Cromoblastomicosis: abordaje con terapia combinada / Chromoblastomycosis: a combination therapy approach

La cromoblastomicosis es una micosis de implantación crónica y progresiva causada por diversos hongos de la familia Dematiaceae. En Latinoamérica, las especies en-contradas con más frecuencia son Fonsecaea pedrosoi y Cladophialophora carrionii. El tratamiento de esta micosis puede ser un desafío por la falta de respuesta y la recidiva, en especial en individuos con lesiones crónicas y extensas.Se presenta un individuo con recaída de cromoblastomico-sis (causada por Fonsecaea pedrosoi) en miembro inferior derecho que había realizado tratamiento incompleto con terbinafina e itraconazol. El paciente respondió de mane-ra favorable al retratamiento con itraconazol y terbinafina combinado con resección quirúrgica parcial de la lesión e injerto de piel en sitio quirúrgico

Chromoblastomycosis is a chronic and subcutaneous mycosis caused by various dematiaceous fungi, In Latin America, the most frequently found species are Fonsecaea pedrosoi and Cladophialophora carrionii.Treatment is a challenge because of the lack of response and recurrence in in some cases, especially in patients with extensive and chronic lesions.We report an individual with relapse of chromoblastomycosis (by Fonsecaea pedrosoi) in the right lower limb, who had undergone incomplete treatment with terbinafine and itraconazole. The patient responded favorably to retreatment with itraconazole and terbinafine combined with partial surgical resection of the lesion and skin grafting at the surgical site.

Tratamento bem-sucedido da cromoblastomicose pela associação entre criocirurgia e itraconazol em dose baixa / Successful treatment of chromoblastomycosis by the combination of cryosurgery with low-dose itraconazole

Cromoblastomicose é uma infecção granulomatosa crônica causada por fungos dematiáceos, com apresentações clínicas variadas, que podem representar um desafio terapêutico. Neste relato, apresentamos um caso de cromoblastomicose em forma localizada, de longa evolução, em paciente idoso, resistente a terapêuticas medicamentosas prévias, tratado com sucesso pela associação entre um método físico e tratamento farmacológico sistêmico, o que permitiu o uso de dose reduzida do medicamento.

Chromoblastomycosis is a chronic granulomatous infection caused by dematiaceous fungi with varied clinical presentations, which may represent a therapeutic challenge. In this report, we present a case of chromoblastomycosis in a localized form, with a long evolution, in an elderly patient, resistant to previous drug therapies, successfully treated by the association of a physical method with systemic pharmacological treatment, which allowed the use of a reduced dose of the drug

The importance of considering the possibility of ocular sporotrichosis in areas with high incidence rates of sporotrichosis / Esporotricose ocular: a importância de ser considerada em áreas com grande incidência de esporotricose

ABSTRACT Ocular sporotrichosis involving adnexa can present in 4 types: granulomatous conjunctivitis, dacryocystitis, Parinaud oculoglandular syndrome, and bulbar conjunctivitis. The incidence of ocular sporotrichosis has increased in regions with high incidence rates of sporotrichosis. We present a series of three cases of ocular involvement by the fungus Sporothrix species, including its manifestations, approaches, and relevance in areas where sporotrichosis has considerable incidence rates.

RESUMO A esporotricose ocular envolvendo anexos pode se apresentar de quatro formas: conjuntivite granulomatosa, dacriocistite, Síndrome Oculoglandular de Parinaud e conjuntivite bulbar. A esporotricose ocular, apesar de incomum, tem aumentado em regiões com alta incidência de esporotricose. Apresentamos uma série de três casos de envolvimento ocular pelo fungo Sporothrix sp.: suas manifestações, abordagem e sua relevância em áreas com alta incidência de esporotricose.

Leishmaniasis cutánea resistente al antimoniato de meglumina intramuscular / Resistance to Intramuscular Meglumine Antimoniate in Cutaneous Leishmaniasis

La leishmaniasis es una enfermedad causada por pará- sitos protozoarios del género Leishmania. Se clasifica como: cutánea, mucocutánea y visceral. De las ante- riores, la Leishmaniasis cutánea (LC) es la forma más común a nivel mundial, transmitida a humanos por la picadura del mosquito hembra, el cual pertenece a la familia Phlebotominae y Lutzomyia. La cutánea gene- ralmente se manifiesta clínicamente por presentar una pápula ulcerada con exudado seroso, con fondo limpio de aspecto granular y bordes hiperémicos y engrosados. Presentamos el caso de un adolescente de 16 años de edad, procedente de Aldea Peña Blanca Norte, San Pe- dro Sula, con lesión eritemato-costrosa, tumefacta no dolorosa de 2 meses de evolución, en pabellón auri- cular derecho. El paciente fue visto en consulta exter- na de Dermatología Pediátrica del Instituto Hondure- ño de Seguridad Social Regional del Norte (I.H.S.S.), recibiendo tratamiento con antibióticos sistémicos y tópicos (trimetoprim sulfametoxazol, mupirocina un- güento), por 7 días. Previamente había recibido varios tratamientos sistémicos orales y parenterales (amoxici- lina/ ácido clavulánico, dicloxacilina, penicilina benza- tínica, y aplicación tópica de ácido fusídico) sin obtener mejoría clínica alguna; se le envió a realizar microsco- pía directa con tinción de Giemsa de frotis obtenido de la lesión en el Centro de Salud "Miguel Paz Barahona", demostrando la presencia de amastigotes. Se inició al antimoniato de meglumina según esquema estableci- do por la Organización Mundial de la Salud (OMS) a razón de 20 mg/kg/día intramuscular por 30 días. Debido a la falla de tratamiento se deci- de utilizar itraconazol durante 3 meses con buena respuesta y sin efectos adversos...(AU)

