Espina de pescado alojada en la glándula tiroides / Fishbone lodged in the thyroid gland

Los cuerpos extraños alojados en la vía aéreodigestiva superior son un motivo de consulta frecuente para el otorrinolaringólogo. Uno de los más frecuentes son las espinas de pescado. En raras ocasiones, éstas migran hacia tejidos adyacentes y generan complicaciones importantes. Presentamos el caso de una paciente que tras la ingesta de pescado manifiesta sensación de cuerpo extraño faríngeo, odinofagia y dolor látero cervical derecho. Dada la ausencia de hallazgos a la exploración física y laringoscópica se realiza una tomografia computarizada cervical, visualizando un cuerpo extraño alojado en la glándula tiroidea. Se interviene mediante cervicotomía media, realizando la extracción de la espina sin complicaciones. El diagnóstico precoz y manejo adecuado es determinante para prevenir complicaciones en estos casos.

Foreign bodies in the aerodigestive tract are commonly confronted in otolaryngology practice. The most frequent are the fish bones. In rare cases they can move and cause numerous complications. We report the case of a patient that manifest the sensation of pharyngeal foreign body, after fish ingestion. She also referred odynophagia and right cervical pain. Physical and laryngoscopic examination were normal. A cervical CT was performed, where a foreign body lodged in the thyroid gland was visualized, median cervicotomy was done and the foreign body was extracted. Early diagnosis and adequate management are crucial to prevent complications in these cases.

GC-MS Metabolite Profile and Identification of Unusual Homologous Cannabinoids in High Potency Cannabis sativa.

Phytochemical investigation of the lipids extracted from seeds of Cannabis sativa by GC-MS showed 43 cannabinoids, 16 of which are new. The extract is dominated by Δ9-tetrahydrocannabinolic acid (A) and its neutral derivative trans-Δ9-tetrahydrocannabinol-C5 (THC) Cis and trans-Δ9-tetrahydrocannabinol-C7 isomers with an ethyl-pentyl branched chain together with minor amounts of trans-Δ9-tetrahydrocannabinol with a methyl-pentyl C6 branched side chain were identified as new natural compounds. Four cannabichromene isomers with a C5 side chain are postulated to be derived from the double bond migration at the terminal isoprenyl unit. C7 cannabichromene together with the neutral and acidic forms of cannabinol-C7 were also detected. The mass spectrum of these homologues as trimethylsilyl (TMS) derivatives are presented, and the fragmentation patterns are discussed.

Osteosarcomas de la región de cabeza y cuello / Osteosarcoma of the head and neck area: analysis of 12 patients

Background: Less than 10 percent of osteosarcomas are located the head and neck region, mainly affecting the mandible and maxillary region. Aim: To analyze the therapeutic modality, types of reconstruction, surgical complications and survival of patients treated for osteosarcoma of the head and neck. Material and Methods: Review of medical records of 12 patients aged 17 to 34 years (6 women) treated for osteosarcoma of the head and neck between September 1998 and may 2009. Results: The localization of the tumor was maxillary in eight, mandibular three and ethmoidal in one patient. According to histologic grade, seven tumors were grade 1, four were grade 2 and one was grade 3. Adjuvant and neoadjuvant chemotherapy were administered to all and seven patients, respectively. The surgical treatment for maxillary tumors was maxillectomy. A reconstruction with rectum abdomini free flap was done in four patients and with dermoepidermic graft and an obturator prosthesis in three. In one patient, the defect was covered with a dental prosthesis. Treatment for mandibular tumors was mandibular excision. A reconstruction with peroneal free flap was performed in two patients and with an iliac crest graft in one. The ethmoidal tumor was resected and covered with local flaps. There were four complications. Two patients had a cutaneous fistula, one patient had a free flap partial atrophy and one patient had surgical site infection. Two patients who had positive margins died from local recurrence. Of the 10 patients with negative margins, seven are alive without recurrence, one died due to the disease, one has disseminated disease and one died from another cause. Conclusions: Our results in the treatment of head and neck osteosarcomas are consistent with published data.

