group includes several important human pathogens: Blastomyces dermatitides, Coccidioides immitis and C. posadasii, Histoplasma capsulatum, Paracoccidioides brasiliensis, P. lutzii, and Talaromyces (Penicillium) marneffei. They usually are geographically restricted and have natural habitats in soil or in plants, and when fungal propagules invade mammalian host by inhalation, they initiate an inflammatory reaction that can result in self-resolution of the infection or cause an acute or chronic disease. In the setting of the AIDS pandemic and the developments in modern medicine, such as immunosuppressive therapy in cancer surgery patients and in transplantation and autoimmune diseases, the incidence of endemic mycoses has progressively increased. Another important factor of the increased incidence of systemic mycoses in certain regions is the progressive devastation of tropical and subtropical forests. In this review, we focus on two of the most important systemic mycoses: paracoccidioidomycosis and histoplasmosis, and their major characteristics in epidemiology, clinical aspects and laboratorial diagnosis.

Zinc Induces Dendritic Cell Tolerogenic Phenotype and Skews Regulatory T Cell-Th17 Balance.

Zinc (Zn) is an essential metal for development and maintenance of both the innate and adaptive compartments of the immune system. Zn homeostasis impacts maturation of dendritic cells (DCs) that are important in shaping T cell responses. The mechanisms by which Zn regulates the tolerogenic phenotype of DCs remain largely unknown. In this study, we investigated the effect of Zn on DC phenotype and the generation of Foxp3(+) regulatory T cells (Tregs) using a model of Histoplasma capsulatum fungal infection. Exposure of bone marrow-derived DCs to Zn in vitro induced a tolerogenic phenotype by diminishing surface MHC class II (MHCII) and promoting the tolerogenic markers, programmed death-ligand (PD-L)1, PD-L2, and the tryptophan degrading enzyme, IDO. Zn triggered tryptophan degradation by IDO and kynurenine production by DCs and strongly suppressed the proinflammatory response to stimulation by TLR ligands. In vivo, Zn supplementation and subsequent H. capsulatum infection supressed MHCII on DCs, enhanced PD-L1 and PD-L2 expression on MHCII(lo) DCs, and skewed the Treg-Th17 balance in favor of Foxp3(+) Tregs while decreasing Th17 cells. Thus, Zn shapes the tolerogenic potential of DCs in vitro and in vivo and promotes Tregs during fungal infection.

Ciprofloxacin shows synergism with classical antifungals against Histoplasma capsulatum var. capsulatum and Coccidioides posadasii.

This study evaluated the in vitro interaction between ciprofloxacin (CIP) and classical antifungals against Histoplasma capsulatum var. capsulatum in mycelial (n = 16) and yeast-like forms (n = 9) and Coccidioides posadasii in mycelial form (n = 16). This research was conducted through broth microdilution and macrodilution, according to Clinical Laboratory Standards Institute. Inocula were prepared to obtain from 0.5 × 10(3) to 2.5 × 10(4) cfu ml(-1) for H. capsulatum and from 10(3) to 5 × 10(3) cfu ml(-1) for C. posadasii. Initially, minimum inhibitory concentration (MIC) for each drug alone was determined. Then, these MICs were used as the highest concentration for each drug during combination assays. The procedures were performed in duplicate. For all combination assays, MICs were defined as the lowest concentration capable of inhibiting 80% of visible fungal growth, when compared to the drug-free control. Drug interaction was evaluated by paired sample t-Student test. The obtained data showed a significant MIC reduction for most tested combinations of CIP with antifungals, except for that of CIP and voriconazole against yeast-like H. capsulatum. This study brings potential alternatives for the treatment of histoplasmosis and coccidioidomycosis, raising the possibility of using CIP as an adjuvant antifungal therapy, providing perspectives to delineate in vivo studies.

Histoplasmosis in HIV-positive patients in Ceará, Brazil: clinical-laboratory aspects and in vitro antifungal susceptibility of Histoplasma capsulatum isolates.