Granulomatous tracheitis and dermatitis due to Curvularia sp. in a horse: case report / [Traqueíte e dermatite granulomatosas associadas a Curvularia sp. em um equino: relato de caso]

Tracheal fungal infections in horses are rare. This case report describes surgical and clinical management of a filly with a Curvularia sp. infection within the trachea and skin that caused severe intraluminal granulomas and cutaneous nodules, respectively. The patient was successfully treated with itraconazole and surgical excision.(AU)

Infecções fúngicas traqueais em equinos são raras. Este relato de caso descreve condutas clínicas e cirúrgicas em uma égua com infecção por Curvularia sp. na traqueia e na pele, causando granulomas intraluminais severos e nódulos cutâneos, respectivamente. O animal foi tratado com sucesso com itraconazol e exérese cirúrgica.(AU)

Actividad combinada de itraconazol y terbinafina sobre aislamientos clínicos de Neoscytalidium dimidiatum / Combined activity of Itraconazole and Terbinafine over clinical isolates of Neoscytalidium dimidiatum

Resumen Objetivo: Analizar la susceptibilidad de N. dimidiatum ante el efecto combinado de itraconazol y terbinafina. Métodos: Se determinó la concentración mínima inhibitoria y la concentración inhibitoria fraccionada in vitro, mediante el método del tablero de ajedrez, a 15 aislamientos clínicos provenientes de onicomicosis de diferentes pacientes, todos positivos por N. dimidiatum. Se prepararon ensayos por duplicado con diluciones combinadas de los antifúngicos y se evaluó el efecto de ambos fármacos. Resultados: La concentración mínima inhibitoria promedio de solo itraconazol aplicado a los aislamientos fue de 30,83 μg/mL y de 4,49 μg/mL combinado con terbinafina. La concentración mínima inhibitoria promedio de solo terbinafina fue de 0,33 μg/mL y de 0,07 μg/mL combinada con itraconazol. Hay diferencias estadísticamente significativas entre las concentraciones mínimas inhibitorias promedio de los antifúngicos analizados en solitario respecto de las concentraciones mínimas inhibitorias combinadas; para itraconazol (t = 2,958; gl = 14; p = 0,01) y (t = 4,721; gl = 14; p < 0,001) para terbinafina. El uso combinado evidenció 40 % de sinergismo. Conclusiones: La combinación itraconazol-terbinafina presentó un efecto sinérgico total para inhibir el crecimiento de N. dimidiatum; esto ofrece una alternativa terapéutica en el tratamiento de las onicomicosis.

Abstract Aim: Study the combined susceptibility patterns of Neoscytalidium dimidiatum to the effect of Itraconazole and Terbinafine. Background: The Minimum Inhibitory Concentration and Fractional Inhibitory Concentration were determined in vitro by the chessboard method for 15 clinical isolates of onychomycosis, from different patients, all positives for N. dimidiatum. Duplicated trials were prepared with combined dilutions of antifungals and the effect of both drugs was evaluated. Results: The average Minimum Inhibitory Concentration of Itraconazole when applied alone for the isolates was 30.83 μg/mL and 4.49 μg/mL when combined with Terbinafine. The average Minimum Inhibitory Concentration of Terbinafine alone was 0.33 μg/mL and 0.07 μg/mL when combined with Itraconazole. Statistically significant differences were found between the average Minimum Inhibitory Concentrations of the antifungals analyzed alone versus the Minimum Inhibitory Concentrations obtained by mixing both compounds. That is for Itraconazole (t = 2,958; gl = 14; p = 0,01) and (t = 4,721; gl = 14; p <0,001) for Terbinafine. Combined use showed 40 % synergism. Conclusions: The Itraconazole-Terbinafine combination had synergistic effect to inhibit the growth of N. dimidiatum, which offers a therapeutic alternative in the treatment of onychomycoses caused by this fungus.

Primary cutaneous histoplasmosis difficult to treat in immunocompetent patient: case report and literature review / Histoplasmose cutânea primária de difícil tratamento em paciente imunocompetente: relato de caso e revisão da literatura

ABSTRACT Histoplasmosis is an infection caused by the dimorphic fungus Histoplasma capsulatum. The disease is endemic in several regions of tropical and temperate climate. The fungus presents opportunistic behavior, causing widespread infection in immunocompromised patients, resulting from complication of primary pulmonary infection, due to exogenous reinfection or reactivation of a quiescent source. In immunocompetent individuals, approximately 95% of pulmonary infections are asymptomatic. However, prolonged exposure to high amount spores may lead to acute or chronic lung infection. Due to the low amount of inoculum, primary cutaneous histoplasmosis caused by traumatic implantation is extremely rare and effectively treated with triazoles. Thus, the present study aims to report a case of primary cutaneous histoplasmosis that is difficult to treat in an immunocompetent patient, and to review the literature on the incidence of drug-resistant Histoplasma capsulatum strains in clinical practice.