Objetivos: Analizar la modalidad terapéutica, tipos de reconstrucción, complicaciones quirúrgicas y sobrevida de un grupo de pacientes tratados por esta patología. Métodos: Revisión de fichas clínicas de 12 pacientes portadores de osteosarcoma de cabeza y cuello entre septiembre de 1998 y mayo de 2009. Resultados: Edad promedio 30 años (17-34), 6 mujeres y 6 hombres. Localización fue 8 maxilar, 3 mandibular y 1 etmoidales. 7 tumores G1, 4 G2 y 1 G3. Siete pacientes recibieron quimioterapia neoadyuvante y todos adyuvante. El tratamiento de tumores maxilares fueron maxilectomías reconstruidas 4 con colgajo libre de recto abdominal, 3 con injerto dermoepidérmico más prótesis obturadora y una con prótesis dentaria. Se realizó mandibulectomía a los tumores mandibulares, 2 reconstruidos con colgajo libre de peroné y uno con injerto de cresta ilíaca. El tratamiento del tumor etmoidal fue resección craneofacial y se reparó con colgajos locales. Hubo 4 complicaciones; 2 fístulas cutáneas, una atrofia parcial de colgajo libre y una infección de herida operatoria. Dos pacientes tuvieron bordes comprometidos, quienes murieron por recidiva local. De los 10 pacientes con bordes libres, 7 se encuentran sin evidencia de recidiva, uno con enfermedad diseminada, uno fallecido por la enfermedad y uno fallecido por otra causa. Conclusiones: Nuestros resultados son consistentes con la literatura.

Contractura axilar por quemadura tratada con Integra® / Axillary burn contracture treated with Integra®

Introduction: Severe axillary burn is an unusual accident that frequently evolves to contracture generating important cosmetic and functional deficiencies. Contracture scars in this region are difficult to treat because of the anatomic characteristics of the area that has multiple power vectors. Functional restoration has to be one of the main goals in the management of burns in the axilla and flaps have shown high rate of morbidity. Integra® provides satisfactory elasticity and dermal resistance which results in positive functional results. Objective: Analyze the results of the use of Integra® in axillary burn contracture scars at a specialized Burns Center. Materials and Methods: There were 4 patients who underwent reconstructive surgery using Integra® for axillary burn contractures between January 2002 and March 2006. Follow-up was divided into perioperative and late. Early follow-up checked general post-operative evolution and late follow-up was focused on functionality and patient independence evaluated using Barthel's index of daily living activities. Results: There were 3 males and 1 female, average age 27 (18-41) with a minimum follow up of 9 months. There were no perioperative complications and good or very good range of motion results. Conclusions: Our results are similar to artificial skin substitutes used in other anatomical regions.

Las quemaduras axilares severas son un accidente infrecuente que evolucionan a la retracción generando deficiencias cosméticas y funcionales. Estas cicatrices son difíciles de tratar por las características anatómicas del área, donde la corrección de un vector de movimiento puede alterar otro. Objetivo: Mostrar nuestros resultados utilizando el sustituto cutáneo Integra® en el tratamiento de cicatrices retráctiles axilares por quemadura. Pacientes y Métodos: Se recolectaron antecedentes médicos y fotográficos de pacientes portadores de cicatrices retráctiles axilares por quemadura entre enero de 2002 y marzo de 2006 en el Hospital del Trabajador de Santiago. Se evaluó pre y postoperatoriamente a los pacientes en forma subjetiva por fisiatra y con el Test de Barthel. Resultados: Se incluyeron 4 pacientes en el estudio (3 mujeres y 1 hombre), edad media 27 años (18-41). Todas las quemaduras fueron producidas por fuego. Índice de Barthel preoperatorio fue de 87,5 (levemente dependiente para las actividades de la vida diaria) y rango de movimiento moderadamente afectado. En el postoperatorio los pacientes fueron catalogados como independientes según el Test de Barthel y el rango de movimiento fue descrito como bueno o muy bueno por el fisiatra. No hubo complicaciones peri operatorias, Integra® prendió adecuadamente en todos los casos. Los pacientes fueron seguidos en promedio 16 meses (9-22). Conclusiones: Los sustitutos dérmicos han sido usados para la corrección de cicatrices de quemaduras con buenos resultados, pero no hay reportes en la axila. El pequeño número de pacientes que presentamos tienen un excelente resultado funcional, lo que nos estimula a seguir trabajando en este rumbo.

Tracheal chondrosarcoma--a rare complication in Maffucci syndrome.