This study contains a descriptive analysis of histoplasmosis in AIDS patients between 2006 and 2010 in the state of Ceará, Brazil. Additionally, the in vitro susceptibility of Histoplasma capsulatum isolates obtained during this period was assessed. We report 208 cases of patients with histoplasmosis and AIDS, describing the epidemiological, clinical, laboratory and therapeutic aspects. The in vitro antifungal susceptibility test was carried out by the microdilution method, according to Clinical and Laboratory Standards Institute, with H. capsulatum in the filamentous and yeast phases, against the antifungals amphotericin B, fluconazole, itraconazole, voriconazole and caspofungin. In 38.9% of the cases, histoplasmosis was the first indicator of AIDS and in 85.8% of the patients the CD4 cell count was lower than 100 cells/mm(3). The lactate dehydrogenase levels were high in all the patients evaluated, with impairment of hepatic and renal function and evolution to death in 42.3% of the cases. The in vitro susceptibility profile demonstrated there was no antifungal resistance among the isolates evaluated. There was a significant increase in the number of histoplasmosis cases in HIV-positive patients during the period surveyed in the state of Ceará, northeastern Brazil, but no antifungal resistance among the recovered isolates of H. capsulatum.

Actividad antifúngica in vitro del ajoeno en cinco aislamientos clínicos de Histoplasma capsulatum var. capsulatum / In vitro antifungal activity of ajoene on five clinical isolates of Histoplasma capsulatum var. capsulatum

Antecedentes. Con el advenimiento del sida, la histoplasmosis ha aumentado considerablemente y su tratamiento continúa siendo relativamente eficaz, si bien provoca efectos adversos. Objetivo. Evaluar el efecto inhibitorio del ajoeno sobre Histoplasma capsulatum, en fase micelial, utilizando como medios de cultivo caldo glucosado de Sabouraud y RPMI-1640. Métodos. Las curvas de crecimiento y el efecto inhibitorio del ajoeno (1,25-20mg/ml) se realizaron a temperatura ambiente, en agitación y se registraron turbidimétricamente (540nm) cada 48h, durante 14 días. Se construyeron gráficas para estimar el tiempo de generación (Tg), concentración mínima inhibitoria (CMI) y concentración inhibitoria 50% (CI50). La concentración fungicida mínima (CFM) se determinó por el método de cultivo en placas. Se usaron las pruebas de Mann-Whitney y T-test para evaluar la significación estadística entre los medios de cultivo y los parámetros Tg, CIM, CI50, CFM y efecto fungistático (EF) con un nivel de significación de 0,05. Resultados. Para los dos medios de cultivo, en todos los aislamientos se obtuvieron curvas de crecimiento con Tg de 43 a 67h, EF a concentraciones de 1,25 y 2,5mg/ml y CFM de 5 y 10mg/ml. Los valores de la CIM, en CSD fueron de 2,5 y 5 y en RPMI, de 1,25 a 5mg/ml. La CI50 en CSD fue de 1,9 a 2,6 y en RPMI, de 3,8 a 4,3mg/ml de ajoeno. No hubo diferencias significativas entre los medios de cultivo para los parámetros estudiados (p>0,05). Conclusiones. Los hallazgos del presente trabajo corroboran que el ajoeno inhibe el desarrollo de H. capsulatum en fase micelial(AU)

Background. The number of histoplasmosis cases have considerably increased since the advent of AIDS, and the therapy for this mycosis is not always effective, as well as having adverse effects. Aims. To evaluate the inhibitory effect of ajoene on five clinical isolates of Histoplasma capsulatum, on the mycelial form, using Sabouraud dextrose broth (SDB) and RPMI-1640 culture media. Methods. Growth curves and inhibitory activity of the drug (at concentrations of 1.25 mg/ml to 20mg/ml) were performed at room temperature, under mechanical agitation, and the turbidimetric readings (540nm) were recorded every 48h for 14 days, in both culture media. Generation times (GT) were calculated and graphs were constructed to estimate Minimal Inhibitory Concentrations (MIC) and Inhibitory Concentration 50% (IC50). The fungicidal minimal concentrations (FMC) were determined by plate cultures. The U-Mann-Whitney and t-test with a significance level of 0.05 were used to evaluate the statistical significance between culture media and GT, MIC, IC50 MFC and fungistatic effect (FE). Results. In both media and for all isolates, growth curves showed a GT of 43 to 67hrs, an FE at 1.25-2.5mg/ml, and a MFC at 5-10mg/ml of ajoene. Values of MIC were 2.5-5 in SDB and in RPMI medium these values were 1.25-5mg/ml of ajoene. For IC50, in SDB, the values were 1.9-2.6 mg/ml and in RPMI medium, they were of 3.8-4.3mg/ml of ajoene. There were no significance differences between culture media for GT, FE, MIC, IC50 and MFC (p>0.05). Conclusions. These findings corroborate that ajoene inhibits the growth of the mycelial form of H. capsulatum(AU)

[Relevant aspects of the Hcp100 molecular marker of Histoplasma capsulatum and its potential therapeutic use in histoplasmosis]. / Aspectos relevantes del marcador molecular Hcp100 de Histoplasma capsulatum y su potencial uso terapéutico en la histoplasmosis.