RESUMO A histoplasmose é uma infecção causada pelo fungo dimórfico Histoplasma capsulatum. A doença é endêmica em diversas regiões de clima tropical e temperado. O fungo apresenta comportamento oportunístico, causando infecção disseminada em pacientes imunocomprometidos, resultante da complicação da infecção pulmonar primária, por reinfecção exógena ou reativação de um foco quiescente. Em indivíduos imunocompetentes, cerca de 95% das infecções pulmonares são assintomáticas. No entanto, a exposição prolongada à quantidade elevada de esporos pode levar à infecção pulmonar aguda ou crônica. Devido à baixa quantidade de inóculo, a histoplasmose cutânea primária causada por implantação traumática é extremamente rara e efetivamente tratada com triazóis. Assim, o presente estudo tem como objetivos relatar um caso de histoplasmose cutânea primária de difícil tratamento em paciente imunocompetente, e revisar a literatura a respeito da incidência de cepas de Histoplasma capsulatum resistentes aos fármacos utilizados na prática clínica.

Candida auris infection in the central catheter of a patient without sepsis symptoms / Infección por Candida auris en el catéter central de un paciente sin síntomas de sepsis

Abstract Background: Candida auris is an emerging yeast frequently reported as resistant to multiple antifungal drugs commonly used to treat Candida infections. This specie can colonize the patient's skin and has great ability for producing outbreaks in hospitals. C. auris is phylogenetically related to other Candida species, can be misidentified using conventional biochemical or commercial methods and requires specific technology for its identification. Case report: We report the first isolate of C. auris in Cali, Colombia, from a central venous catheter in a 37-year-old patient with rheumatoid arthritis and endocarditis who did not have symptoms of sepsis. The yeast was initially misidentified as C. haemulonii using the Phoenix system and subsequently identified as C. auris by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The broth microdilution method was used to determine the minimum inhibitory concentration; the isolate was susceptible to fluconazole, itraconazole, voriconazole and amphotericin B. Conclusions: This report contributes to knowledge of the epidemiology of C. auris infections in individuals with underlying disease and describes an isolate with a behavior different from what is usually reported.

Resumen Antecedentes: Candida auris es una levadura emergente, informada con frecuencia como resistente a diversos antifúngicos usados comúnmente para tratar infecciones por Candida. Esta especie puede colonizar la piel y tiene gran capacidad de producir brotes en ambientes hospitalarios. Está filogenéticamente relacionada con otras especies de Candida, es mal identificada por los métodos bioquímicos o comerciales, y requiere tecnología específica para su identificación. Reporte de caso: Se informa el primer aislamiento de C. auris en Cali, Colombia en un paciente de 37 años con artritis reumatoide y endocarditis, sin síntomas de sepsis, a partir de la punta de catéter venoso central. La levadura inicialmente se identificó como C. haemulonii por el sistema Phoenix® y posteriormente como C. auris por espectrometría de masas desorción/ionización láser asistida por una matriz con detección de masas por tiempo de vuelo (MALDI-TOF MS). Se determinó la concentración inhibitoria mínima por el método de microdilución en caldo que mostró un aislamiento sensible a fluconazol, itraconazol, voriconazol y anfotericina B. Conclusión: Este informe contribuye al conocimiento de la epidemiología de las infecciones por C. auris en individuos con enfermedad subyacente y describe un aislamiento con un comportamiento diferente a lo indicado en otros estudios.

In vitro inhibitory activity of sertraline against clinical isolates of Sporothrix schenckii.

BACKGROUND: Sertraline (SRT) is an antidepressant that has proven its activity in vitro against Cryptococcus, Coccidioides, Trichosporon and other fungi. Disseminated sporotrichosis, although rare, has a high mortality and its treatment is difficult and prolonged, often relying in combining two or more antifungals. AIMS: In our study we evaluate the antifungal activity of SRT, alone and in combination with itraconazole (ITC), voriconazole (VRC) and amphotericin B (AMB), against 15 clinical isolates of Sporothrix schenckii. METHODS: We used the broth microdilution method as described by the CLSI to test the susceptibility to antifungals, and the checkerboard microdilution method to evaluate drug interactions. RESULTS: The minimum inhibitory concentration (MIC) with SRT was in the range of 4-8µg/ml, while for AMB, VRC and ITC were 0.5-4µg/ml, 0.5-8µg/ml and 0.125-2µg/ml, respectively. In addition, SRT showed synergy with ITC in one strain, mainly additivity with VRC, and indifference with AMB in others. CONCLUSIONS: The MIC values with SRT for the isolates studied show the potential role of this drug as an adjuvant in the treatment of sporotrichosis, especially in disseminated or complicated cases.