Maffucci syndrome is a rare congenital non-hereditary disease characterised by subcutaneous haemangiomata and multiple enchondromata. We present a case of an intermediate grade myxoid chondrosarcoma of the tracheal cartilage in a 34-year-old man with a history of Maffucci syndrome. Chondrosarcoma of the trachea are extremely rare tumours. A review of the radiological literature reveals approximately 15 previously published cases. No case was found with a history of Maffucci syndrome.

Colgajo miocutáneo de gastrocnemius medial con isla triangular de piel y cierre en V-Y / Gastrocnemius muscle myocutaneous flap with a triangular skin isle and V-Y closure: report of five patients

A gastrocnemius muscle myocutaneous flap with a triangular skin isle and V-Y closure can be used to correct cutaneous defects with exposure of the proximal part of the tibia. The advantages of this technique are an excellent irrigation and the cutaneous closure using a flap in a zone that is exposed to multiple trauma. The presence of a arteriovenous perforating vessel previously located with color Doppler, ensures the vitality of the flap. We report five males patients aged 20 to 70 years, in whom this technique as used to correct traumatic defects of a mean diameter of 11 cm. All flaps remained viable.

Para corregir defectos cutáneos con exposición de fractura de tibia a nivel del tercio proximal, una buena alternativa es el colgajo miocutáneo de gastrocnemius medial con isla triangular de piel con cierre en V-Y. Las ventajas estriban en la excelente irrigación del colgajo, y en proporcionar un cierre cutáneo con colgajo, en una zona expuesta a múltiples traumatismos. El hecho de tener una perforante arterio venosa previamente ubicada con doppler color, asegura la vitalidad del colgajo. Se presenta la experiencia del Servicio de Cirugía Plástica del Hospital del Trabajador de Santiago consistente en 5 pacientes masculinos en los que se realiza un colgajo de perforante de gastrocnemius medial, con edad entre 20 y 70 años. La etiología del defecto fue traumática. El defecto a corregir fue en promedio de 11 cms de diámetro. Todos los colgajos fueron viables. Se destaca que este es un colgajo inédito, descrito por primera vez por el autor principal en el año 2006.

Fresh osteochondral allografts for posttraumatic knee defects: long-term followup.

Fresh osteochondral allograft transplantation has been an effective treatment option with promising long-term clinical outcomes for focal posttraumatic defects in the knee for young, active individuals. We examined histologic features of 35 fresh osteochondral allograft specimens retrieved at the time of subsequent graft revision, osteotomy, or TKA. Graft survival time ranged from 1 to 25 years based on their time to reoperation. Histologic features of early graft failures were lack of chondrocyte viability and loss of matrix cationic staining. Histologic features of late graft failures were fracture through the graft, active and incomplete remodeling of the graft bone by the host bone, and resorption of the graft tissue by synovial inflammatory activity at graft edges. Histologic features associated with long-term allograft survival included viable chondrocytes, functional preservation of matrix, and complete replacement of the graft bone with the host bone. Given chondrocyte viability, long-term allograft survival depends on graft stability by rigid fixation of host bone to graft bone. With the stable osseous graft base, the hyaline cartilage portion of the allograft can survive and function for 25 years or more.

Removal of PAHs from water using an immature coal (leonardite).

It has been studied an immature coal (leonardite) as an adsorbent for removing PAHs [fluorene, pyrene, benzo(k)fluoranthene, benzo(a)pyrene and benzo(g,h,i)perylene] from water. To determine the efficiency of leonardite as an adsorbent of PAHs, factors such as pH, contact time and equilibrium sorption were evaluated in a series of batch experiments. There were no significant differences in the removal percentages for the various pH values studied, except for fluorene. The adsorption of fluorene was higher at lower pH values. The equilibrium time was reached at 24h. At this time, more than 82% of the pyrene, benzo(k)fluoranthene, benzo(a)pyrene and benzo(g,h,i)perylene had been removed. During the first 2h, the adsorption rate increased rapidly. After that time, however, there was a minor decrease. Equilibrium data were fitted to Freundlich models to determine the water-leonardite partitioning coefficient. Physical adsorption caused by the aromatic nature of the compounds was the main mechanism that governed the removal process. The polarity of the humic substances in leonardite may also have influenced the adsorption capacity.

Distribution of polycyclic aromatic hydrocarbons in riverine waters after Mediterranean forest fires.

