Controlling antifungal activity with light: Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors

Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80 ≥ 64 μg/mL) could be efficiently recovered (MIC80 = 0.5-8 μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by in vivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

A descrição matemática da detecção eletroquímica da ergina, assistida pelos novos derivados triazólicos, dopados pelo íon amavadina / The mathematical description for the ergin electrochemical detection, assisted by amavadin ion doped triazolic derivatives / Descripción matemática de la detección electroquímica de ergina, asistida por los nuevos derivados de triazol, dopados por el ión amavadina

RESUMO Introdução: Pela primeira vez, o processo eletroanalítico da detecção da ergina (LSA) sobre um elétrodo, modificado por um derivado triazólico, dopado pelo íon amavadina, tem sido descrito teoricamente. Métodos: O modelo matemático, correspondente ao desempenho do sensor, tem sido desenvolvido e analisado do ponto de vista da teoria de estabilidade linear. Foi mostrado que a amavadina pode servir de modificador eficiente para a detecção eletroanalítica da ergina. Outrossim, a presença de um material orgânico no modificador reforça a capacidade da ergina de polimerizar-se, formando um compósito polimérico. Resultados: Os comportamentos oscilatório e monotô-nico são mais prováveis que no caso mais comum, haja vista a formação-deformação de compostos iônicos aquando da detecção eletroanalítica.

SUMMARY Introduction: For the first time, the electroanalytical process of ergin (LSA) determination over an electrode, modified by triazolic derivative, doped by an amavadin-ion, has been theoretically described. Methods: The mathematical model, correspondent to the sensor function, has been developed and analyzed by means of linear stability theory. It has been shown that the amavadin may serve as an efficient electrode modifier for the electroanalytical detection of ergin. Moreover, the presence of an organic material as electrode modifier reinforces the possibility of ergin polymerization, yielding a polymer composite. Results: The oscillatory and monotonic behavior is more probable than in the common case, considering the formation and destruction of the ionic compounds during the electroanalytical detection.

RESUMEN Introducción: Por primera vez se ha descrito teóricamente el proceso eletroanalítico de detección de ergina (LSA) en un electrodo, modificado por un derivado triazólico, dopado por el ión amavadina. Métodos: El modelo matemático, correspondiente al rendimiento del sensor, ha sido desarrollado y analizado desde el punto de vista de la teoría de la estabilidad lineal. Se ha demostrado que la amavadina puede servir como un modificador eficaz para la detección eletroanalítica de ergina. Además, la presencia de un material orgánico en el modificador refuerza la capacidad de la ergina para polimerizar, formando un compuesto polimérico. Resultados: Los comportamientos oscilatorios y monótonos son más probables que en el caso más común, dada la formación-deformación de compuestos iónicos durante la detección eletroanalítica.

Clinical and epidemiological aspects of Candidemia in eight medical centers in the state of Parana, Brazil: Parana Candidemia Network

ABSTRACT Objectives: Candida spp. has been reported as one of the common agents of nosocomial bloodstream infections and is associated with a high mortality. Therefore, this study evaluated the clinical findings, local epidemiology, and microbiological aspects of candidemia in eight tertiary medical centers in the state of Parana, South of Brazil. Methods: In this study, we reported 100 episodes of candidemia in patients admitted to eight different hospitals in five cities of the state of Parana, Brazil, using data collected locally (2016 and 2017) and tabulated online. Results: The incidence was found to be 2.7 / 1000 patients / day and 1.2 / 1000 admissions. C. albicans was responsible for 49% of all candidemia episodes. Cancer and surgery were the two most common underlying conditions associated with candidemia. The mortality rate within 30 days was 48%, and removal of the central venous catheter (p = 0.029) as well as empirical or prophylactic exposure to antifungals were both related to improved survival (p = 0.033). Conclusions: This study highlights the high burden and mortality rates of candidemia in hospitals from Parana as well as the need to enhance antifungal stewardship program in the enrolled medical centers.