Curso clínico de micosis producidas por Exophiala xenobiotica en paciente trasplantado renal en el Hospital Universitario de Burgos / Clinical course of micosis produced by exophiala xenobiotica in renal transplanted patient at the University Hospital of Burgos

Resumen Las micosis por Exophiala xenobiotica comprenden un amplio espectro clínico en pacientes inmunosuprimidos, desde infecciones localizadas, hasta diseminadas. Son incluidas como etiología de las feohifomicosis, actualmente consideradas como infecciones fúngicas emergentes en pacientes trasplantados de órgano sólido. Presentamos 2 casos de micosis por Eexophiala xenobiotica en paciente trasplantado renal, una micosis cutánea localizada y una infección sistémica con afectación del sistema nervioso central.

Abstract Mycosis by exophiala xenobiotica comprise a broad clinical spectrum in immunosuppressed patients, from localized to disseminated infections. They are a recognized etiology of phaeohyphomycosis, currently considered as emerging fungal infections in transplanted solid organ recipients. We present 2 cases of mycosis by exophiala xenobiotica in kidney transplant recipients, a localized cutaneous mycosis and a systemic infection with central nervous system involvement.

Chemical and cytotoxic analyses of three varieties of Brazilian propolis (green propolis, jataí propolis and brown propolis) and its anti-Sporothrix brasiliensis in vitro activity / [Análises químicas e citotóxicas de três variedades de própolis brasileiras (própolis verde, própolis jataí e própolis marrom) e sua atividade in vitro anti-Sporothrix brasiliensis]

In this study, we described the antifungal activity of three Brazilian propolis extracts: brown, green and from jataí bees against Sporothrix brasiliensis. The extracts were obtained from ethanolic extraction and their chemical composition was determined by high-performance liquid chromatography coupled to mass spectrometry. The cellular toxicity was measured in MDBK (Madin-Darby Bovine Kidney) cells and quantified by the MTT assay (3- (4,5 dimethylthiazol-2yl -2,5-diphenyl-2H bromine tetrazolato). For antifungal activity, the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were determined by broth microdilution. The results showed that cell toxicity was not observed at lower concentrations (0.097 to 0.39μg/ml) for all extracts in comparison to cell control. Among the chemical compounds identified, caffeic acid, p-coumaric acid, chlorogenic acid, ferulic acid and rutin were quantified. In antifungal activity, green and jataí did not exhibit activity against the isolates (MIC and MFC greater than 0.78mg/ml). However, all isolates of S. brasiliensis were sensitive to brown propolis (MIC of 0.09 to 0.78mg/ml), including the standard strain (P<0.001). Among the Brazilian propolis studied, the brown propolis showed activity against the S. brasiliensis isolates and more studies should be undertaken in order to evaluate its promising use in the treatment of sporotrichosis.(AU)

Neste estudo, descreveu-se a atividade antifúngica de três extratos de própolis brasileiras: marrom, verde e de abelhas jataí (Tetragonisca angustula), contra Sporothrix brasiliensis. Os extratos foram obtidos de extração etanólica, e a sua composição química foi determinada por cromatografia líquida de alta eficiência, acoplada à espectrometria de massa. A toxicidade celular foi medida em células MDBK (Madin-Darby Bovine Kidney), avaliada por observação microscópica e quantificada pelo ensaio MTT (3- (4,5-dimetiltiazol-2-ilo -2,5-difenil-2H bromo tetrazolato). Para a atividade antifúngica, determinou-se a concentração inibitória mínima (CIM) e a concentração fungicida mínima (CFM) por meio de microdiluição em caldo. Os resultados mostraram que a toxicidade celular não foi observada em concentrações menores (0,097 a 0,39μg/ml). Entre os compostos químicos identificados, foram quantificados o ácido cafeico, ácido p-cumárico, ácido clorogênico, ácido ferúlico e a rutina. Na atividade antifúngica, as própolis verde e jataí não apresentaram atividade contra os isolados (CIM e CFM maior que 0,78mg/ml), porém todos os isolados de S. brasiliensis foram sensíveis à própolis marrom (CIM de 0,09 a 0,78mg/ml), incluindo a cepa padrão (P<0,001). Entre as própolis brasileiras estudadas, a marrom mostrou atividade contra S. brasiliensis, e mais estudos devem ser realizados para avaliar seu uso promissor no tratamento da esporotricose.(AU)

Multi-azole-resistant strain of Malassezia pachydermatis isolated from a canine Malassezia dermatitis.

In the case presented here, we describe the isolation of an azole-resistant strain of M. pachydermatis from a canine Malassezia dermatitis. The isolate (NUBS18001) from this case exhibited a minimum inhibitory concentration (MIC) of 320 µg/ml to itraconazole (ITZ) by broth microdilution (BM) assay, >32 µg/ml to ITZ by E-test, and >32 µg/ml to KTZ by E-test. Synergistic effects between FK506 and ITZ in the azole-resistant strain was evaluated using the microdilution checker-board method. The ITZ-resistant strain exhibited MICs of 320 µg/mL of ITZ alone and 5 µg/ml of FK506 alone; the addition of FK506 attenuated the ITZ MIC to 2.5 µg/ml, yielding an ITZ FICI value of 0.507. This result suggested that the combination of ITZ and FK506 exerted an additive effect against the ITZ-resistant strain. To understand the other mechanism inferred to be present in our multi-azole-resistant strain, we sequenced the ERG11 gene from this isolate, and detected missense mutations (A412G and C905T) in the sequence of the ERG11 open reading frame (ORF). To the best of our knowledge, this work is the first report that a multi-azole-resistant M. pacydermatis strain contains mutations in ERG11.