Extensive forest fires occurred in Catalonia, northern Spain, in 1994. In our study, concentrations and profiles of 12 parent polycyclic aromatic hydrocarbons (PAHs) were determined in riverine waters, ash and sediment samples at nine sampling sites (W1-W9) and at three sampling dates from Llobregat hydrographic basin: in August, 1994, one month after the extensive forest fires; in September, 1994, after the first heavy autumn rainfalls and in January, 1995, six months after forest fires. In August 1994, the total concentrations of 12 PAHs measured in riverine waters varied from 2 ng/l to 336 ng/l. In September 1994, the total PAH concentrations decreased to 0.2-31 ng/l and in January 1995, from 9 ng/l to 73 ng/l. In August, the composition pattern of PAHs showed a distribution dominated by 4-ring PAHs (pyrene, chrysene+triphenylene, benzo(a)anthracene) at W3-W6, W8 and W9 and 3-ring PAHs (phenanthrene) at W1, W2 and W7. In September, a preference by 3-ring PAHs (phenanthrene) at all sampling sites except W5 was shown and in January was clearly dominated by 4-ring PAHs (chrysene+triphenylene, pyrene, benzo(a)anthracene) at all sampling sites. In ash and sediment samples, the total concentrations of 12 PAHs ranged from 1.3 ng/g to 19 ng/g. The dominant compound was phenanthrene.

Antifungal activities of two new azasordarins, GW471552 and GW471558, in experimental models of oral and vulvovaginal candidiasis in immunosuppressed rats.

Sordarins constitute a new class of antifungal agents with a novel mechanism of action involving the selective inhibition of fungal protein synthesis. A further evolution of this class of antifungals has led to a new family of sordarin derivatives called azasordarins. The therapeutic efficacies of two new azasordarins, GW471552 and GW471558, were studied in experimental models of oral and vulvovaginal candidiasis in immunosuppressed rats. In all cases rats were immunosuppressed with dexamethasone in the drinking water. Oral candidiasis was established by inoculating 0.1 ml of a yeast suspension containing 5 x 10(8) cells of Candida albicans 4711E with a cotton swab on three alternate days. Vulvovaginal candidiasis was established in ovariectomized and estrus-induced rats by intravaginal inoculation of 10(7) CFU of C. albicans 4711E in 0.1 ml of saline. GW471552 and GW471558 were administered at 1, 5, and 10 mg/kg of body weight via the subcutaneous route. In oral candidiasis, azasordarins were administered each 8 h for 7 consecutive days, while in vaginal candidiasis the compounds were given each 4 h for 3 consecutive days. Antifungal activity of azasordarins was assessed by colony counts and by histological examination 1 day after treatment. In the oral infection model, GW471552 and GW471558 administered at 5 mg/kg significantly reduced (P < 0.05) the number of CFU of C. albicans compared with untreated controls. In addition, GW471552 and GW471558 given at 10 mg/kg eradicated C. albicans from the oral cavities of 100% of infected animals. Against vulvovaginal infection, both compounds showed significant therapeutic efficacy. GW471552 was able to eradicate the vaginal fungal burden at a dose of 10 mg/kg, and it significantly reduced the number of CFU of C. albicans in vaginas of rats treated with a dose of 5 mg/kg (P < 0.05). GW471558 showed greater efficacy, eradicating the fungal burden of 100% of infected rats at a dose of 5 mg/kg and significantly reducing (P < 0.05) the C. albicans vaginal counts even at a dose of 1 mg/kg. In both therapeutic efficacy studies, the histological findings confirmed the microbiological results. The experimental results presented show that the tested azasordarins are effective against oral and vulvovaginal candidiasis in immunosuppressed rats and could be promising antifungal agents for use in humans.

Antifungal activities and cytotoxicity studies of six new azasordarins.

GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 are members of a new family of sordarin derivatives called azasordarins. The in vitro activities of these compounds were evaluated against clinical isolates of yeasts, including Candida albicans, Candida non-albicans, and Cryptococcus neoformans strains. Activities against Pneumocystis carinii, Aspergillus spp., less common molds, and dermatophytes were also investigated. Azasordarin derivatives displayed significant activities against the most clinically important Candida species, with the exception of C. krusei. Against C. albicans, including fluconazole-resistant strains, MICs at which 90% of the isolates tested are inhibited (MIC(90)s) were 0.002 microg/ml with GW 479821, 0.015 microg/ml with GW 515716 and GW 587270, and 0.06 microg/ml with GW 471552, GW 471558, and GW 570009. The MIC(90)s of GW 471552, GW 471558, GW 479821, GW 515716, GW 570009, and GW 587270 were 0.12, 0.12, 0.03, 0.06, 0.12, and 0.06 microg/ml, respectively, against C. tropicalis and 4, 0.25, 0.06, 0.25, 0.5, and 0.5 microg/ml, respectively, against C. glabrata. In addition, some azasordarin derivatives (GW 479821, GW 515716, GW 570009, and GW 58720) were active against C. parapsilosis, with MIC(90)s of 2, 4, 4, and 1 microg/ml, respectively. The compounds were extremely potent against P. carinii, showing 50% inhibitory concentrations of 16 microg/ml). These azasordarin derivatives also showed significant activity against emerging fungal pathogens, which affect immunocompromised patients, such as Rhizopus arrhizus, Blastoschizomyces capitatus, and Geotrichum clavatum. Against these organisms, the MICs of GW 587270 ranged from 0.12 to 1 microg/ml, those of GW 479821 and GW 515716 ranged from 0.12 to 2 microg/ml, and those of GW 570009 ranged from 0.12 to 4 microg/ml. Against Fusarium oxysporum, Scedosporium apiospermum, Absidia corymbifera, Cunninghamella bertholletiae, and dermatophytes, GW 587270 was the most active compound, with MICs ranging from 4 to 16 microg/ml. Against Aspergillus spp., the MICs of the compounds tested were higher than 16 microg/ml. The in vitro selectivity of azasordarins was investigated by cytotoxicity studies performed with five cell lines and primary hepatocytes. Concentrations of compound required to achieve 50% inhibition of the parameter considered (Tox(50)s) of GW 570009, GW 587270, GW 479281, and GW 515716 in the cell lines ranged from 60 to 96, 49 to 62, 24 to 36, and 16 to 38 microg/ml, respectively. The cytotoxicity values of GW 471552 and GW 471558 were >100 microg/ml for all cell lines tested. Tox(50)s on hepatocytes were in the following order: GW 471558 > GW 471552 > GW 570009 > GW 587270 > GW 515716 > GW 479821, with values ranging from higher than 100 microg/ml to 23 microg/ml. The cytotoxicity results obtained with fully metabolizing rat hepatocytes were in total agreement with those obtained with cell lines. In summary, the in vitro activities against important pathogenic fungi and the selectivity demonstrated in mammalian cell lines justify additional studies to determine the clinical usefulness of azasordarins.

Correlation between in vitro and in vivo activities of GM 237354, a new sordarin derivative, against Candida albicans in an in vitro pharmacokinetic-pharmacodynamic model and influence of protein binding.

The antifungal effect of GM 237354, a sordarin derivative, was studied in an in vitro pharmacokinetic (PK)-pharmacodynamic dynamic system (bioreactor) which reproduces PK profiles observed in a previously described model of drug efficacy against murine systemic candidiasis. Immunocompetent mice infected intravenously with 10(5) CFU of Candida albicans were treated with GM 237354 at 2.5, 10, and 40 mg/kg of body weight every 8 h subcutaneously for 7 days. Free concentrations in serum were calculated by multiplying total concentrations measured in vivo by 0.05, the free fraction determined in vitro by equilibrium dialysis. In the bioreactor the inoculum was approximately 10(6) CFU/ml; and a one-compartment PK model was used to reproduce the PK profiles of free and total GM 237354 in serum obtained in mice, and clearance of C. albicans was measured over 48 h. A good correlation was observed when the in vivo fungal kidney burden and the area under the survival time curve were compared with the in vitro broth "burden," although only when free in vivo levels in serum were reproduced in vitro. GM 237354 displayed a 3-log decrease effect both in vivo and in vitro. The very few reports available on in vitro-in vivo correlations have been obtained with antibiotics. The good in vitro-in vivo correlation obtained with an antifungal agent shows that the in vitro dynamic system could constitute a powerful investigational tool prior to assessment of the efficacy of an anti-infective agent in animals and humans.

Animal pharmacokinetics and interspecies scaling of sordarin derivatives following intravenous administration.