BACKGROUND: Fungal pathogens have developed strategies, involving genes expression that favors their persistence and multiplication in the host. The absence of molecules encoded by these genes could interfere with the growth and death of these fungi. In the past, a coactivator protein coding gene (Hcp100) of the fungus Histoplasma capsulatum was reported, which is overexpressed after 1h of contact between fungal yeast-cells and murine macrophages. The product of this gene, a protein of 100 kDa (Hcp100) of H. capsulatum, is probably a regulatory protein involved in the processes required for fungal adaptation and its survival in the intracellular hostile conditions of the macrophages. A 210-bp fragment of the Hcp100 marker has proved to be an excellent tool for H. capsulatum molecular detection in clinical samples. The potential use of this gene as a therapeutic target in Plasmodium falciparum has been explored through the inhibition of both, the gene and the protein p100 of the parasite, by blocking its growth. METHODS: Based on the above mentioned antecedents, we believe that the Hcp100 has an important role in the development and maintenance of the H. capsulatum yeast cells within macrophages. RESULTS AND CONCLUSIONS: To study the probable function of Hcp100 in the yeast-phase of this fungal pathogen is relevant to understand its activity and to propose it as a therapeutic target for histoplasmosis treatment.

Evaluation of berries of Phytolacca dodecandra for growth inhibition of Histoplasma capsulatum var. farciminosum and treatment of cases of epizootic lymphangitis in Ethiopia.

OBJECTIVE: To evaluate the berries of Phytolacca dodecandra (P. dodecandra) for its effect on Histoplasma capsulatum var. farciminosum (HCF) and for the treatment of cases of epizootic lymphangitis (EL). METHODS: Samples were collected from un-ruptured nodules of cases of EL at Debre Zeit and Akaki (central Ethiopia). Mycological culture and isolation of HCF were performed at the Aklilu Lemma Institute of Pathobiology. Phytochemical screening was done for n-butanol extract of P. dodecandra to detect alkaloids, saponins, phenolic compounds and flavonoids. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of aqueous and n-butanol extracts of P. dodecandra against HCF were determined by agar dilution assay. For the in vivo trial, 5% simple ointment was prepared from n-butanol extract and applied topically to 24 (twelve early and twelve moderate) cases of EL. RESULTS: Phytochemical screening showed that n-butanol extract of P. dodecandra was positive for alkaloids, saponins and phenolic compounds but negative for flavonoids. The MICs of n-butanol and aqueous extracts of P. dodecandra were (0.039%-0.078%) and (0.625%-1.250%), respectively. The MFCs of n-butanol and aqueous extracts of P. dodecandra were (0.078%-0.156%) and (1.250%-2.500%), respectively. The MIC and MFC of ketoconazole (positive control) was (1.200×10(-5)%-2.500×10(-5)%) and (5.000×10(-5)%-1.000×10(-4)%), respectively while growth was observed on free medium (negative control). From the total of 24 treated cases of EL, 14 (58.3%) responded to treatment; however, 10 (41.7%) did not respond to treatment. There was no significant difference in the degree of response to treatment between early and moderate cases (χ(2)=0.686; P=0.408). CONCLUSIONS: It can be concluded that n-butanol extract of P. dodecandra demonstrates antifungal effects while the aqueous extract shows no antifungal activity.

Validation and clinical application of a molecular method for identification of Histoplasma capsulatum in human specimens in Colombia, South America.