O fator de crescimento dos vasos (VEGF) como mediador neuroprotetor na quebra da barreira hematoencefálica no envenenamento pela aranha "Phoneutria nigriventer" em ratos: análise das vias de sinalização e da neuroquímica cerebral por espectroscopia no infravermelho com transformada de Fourier / Vascular endothelial growth factor (VEGF) as a neuroprotector mediator in the blood-brain barrier breakdown caused by "Phoneutria nigriventer" spider envenomation in rats: analysis of signaling pathways and cerebral neurochemistry by Fourier transform infrared spectroscopy

Resumo: O veneno da aranha Phoneutria nigriventer (PNV) contém neuropeptídeos que afetam canais iônicos e a neurotransmissão, induzindo a quebra da barreira hematoencefálica (BHE) no hipocampo de ratos, o que ocorre paralelamente ao aumento do fator de crescimento endotelial vascular (VEGF). Sabe-se que a resposta biológica do VEGF é desencadeada através da regulação transcricional promovida pelo domínio tirosina-quinase de receptores transmembranares do VEGF, dos quais o VEGFR-2 (Flk-1) é considerado o principal mediador e ativador de várias vias de sinalização. O trabalho propõe investigar o possível papel neuroprotetor do VEGF após inibir sua ligação ao receptor Flk-1 pelo itraconazol (ITZ). Para isso, examinamos o status bioquímico do hipocampo por espectroscopia no Infravermelho com Transformada de Fourier (FT-IR), bem como avaliamos as proteínas envolvidas nas rotas paracelular e transcelular da BHE e quais vias de sinalização, relacionadas à neuroproteção do VEGF, foram ativadas. Os ratos receberam PNV ou foram pré-tratados com ITZ (30 min) seguido de PNV pela veia da cauda e depois sacrificados em 1 e 2 h (intervalos com maiores sinais de intoxicação), 5 h (intervalo com sinais incipientes de recuperação) e 24 h (intervalo sem sinal visual detectável de envenenamento), sendo comparados aos controles, salina e ITZ. O pré-tratamento com o antifúngico agravou os efeitos do veneno e aumentou danos à BHE. Os espectros FT-IR do veneno, hipocampo dos controles, PNV e ITZ-PNV mostraram as bandas de 1400 cm-1 (carboxilato) e de 1467 cm-1 (flexão de CH2: principalmente lipídios), que foram considerados bandas biomarcadora e referência, respectivamente. A inibição da ligação VEGF/Flk-1 produziu mudanças marcantes na estabilidade lipídios/proteínas em 1-2 h. As maiores diferenças ocorreram nas regiões espectrais atribuídas à lípides simétricos (2852 cm-1) e assimétricos (2924 e 2968 cm-1). As análises quantitativas mostraram maiores aumentos na razão 1400 cm-1/1467 cm-1 no período de intoxicação grave (1 h), e referem-se à região espectral de 3106 cm-1 a 687 cm-1. Ademais, a desativação da ligação VEGF/Flk-1 pelo itraconazol (ITZ) aumentou o fator indutor de hipóxia (H1F1-?), VEGF, Flk-1, Flt-1, Neu-N e caspase-3 às 5 horas após a injeção do PNV. No mesmo intervalo, a permeabilidade transcelular da BHE aumentou (caveolina-1?, dinamina-2 e família Src de não receptores tirosina-quinase (SKFs)), enquanto laminina e a via paracelular (occludina, ?-catenina) foram reforçadas e a proteína de efluxo glicoproteína-P (P-gp) aumentou. Ao mesmo tempo (5 h), ocorreu auto-fosforilação da via pró-proliferação celular (p38-fosforilada). Às 24 h, apesar da ausência de sinais de intoxicação, a via pró-sobrevivência celular (Akt-fosforilada) diminuiu nos animais pré-tratados com ITZ, enquanto aumentou nos tratados com PNV apenas. Os dados indicam ativação de mecanismos de neuroproteção relacionados ao VEGF envolvendo o receptor Flk-1 e principalmente à serina-treonina-quinase Akt, provavelmente via PI3K. ERK-fosforilada (2 h) e p38-fosforilada (5 h) sugerem interação entre as vias de sinalização com o objetivo de restabelecer a homeostase do hipocampo. O intervalo de 5 h parece ser o ponto de virada orquestrando respostas biológicas variadas. Os dados permitem concluir sobre o papel neuroprotetor do VEGF e que o mesmo pode ser explorado como possível alvo terapêutico no envenenamento por P. nigriventer.(AU)