Sordarin derivatives constitute a new group of synthetic antifungal agents that selectively inhibit fungal protein synthesis. They have demonstrated in vitro activity against the most important fungal pathogens, both yeast and filamentous. This new family of compounds has also shown in vivo activity against murine Candida albicans, Histoplasma capsulatum, and Coccidioides immitis experimental infections, as well as against Pneumocystis carinii pneumonia in rats. After intravenous dosing in animals, both the area under the concentration-time curve and the elimination half-life were highest in Cynomolgus monkeys, followed by those in rats, mice, and rabbits. The volume of distribution at steady state for sordarin derivatives was similar in all species tested. The clearance in rats and mice was higher than for other species. GM 237354, a sordarin derivative, was characterized by high serum protein binding in mouse, rat, and monkey serum (unbound fraction, < or =5%). An indirect evaluation of the effect of liver function upon the metabolism of this class of compounds has been made in animals with impaired liver function such as Gunn rats, as well as in allometric studies that showed better correlations of half-life to liver blood flow than to animal body weight. Linearity of the main pharmacokinetic parameters was demonstrated after intravenous dosing of the representative compound GM 193663 at 10 and 20 mg/kg of body weight in rats. Allometry was used to determine whether human pharmacokinetic parameters can be predicted from animal data by regression analysis against body weight and liver blood flow. All these results have demonstrated that the human pharmacokinetics of sordarin derivatives can be forecast from animal data.

Nitric oxide-producing CD11b(+)Ly-6G(Gr-1)(+)CD31(ER-MP12)(+) cells in the spleen of cyclophosphamide-treated mice: implications for T-cell responses in immunosuppressed mice.

During recovery from intensive chemotherapy with cyclophosphamide (CTX), mice suffer a severe but transitory impairment in spleen cell proliferation to T-cell mitogens (Con A or anti-CD3 plus IL-2). Although CTX treatment reduced spleen T-cell cellularity, this cannot fully account for T-cell unresponsiveness. The results showed that CTX induces the colonization of spleen by an immature myeloid CD11b(+)Ly-6G(+)CD31(+) population. Its presence closely correlated with the maximum inhibition of T-cell proliferation. Moreover, this suppressive activity was dependent on nitric oxide (NO) production in cultures since (1) higher amounts of nitric oxide and inducible nitric oxide synthase (iNOS) mRNA were produced in CTX spleen cells (CTX-SC) than in control splenocyte cultures and (2) NOS inhibitors greatly improved the proliferation of T lymphocytes. Nitric oxide production and suppressive activity were also dependent on endogenous interferon-gamma (IFN-gamma) production since anti-IFN-gamma abrogated both effects. Finally, iNOS protein expression was restricted to a heterogeneous population of CD31(+) cells in which CD11b(+)Ly-6G(+) cells were required to suppress T-cell proliferation. These results indicated that CTX might also cause immunosuppression by a mechanism involving the presence of immature myeloid cells with suppressor activity. This may have implications in clinical praxis since inappropriate immunotherapies in patients treated with intensive chemotherapy could lead to deleterious T-cell responses. (Blood. 2000;95:212-220)

Activities of sordarins in murine histoplasmosis.

Sordarins are new antifungals which inhibit fungal protein synthesis by blocking elongation factor 2. Three compounds were evaluated in a murine model of histoplasmosis. Immune-competent mice were infected intravenously with 10(6) to 10(8) CFU of Histoplasma capsulatum yeast cells. Mice were treated either orally with sordarins or fluconazole from day 2 through 8 after infection or intraperitoneally with amphotericin B during the same period. Protection was measured by increased rates of survival for 30 days after infection or reduction of lung or kidney tissue counts 9 days after infection. All three of the antifungal drugs tested were protective compared with controls. Sordarins were effective at doses as low as 2 mg/kg of body weight/day. This novel class of drugs compared favorably with amphotericin B and fluconazole for the treatment of histoplasmosis.

Sordarins: in vitro activities of new antifungal derivatives against pathogenic yeasts, Pneumocystis carinii, and filamentous fungi.