The conventional means of diagnosis of histoplasmosis presents difficulties because of the delay to the time that the diagnosis is made, indicating the need for the implementation of molecular assays. We evaluated 146 clinical samples from 135 patients suspected of having histoplasmosis using a previously reported nested PCR assay for the Histoplasma capsulatum-specific 100-kDa protein (the Hc100 PCR). In order to determine the specificity of this molecular test, we also used samples from healthy individuals (n = 20), patients suspected of having respiratory disease with negative fungal cultures (n = 29), and patients with other proven infections (n = 60). Additionally, a sizable collection of DNA from cultures of H. capsulatum and other medically relevant pathogens was studied. A panfungal PCR assay that amplified the internal transcribed spacer 2 region was also used to identify all fungal DNAs. All PCR-amplified products were sequenced. Of the 146 clinical samples, 67 (45.9%) were positive by culture and PCR, while 9 samples negative by culture were positive by PCR. All the sequences corresponding to the 76 amplified products presented > or =98% identity with H. capsulatum. The Hc100 PCR exhibited a sensitivity of 100% and specificities of 92.4% and 95.2% when the results were compared to those for the negative controls and samples from other proven clinical entities, respectively; the positive predictive value was 83% and the negative predictive value was 100%; the positive and negative likelihood rates were 25 and 0, respectively. These results suggest that the Hc100 nested PCR assay for the detection of H. capsulatum DNA is a useful test in areas where mycosis caused by this organism is endemic.

Combined therapy with amphotericin B and caspofungin in an experimental model of disseminated histoplasmosis.

OBJECTIVE: To assess the effect of amphotericin B and caspofungin, as well as their combinations in the therapy of experimental disseminated histoplasmosis. MATERIAL AND METHODS: BALB/c mice were intraperitoneally infected with four different strains of Histoplasma capsulatum and given to antifungal treatments. The response to intraperitoneal therapy with amphotericin B (0.5, 1.0, and 2.0 mg/kg of body weight) or caspofungin (10 mg/kg of body weight) and their combinations, was evaluated by the quantification of yeast colony-forming units (CFU) per gram of spleen or lung, from each animal. Additionally, the pathogen was monitored histopathologically in the excised organs. Data were analyzed with the Kruskall-Wallis and Tukey tests. RESULTS: Caspofungin was more effective than amphotericin B in reducing the CFU/ g. A synergistic effect was observed when caspofungin (10 mg/ kg) was combined with amphotericin B (0.5 or 1.0 mg/kg). Significant differences in CFU values, H = 119.78 (P = 0.00001), were found among the treatment groups. However, statistical analyses did not reveal significant differences, H = 2.837 (P = 0.428), in the therapeutic responses with the four H. capsulatum strains tested. CONCLUSION: Combined therapy with amphotericin B and caspofungin could represent an alternative treatment to be explored in severe human histoplasmosis.

Equine histoplasmosis: treatment trial in cart horses in Central Ethiopia.

Therapeutic effects of Sodium Iodide (NaI), Potassium Iodide (KI), ground berries of "Endod" (Phytolacca dodecandra) and Penstrip were evaluated on 70 cases of equine hitoplasmosis (EH). Response to each treatment was assessed using clinical examination of the lesions. Statistically significant difference (P = 0.0036) in therapeutic effect was observed among the different remedies. Cases treated either with a combination of NaI and Penstrip (F = 6.34, P = 0.004) or "Endod" and Penstrip (F = 3.64, P = 0.031) demonstrated significant response. The difference in response to treatment between early and advanced cases of EH was statistically significant (t = 2.22, P = 0.0148).

Ferrous, but not ferric, iron maintains homeostasis in Histoplasma capsulatum triacylglycerides.

Iron is an indispensable micronutrient for virtually all microorganisms, where it acts as a cofactor of many enzymes involved in regulation of multiple cellular and physiological functions. This metal is also considered an important determinant contributing to the pathogenesis of fungal infectious diseases, and therefore the identification of iron-regulated metabolic processes occurring within the invading fungal cell can help the development of new antifungal therapeutic strategies. In this study, we examined relationships between iron availability and neutral storage lipids in Histoplasma capsulatum, a dimorphic fungus responsible for the most common respiratory and systemic mycosis in humans. Yeast cells were grown in a defined minimal medium supplemented with or without iron. Lipids were extracted from cells at the log and late stationary growth phases, then separated by thin-layer chromatography, and fatty acids were analyzed by gas chromatography. A culture age-related decrease in the unsaturated fatty acid content was observed in all four neutral lipid classes examined. Iron-related alterations could be seen in relation to triacylglycerol and free fatty acid pools, whereas no iron-dependent effects were detected in diacylglycerol and steryl ester fractions. Regarding triacylglycerols, the presence of iron positively affected the content of unsaturated fatty acids, and this stabilizing action of iron was notably increased when ferrous ions were added. Subsequent iron uptake studies showed a definite preference of H. capsulatum to acquire iron in its reduced, more soluble, ferrous form, and therefore, the availability of iron may be the underlying reason for the observed iron-maintained homeostasis in H. capsulatum triacylglycerols.