Abstract: Phoneutria nigriventer spider venom (PNV) contains ion channels-acting neuropeptides that affect neurotransmission and induces transitory blood-brain barrier (BBB) breakdown in rat¿s hippocampus, which run in parallel with (vascular endothelial growth factor) VEGF upregulation. It is known that VEGF biological response is triggered through transcriptional regulation promoted by transmembrane tyrosine kinase receptors, being VEGFR-2 (Flk-1) considered the major mediator of VEGF effect through activation of a number of signaling pathways. The purpose of this work is to investigate a putative neuroprotective role of VEGF by inhibiting its binding to receptor Flk-1 by itraconazole (ITZ). To do this, we examined the biochemical status of the hippocampus by Infrared Spectroscopy and Fourier Transform (FT-IR), as well as evaluated the proteins involved in the BBB paracellular and transcellular routes and which signaling pathways related to VEGF neuroprotection were activated. Rats were administered PNV alone or were pre-treated with ITZ (30 min) followed by PNV through the tail vein, and then euthanized at 1 and 2 h (intervals with greatest signs of intoxication), 5 h (interval with incipient signs of animals¿ recovery) and 24 h (interval with no visually detectable envenomation sign) and compared to saline and ITZ controls. The antifungal pre-treatment aggravated PNV toxic effects and increased BBB damage. FT-IR spectra of venom and from hippocampi of controls, PNV and ITZ-PNV showed a 1400 cm-1 band linked to symmetric stretch of carboxylate and 1467 cm-1 band (CH2 bending: mainly lipids), which were considered biomarker and reference bands, respectively. Inhibition of VEGF/Flk-1 binding produced marked changes in lipid/protein stability at 1-2 h. The largest differences were observed in spectra regions assigned to lipids, both symmetric (2852 cm-1) and asymmetric (2924 and 2968 cm-1). Quantitative analyses showed greatest increases in the 1400 cm-1/1467 cm-1 ratio also at 1 h. Such changes at period of rats¿ severe intoxication referred to wavenumber region from 3106 cm-1 to 687 cm-1. Furthermore, the deactivation of Flk-1 receptor by VEGF through itraconazole (ITZ) showed increased hypoxia inducible factor (H1F-1?), VEGF, Flk-1, Flt-1, Neu-N and caspase-3 at 5 h after PNV injection. At same interval, BBB transcellular permeability increased (caveolin-1?, dynamin-2 and Src family of non-receptor tyrosine kinases (SKFs)), while laminin and paracellular route (occludin, ?-catenin) were reinforced and P-glycoprotein (P-gp) efflux protein was increased. Such effects were timely followed by upregulation of auto-phosphorylation of the pro-proliferation (phosphorylated-p38) pathway. At 24 h, despite absence of intoxication signs, the pro-survival (p-Akt) pathway was downregulated in animals underwent inhibition of VEGF-Flk-1 binding, whereas it was upregulated in PNV rats non-treated with ITZ. The data indicate triggering of VEGF-related mechanisms involving Flk-1 receptor and serine-threonine kinase Akt, probably via PI3K, as the main mechanism of neuroprotection. Phosphorylated ERK (2 h) and p-p38 (5 h) indicates interplay among transduction pathways likely aiming at re-establishment of hippocampal homeostasis. The findings suggest 5 h interval as the turning point that orchestrates varied biological responses. Taking together the data of the present study allow concluding that VEGF expression exerts neuroprotective role and can be explored as a possible therapeutic target in P. nigriventer envenomation.(AU)

Mucocutaneous Manifestations of Infection by Histoplasma capsulatum in HIV-Negative Immunosuppressed Patients. / Manifestaciones mucocutáneas de la infección por Histoplasma capsulatum en pacientes inmunosuprimidos.

Histoplasmosis is a systemic mycosis caused by the dimorphous fungus Histoplasma capsulatum (H. capsulatum). The fungus enters the body through the respiratory tract in the form of microconidia, which are transformed into intracellular yeast-like structures in the lungs before disseminating hematogenously. Primary infection is usually asymptomatic and self-resolving. Some patients develop severe disease with acute or chronic respiratory involvement. Immunosuppressed patients, mainly those with altered cellular immunity, may have disseminated disease with variable mucocutaneous involvement characterized by papules, nodules, gummas, or ulcers with a granulomatous base. We report the case of 3 HIV-negative patients infected by H capsulatum in whom diagnosis based on the skin lesions proved essential for early initiation of treatment.

Esporotricosis del pabellón auricular: comunicación de un caso atípico simulando una celulitis bacteriana / Auricular sporotrichosis: atypical case report simulating bacterial cellulitis

Resumen La esporotricosis es la micosis subcutánea o por implantación más frecuente en México. Se comunica el caso de una esporotricosis cutánea-fija preauricular que simuló una celulitis bacteriana atípica, en una paciente anciana sin antecedente de traumatismo. La biopsia mostró un granuloma supurativo con presencia de levaduras escasas. En el cultivo se identificó Sporothrix schenckii que se confirmó por biología molecular. Se trató con itraconazol obteniéndose una curación clínica y micológica. Se presenta el caso de presentación atípica, proveniente de una zona semidesértica con clima extremo.

Sporotrichosis is the most common subcutaneous or implantation mycosis in Mexico. The case of a preauricular cutaneous-fixed sporotrichosis simulating atypical bacterial cellulitis is reported in an elderly patient with no history of trauma. The biopsy showed a suppurative granuloma with scarce yeast. Sporothrix schenckii was identified in the culture and confirmed by molecular biology. She was treated with itraconazole and a clinical and mycological cure was obtained. The case of atypical presentation is presented, coming from a semi-arid zone with extreme weather.