GM 193663, GM 211676, GM 222712, and GM 237354 are new semisynthetic derivatives of the sordarin class. The in vitro antifungal activities of GM 193663, GM 211676, GM 222712, and GM 237354 against 111 clinical yeast isolates of Candida albicans, Candida kefyr, Candida glabrata, Candida parapsilosis, Candida krusei, and Cryptococcus neoformans were compared. The in vitro activities of some of these compounds against Pneumocystis carinii, 20 isolates each of Aspergillus fumigatus and Aspergillus flavus, and 30 isolates of emerging less-common mold pathogens and dermatophytes were also compared. The MICs of GM 193663, GM 211676, GM 222712, and GM 237354 at which 90% of the isolates were inhibited (MIC90s) were 0.03, 0.03, 0.004, and 0.015 microg/ml, respectively, for C. albicans, including strains with decreased susceptibility to fluconazole; 0.5, 0.5, 0.06, and 0.12 microg/ml, respectively, for C. tropicalis; and 0.004, 0.015, 0.008, and 0.03 microg/ml, respectively, for C. kefyr. GM 222712 and GM 237354 were the most active compounds against C. glabrata, C. parapsilosis, and Cryptococcus neoformans. Against C. glabrata and C. parapsilosis, the MIC90s of GM 222712 and GM 237354 were 0.5 and 4 microg/ml and 1 and 16 microg/ml, respectively. The MIC90s of GM 222712 and GM 237354 against Cryptococcus neoformans were 0.5 and 0.25 microg/ml, respectively. GM 193663, GM 211676, GM 222712, and GM 237354 were extremely active against P. carinii. The efficacies of sordarin derivatives against this organism were determined by measuring the inhibition of the uptake and incorporation of radiolabelled methionine into newly synthesized proteins. All compounds tested showed 50% inhibitory concentrations of <0.008 microg/ml. Against A. flavus and A. fumigatus, the MIC90s of GM 222712 and GM 237354 were 1 and 32 microg/ml and 32 and >64 microg/ml, respectively. In addition, GM 237354 was tested against the most important emerging fungal pathogens which affect immunocompromised patients. Cladosporium carrioni, Pseudallescheria boydii, and the yeast-like fungi Blastoschizomyces capitatus and Geotrichum clavatum were the most susceptible of the fungi to GM 237354, with MICs ranging from /=2 microg/ml. In summary, we concluded that some sordarin derivatives, such as GM 222712 and GM 237354, showed excellent in vitro activities against a wide range of pathogenic fungi, including Candida spp., Cryptococcus neoformans, P. carinii, and some filamentous fungi and emerging invasive fungal pathogens.

Translation elongation factor 2 is part of the target for a new family of antifungals.

Translation elongation factor 2 (EF2), which in Saccharomyces cerevisiae is expressed from the EFT1 and EFT2 genes, has been found to be targeted by a new family of highly specific antifungal compounds derived from the natural product sordarin. Two complementation groups of mutants resistant to the semisynthetic sordarin derivative GM193663 were found. The major one (21 members) consisted of isolates with mutations on EFT2. The minor one (four isolates) is currently being characterized but it is already known that resistance in this group is not due to mutations on EFT1, pointing to the complex structure of the functional target for these compounds. Mutations on EF2 clustered, forming a possible drug binding pocket on a three-dimensional model of EF2, and mutant cell extracts lost the capacity to bind to the inhibitors. This new family of antifungals holds the promise to be a much needed and potent addition to current antimicrobial treatments, as well as a useful tool for dissection of the elongation process in ribosomal protein synthesis.

Sordarins: A new class of antifungals with selective inhibition of the protein synthesis elongation cycle in yeasts.

GR135402, a sordarin derivative, was isolated in an antifungal screening program. GR135402, sordarin, and derivatives of both compounds were evaluated for their ability to inhibit cell-free translational systems from five different pathogenic fungi (Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Cryptococcus neoformans). The activity profile of GR135402 is extended to other chemical compounds derived from sordarin. Experimental results indicate that sordarin analogs exert their antifungal effects by specifically inhibiting the protein synthesis elongation cycle in yeasts but do not affect protein synthesis machinery in mammalian systems. Intrinsically resistant strains owe their resistance to differences in the molecular target of sordarins in these strains. Preliminary studies performed to elucidate the mode of action of this new class of antifungal agents have shown that the putative target of sordarins is one of the protein synthesis elongation factors.

Distal aphalangia, syndactyly, and extra metatarsal, associated with short stature, microcephaly, and borderline intelligence: a new autosomal dominant disorder.

We report on 3 members of a Spanish family with partial aphalangia, syndactyly with duplication of metatarsal IV, microcephaly, dull intelligence, and short stature. The MCA pattern observed in this family appears to constitute a previously undescribed syndrome.