Sensibilidad in vitro a benznidazol, nifurtimox y posaconazol de cepas de Trypanosoma cruzi de Paraguay / In vitro susceptibility to benznidazole, nifurtimox and posaconazole of Trypanosoma cruzi isolates from Paraguay

Resumen: Introducción. Trypanosoma cruzi, agente causal de la enfermedad de Chagas, exhibe una sustancial heterogeneidad fenotípica y genotípica que puede influir en las variaciones epidemiológicas y clínicas de la enfermedad, así como en la sensibilidad a los fármacos utilizados en el tratamiento. Objetivo. Evaluar la sensibilidad in vitro al benznidazol, el nifurtimox y el posaconazol de 40 cepas clonadas de T. cruzi de Paraguay, con distintos genotipos, huéspedes y localidades de origen. Materiales y métodos. En su estado epimastigote, los parásitos se incubaron en medio de cultivo LIT (Liver Infusion Tryptose) con diferentes concentraciones de cada fármaco en ensayos por triplicado. El grado de sensibilidad se estimó a partir de las concentraciones inhibitorias del 50 y el 90% (IC50 e IC90) y se obtuvieron los valores promedio y la desviación estándar de cada cepa y fármaco. La significación estadística entre grupos se determinó mediante análisis de varianzas con el test no paramétrico de Wilcoxon/Kruskal-Wallis y valores de p<0,05. Resultados. Se observó un amplio rango de respuesta a los fármacos. Se identificaron dos grupos de parásitos (A y B) con diferencias significativas en la sensibilidad al benznidazol (p<0,0001), y tres grupos (A, B, C) en cuanto a la sensibilidad al nifurtimox y el posaconazol (p<0,0001). Conclusiones. En general, las cepas fueron más sensibles al nifurtimox que al benznidazol y el posaconazol. Estas diferencias evidencian la heterogeneidad de las poblaciones de T. cruzi que circulan en Paraguay, lo que debe considerarse en el tratamiento y el seguimiento de las personas afectadas.

Abstract: Introduction: Trypanosoma cruzi, the causative agent of Chagas disease, shows substantial phenotypic and genotypic heterogeneity, which can influence the epidemiological and clinical variations of the disease and the sensitivity to the drugs used in the treatment. Objective: To assess the in vitro susceptibility to benznidazole, nifurtimox, and posaconazole of 40 cloned strains of T. cruzi isolated in Paraguay belonging to different genotypes, hosts, and localities. Materials and methods: We incubated the parasites in their epimastigote stage in LIT culture medium with different concentrations of each drug in triplicate assays. The degree of susceptibility was estimated by the inhibitory concentrations of 50 and 90% (IC50 and IC90) to obtain the average values and the standard deviation for each strain and drug. We determined the statistical significance between groups by analysis of variances with the Wilcoxon/Kruskal-Wallis non-parametric test and values of p<0.05. Results: A wide range of drug response was observed. Two groups of parasites (A and B) were identified as having significant differences in susceptibility to benznidazole (p<0.0001), and three groups (A, B, C) to nifurtimox and posaconazole (p<0.0001). Conclusions: Overall, the isolates were more susceptible to nifurtimox than benznidazole and posaconazole. Such differences highlight the heterogeneity of T. cruzi populations circulating in Paraguay, an aspect to consider in the treatment and follow up of patients.

A descrição matemática da detecção eletroquímica dos alcaloides do grupo da insubosina, assistida pelos novos triazóis com e sem composto de ligação / The mathematical description for the electrochemical determination of insubosin alkaloid group, assisted by new triazoles with and without link compound

RESUMO Pela primeira vez, foi feita uma abordagem teórica do desempenho dos novos derivados triazólicos durante a determinação química dos alcaloides acridínicos do grupo insubosina, na presença de uma concentração pequena de um composto de ligação. A detecção eletroanalítica é realizada mediante um mecanismo híbrido, envolvendo ou não a formação de novos compostos iónicos. É possível mostrar que o estado estacionário é estabilzado, apesar de a região topológica, que lhe é correspondente, ser mais estreita que no caso da detecção mais comum. O comportamento oscilatório, neste caso, é mais provável que nos casos mais comuns, mas o fator adicional é relacionado apenas com a introdução de um composto de ligação.

SUMMARY For the first time, a theoretical investigation of novel triazolic derivatives during the chemical determination of acridinic alkaloids of insubosin group in the presence of the presence of the small quantity of the link compound has been realized. The electrochemical determination is realized by a hybrid mechanism, involving or not the formation of novel ionic compounds. It is possible to show that the steady-state is stabilized, despite ofthe narrower correspondent topological region, while compared to the more common detection case. The oscillatory behavior is more probable than in more common cases, due to the introduction of the link compound.