Sensibilidad in vitro de cepas cubanas de Aspergillus spp. de origen clínico y ambiental / In vitro susceptibility of Cuban Aspergillus spp. strains of clinical and environmental origin

Introducción. En Cuba se desconoce el comportamiento de la sensibilidad de Aspergillus spp. a los antifúngicos recomendados para el tratamiento de la aspergilosis: la anfotericina B, el itraconazol, el voriconazol y las equinocandinas. La influencia del ambiente puede condicionar la aparición de resistencia en estos microorganismos. Objetivo. Evaluar la sensibilidad in vitro de cepas de Aspergillus spp. a la anfotericina B, el itraconazol y el voriconazol, y la relación de los patrones de sensibilidad con su origen. Materiales y métodos. Se determinaron las concentraciones inhibitorias mínimas de la anfotericina B, el itraconazol y el voriconazol para 60 cepas de Aspergillus spp. de origen clínico y ambiental mediante el método M38-A2 del Clinical and Laboratory Standard Institute. Resultados. Se encontraron 21 cepas resistentes a la anfotericina B (principalmente en muestras clínicas y ambientes hospitalarios) y tres cepas resistentes al itraconazol (en ambientes interiores y exteriores no hospitalarios). No se hallaron cepas resistentes al voriconazol. No se encontró relación entre el origen de las cepas y su sensibilidad. Conclusiones. Se sugiere la posible existencia de factores ambientales o interacciones con genotipos resistentes que pueden dar origen a fenotipos resistentes en Cuba. Este es el primer reporte del país de cepas de Aspergillus spp. resistentes in vitro. Los resultados ameritan ampliar el estudio para incluir análisis moleculares y filogenéticos.

Introduction: The behavior of antifungal susceptibility of Aspergillus spp. in Cuba remains unknown. The antifungals recommended to treat aspergillosis are amphotericin B, itraconazole, voriconazole and echinocandins. The influence of the environment may set off the emergence of drug-resistance in these microorganisms. Objective: To evaluate in vitro susceptibility of Aspergillus spp. strains to amphotericin B, itraconazole and voriconazol, and the relationship between susceptibility patterns and their origin. Materials and methods: Minimum inhibitory concentrations of amphotericin B, itraconazole and voriconazole were determined for 60 Aspergillus spp. strains of clinical and environmental origin using the M38-A2 method of the Clinical and Laboratory Standards Institute. Results: We found 21 amphotericin B resistant strains (mainly from clinical samples and hospital environments), as well as three itraconazole resistant strains (from non-hospital outdoor and indoor environments). No voriconazole resistance was found. No relationship was found between strain origin and susceptibility. Conclusions: Results suggest the possible existence of environmental factors or interactions with resistant genotypes which may give rise to resistant phenotypes in our country. This is the first report of in vitro Aspergillus spp. resistant strains in Cuba. These studies should be broadened and include molecular and phylogenetic analyses.

Coccidiodomicosis cutánea: Imagen clínica / Cutaneous coccidiodomycosis: Clinical image

La coccidiodomicosis es una infrecuente micosis sistémica, producida por los hongos dimorfos del género Coccidiodes, immitis y posadasii, cuyos artroconidios generalmente infectan al ser humano, por vía respiratoria. Gracias al adecuado funcionamiento del sistema inmune celular, la mayoría de las infecciones son autolimitadas. En casos de inmunodeficiencia pueden presentarse formas diseminadas y graves, de curso progresivo, que ponen en riesgo la vida del paciente afectado. El diagnóstico se fundamenta en los hallazgos clínicos, la observación y el cultivo de diferentes muestras tisulares, mediante análisis micológico y anátomo-patológico. De ayuda particular representan las pruebas serológicas al demostrar anticuerpos específicos, tales como: la inmunodifusión en gel de agar y la fijación de complemento si están disponibles. El tratamiento con azólicos sistémicos han demostrado ser eficaces; de igual forma la anfotericina-B en administración intravenosa con sus conocidos efectos nefrotóxicos, se indica especialmente en pacientes graves.

Coccidiodomycosis is an uncommon systemic mycosis caused by the dimorphic fungi of the genus Coccidiodes, immitis and posadasii, whose arthroconidia generally infects humans via the respiratory system. Thanks to the proper functioning of the cellular immune system, most infections are self-limiting; in cases of immunodeficiency there may be disseminated and serious progressive forms that endanger the life of the affected patient. The diagnosis is based on the clinical findings, the observation and culture of different tissue samples through mycological and anatomopathological analysis; of particular help represent serological tests by demonstrating specific antibodies, such as: agar gel immunodiffusion and complement fixation, if available. Treatment with systemicazoles have been shown to be effective; similarly, amphotericin-B in intravenous administration with its known nephrotoxic effects is indicated especially in severe patients.