Unusual manifestation of histoplasmosis in connective tissue diseases.

This report describes the coexistence of three patients with rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis, and dermatomyositis) and infections because of Histoplasma capsulatum. Connective tissue diseases and histoplasmosis share several clinical findings. Therefore, histoplasmosis could be misdiagnosed as connective tissue disease or a flare of these diseases. Such cases highlight the importance of awareness of histoplasmosis in immunocompromised patients, particularly in those originating from endemic areas.

Anti-inflammatory activity of Dasyphyllum brasiliensis (Asteraceae) on acute peritonitis induced by beta-glucan from Histoplasma capsulatum.

The tea prepared from leaves and thorns of Dasyphyllum brasiliensis (Asteraceae) is used in the traditional medicine in Brazil for the treatment of oral and oropharyngeal diseases. In this study, we investigated the anti-inflammatory activity of this plant. The aqueous crude extract (ACE), the methanol-water (MeOH-H(2)O) fraction obtained by solvent partition and its fractionation products were evaluated for their anti-inflammatory activities on acute peritonitis induced by beta-glucan from the cell walls of Histoplasma capsulatum. The antiedematogenic activity was also tested using the carrageenan-induced paw edema assay in mice. Oral administration of 100 and 300mg/kg of the ACE in mice caused a significant reduction of neutrophil and eosinophil recruitment in the acute peritonitis assay. In addition, ACE at 300mg/kg inhibited the number of mononuclear cells recruitment. The MeOH-H(2)O fraction and its fractionation products (all at 100mg/kg) also presented anti-inflammatory activities, confirmed by the inhibition of cells recruited to the peritoneal cavity. ACE at 100mg/kg did not show any significant reduction of the edema in the mice paw injected with carrageenan. These data together suggest that Dasyphyllum brasiliensis presents significant anti-inflammatory activity, thus supporting the popular use of the tea in the treatment of inflammatory diseases.

Serious infections associated with anticytokine therapies in the rheumatic diseases.

The ability to target and neutralize macrophage-derived inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), has emerged in recent years as one of the most important advances in the treatment of rheumatoid arthritis, Crohn's disease, and several other systemic inflammatory diseases. In rheumatoid arthritis, for example, these biological agents rapidly reduce signs and symptoms of joint inflammation and profoundly slow the progression of joint damage. However, data that have emerged following Food and Drug Administration approval of these agents have alerted clinicians to an increased likelihood of opportunistic infections in patients treated with these agents, particularly tuberculosis. The effect of TNF inhibition on the frequency of infection with more common bacterial pathogens is less clear. Animal models of tuberculosis and other opportunistic infections have demonstrated the importance of TNF-alpha in controlling and containing intracellular pathogens. The spectrum of infections reported to date in the setting of anti-TNF-alpha treatment is reviewed here. In addition, relevant animal data illustrating potential mechanistic roles for TNF-alpha in host responses to infection are also reviewed.

Sensibilidad in vitro de histoplasma capsulatum var. capsulatum frente a anfotericina B, ketoconazol, itraconazol y fluconazol / Sensitivity in vitro of histoplasma capsulatum var. capsulatum against amphotericin B, ketoconazole, itroconazole and fluconazole

Se determinó la concentración mínima inhibitoria (CMI) mediante un micrométodo de dilución en caldo RPMI-1640, con el objetivo de conocer la sensibilidad a la anfotericina B, el itraconazol, el ketoconazol y el fluconazol de 29 cepas de Histoplasma capsulatum var. capsulatum aisladas en Cuba. La histoplasmosis es una de las principales micosis sistémicas al nivel mundial, cuya incidencia se ha incrementado en los últimos años, asociada principalmente a la infección por el VIH y a la aparición de nuevos brotes epidémicos en diferentes regiones. Los resultados obtenidos permitieron concluir que frente al fluconazol se encontraron valores altos de CMI, con una media geométrica de 55,5 µg/mL. Para la anfotericina B, el ketoconazol y el itraconazol todas las cepas fueron inhibidas a concentraciones bajas, con medias geométricas de 0,26, 0,17 y 0,125 µg/mL, respectivamente. El desarrollo por primera vez en Cuba de un método para la determinación de CMI de las principales drogas antifúngicas frente a H. capsulatum var. capsulatum, permitirá establecer los patrones de sensibilidad y detectar la aparición de resistencia, lo que contribuirá a un mejor conocimiento de esta importante micosis