Cromomicosis: casuística del Servicio de Dermatología del Hospital Nacional, periodo 1991- 2015

RESUMEN Introducción: la cromomicosis es una micosis profunda provocada por la inoculación traumática percutánea, de hongos dematiáceos que habitan el suelo y restos vegetales. Es una micosis de difícil manejo, con importante morbilidad, que afecta una población generalmente de precarias condiciones socioeconómicas, en una etapa productiva de la vida. Objetivos: determinar la frecuencia y características clínicas de la cromomicosis en el Servicio de Dermatología del Hospital Nacional (Itauguá, Paraguay) en el periodo de 24 años (1991- 2015). Metodología: estudio observacional descriptivo de 25 casos de cromomicosis con confirmación micológica y/o anatomopatológica. Resultados: la micosis fue más frecuente en varones adultos, procedentes de áreas rurales, dedicados a labores agrícolas. Predominaron las lesiones ubicadas en miembros inferiores. El agente causal más frecuente fue el Fonsecae sp. El itraconazol fue el tratamiento más utilizado. Conclusiones: la cromomicosis afectó de preferencia a varones adultos del área rural, aislándose con mayor frecuencia Fonsecae sp.

ABSTRACT Introduction: Chromomycosis is a deep mycosis caused by the percutaneous traumatic inoculation of dematiaceous fungi that inhabit soil and vegetal debris. It is a mycosis of difficult management, with important morbidity, that affects a population generally of precarious socio-economic conditions in a productive stage of life. Objectives: To determine the frequency and clinical characteristics of chromomycosis in the Dermatology Service of the National Hospital (Itauguá, Paraguay) over a 24-year period (1991- 2015). Methodology: Observational descriptive study of 25 cases of chromomycosis with mycological and/or anatomopathological confirmation. Results: Mycosis was more frequent in adult men from rural areas, engaged in agricultural work. Lesions in lower limbs prevailed. The most frequent causative agent was Fonsecae sp. Itraconazole was the most commonly used treatment. Conclusions: Chromomycosis affected preferentially adult men from rural areas, and Fonsecae sp. was the most frequently isolated fungus.

Exfoliative erythroderma and palmoplantar hyperkeratosis associated with Majocchi's granuloma by Trichophyton tonsurans in a patient with AIDS.

BACKGROUND: Dermatophytoses are skin superficial mycoses in which clinical manifestations are directly related to the virulence of the infecting microorganism or the host immunity. CASE REPORT: We describe a severe case of dermatophytosis associated with exfoliative erythroderma, substantial palmoplantar keratoderma, onychodystrophy affecting all nails, diffuse non-scarring alopecia and tissue fungal invasion by Trichophyton tonsurans, which led us to the diagnosis of AIDS. Direct examination and culture for fungi from skin scraping from two different sites were performed. Biopsy and histopathological exam were also performed on three different sites. Direct examination of the lesions' scraping revealed septate hyaline hyphae and arthroconidia, identified as Trichophyton tonsurans by culture in glucose Sabouraud agar and Mycosel agar. A scalp biopsy revealed follicular fungal invasion and Majocchi's granuloma. Due to the severity of the presentation we requested an anti-HIV serology, which was positive. The patient was treated with itraconazole, 200mg/day, for 120 days, which promoted a complete regression of the lesions. CONCLUSIONS: Severe and atypical forms of dermatophytosis could lead to a diagnosis of AIDS.

[Efficacy of the treatment and secondary antifungal prophylaxis in AIDS-related histoplasmosis. Experience at the Francisco J. Muñiz Infectious Diseases Hospital in Buenos Aires]. / Eficacia del tratamiento y de la profilaxis antifúngica secundaria en la histoplasmosis asociada al sida. Experiencia del Hospital de Infecciosas Francisco J. Muñiz, de la ciudad de Buenos Aires.

BACKGROUND: Classic histoplasmosis is a systemic endemic mycosis due to Histoplasma capsulatum var. capsulatum. A significant reduction in the morbidity and mortality of AIDS-related histoplasmosis has been observed since the introduction of highly active antiretroviral therapy (HAART) and secondary antifungal prophylaxis. AIMS: The aim of this study was to determine the current state of prognosis and treatment response of HIV-positive patients with histoplasmosis in the Francisco J. Muñiz Infectious Diseases Hospital in Buenos Aires City. METHODS: A retrospective study was conducted using the demographic, clinical, immunological and treatment data of 80 patients suffering from AIDS-related histoplasmosis. RESULTS: Of the 80 cases studied 65 were male, the median age was 36 years, with 73.7% of the patients being drug addicts, 82.5% of the patients was not receiving HAART at diagnosis, and 58.7% of the cases had less than 50 CD4+ cells/µl at the beginning of the treatment. The initial phase of treatment consisted of intravenous amphotericin B and/or oral itraconazole for 3 months, with 78.7% of the cases showing a good clinical response. Only 26/63 patients who were discharged from hospital continued with the follow-up of the HAART, secondary prophylaxis with itraconazole or amphotericin B. Secondary prophylaxis was stopped after more than one year of HAART if the patients were asymptomatic, had two CD4+ cell counts greater than 150cells/µl, and undetectable viral loads. No relapses were observed during a two-year follow up after prophylaxis was stopped. CONCLUSIONS: The treatment of histoplasmosis in HIV-positive patients was effective in 78.8% of the cases. The combination of HAART and secondary antifungal prophylaxis is safe, well tolerated, and effective. The low adherence of patients to HAART and the lack of laboratory kits for rapid histoplasmosis diagnosis should be addressed in the future. The usefulness of primary antifungal prophylaxis for cryptococcosis and histoplasmosis HIV-positive patients should be studied.