Caracterização molecular e perfil de suscetibilidade de Cryptococcus e outras leveduras melanizadas de ambiente contaminado com fungicidas azólicos

Cepas fúngicas ambientais estão sujeitas, continuamente, à grande diversidade de ações antrópicas, como a exposição a f u n g i c i d a, o que poderia induzir à resistência adquirida a fármacos antifúngicos com estrutura química e mecanismo de ação semelhante. A resistência adquirida a fármacos azólicos(fluconazol, itraconazol, v o r i c o n a z o l, etc.) tem importante implicação clínica.O objetivo deste estudo foi isolar e caracterizar leveduras melanizadas de origem ambiental, do gênero Cryptococcus e do grupo Black Yeast Fungi (BYF),e determinar seu perfil de sensibilidade a fármacos e fungicidas azólicos...

Environmental fungal strains are subject continuously to the wide range of humanactivities, such as exposure to fungicide, which could lead to acquired resistance to antifungal drugs with similar chemical structure and mechanism of action. Theacquired resistance to azole drugs (fluconazole, itraconazole, voriconazole, etc.)has important clinical implications. The aim of this study was to isolate and characterize melanized yeast environmental origin, gender Cryptococcus and Black Yeast Fungi group (BYF), and determine its susceptibility profile to drugs and azole fungicides...

Newer antifungal agents micafungin and voriconazole for fungal infection prevention during hematopoietic cell transplantation: meta-analysis / 中国医师杂志

Objective To compare the newer antifungal agents micafungin and voriconazole for prophylaxis effects on the clinical outcomes.Methods We electronically searched the database of Cochrane Central Register of Controlled Trials,Pubmed,EMbase,China Biology Medicine (CBM),China National Knowledge Infrastructure(CNKI),and relevant database articles (1996.01-2014.12).Comparative studies were carried out on proved fungal infections,mortality,and adverse effects.Meta-analysis was performed by Review Manager 5.3 software.Results We found 1 564 records and 16 studies totaling 4 234patients included in analyses.Pooled comparisons of studies found that antifungal prophylaxis with the new agents did reduce the incidence of invasive fungal infections and transplant related mortality than fluconazole or itraconazole [OR =0.41 (0.21 ～ 0.80) and OR =0.40 (0.24 ～ 0.66),respectively,P ＜ 0.01].Voriconazole had higher rates of liver dysfunction,lower gastrointestinal side effects over fluconazole,and lower rates of nephrotoxic effects than amphotericin B.Voriconazole had significant decrease in adverse events requiring drug discontinuation compared to itraconazole [OR =0.43 (0.27 ～ 0.68),P ＜ 0.01].Conclusions This analysis indicated the 2 agents appear to be well tolerated with manageable side effects and beneficial in the prophylaxis of invasive fungal infection (IFI).

The effects on rabbit corneas and retinas after single intravitreal injection of voriconazole at different doses / 中华眼底病杂志

Objective To observe the effects on rabbit corneas and retinas after single intravitreal injection of voriconazole at different doses.Methods According to the randomization table,25 healthy rabbits were randomly divided into control group,and voriconazole 50,100,200,and 400 μg groups.Therefore,there were 5 rabbits in each group.The eyes of control group received intravitreal injection of 0.1 ml balanced saline solution,and those treatment groups received 0.1 ml voriconazole injection of corresponding dose.Before the injection and 1,7,and 14 days after the injection,endothelial cell counts and corneal thicknesses were measured;full-field electroretinogram were performed and b-wave amplitudes in maximal combined reaction (Max-R) were recorded.On 14 days after the injection,histologic structures were observed by light microscope and transmission electron microscope.Results There was no significant difference in endothelial cell counts (F=0.320,0.291,0.467,0.649) and corneal thicknesses (F=0.214,0.284,0.360,0.225) with those of control group at any time points (P＞0.05).Before and 1 day after the injection,b-wave amplitudes of each voriconazole group had no significant difference compared with those of control group (F=0.220,0.106;P＞0.05).On 7 days after the injection,b-wave amplitudes decreased significantly at doses of 200 μg and 400 μg (P＜0.05).On 14 days after the injection,there was no significant difference between the the amplitude of 200 μg group and that of control group (P＞ 0.05).However,the amplitude of the 400 μg group decreased continuously and there was still significant difference (P＜0.05).Light microscopy did not reveal any corneal abnormality in both control group and voriconazole groups.The retinas were normal except that of the 400 μg group,which had a thinner and degenerated inner nuclear layer and disordered photoreceptor layer.Under transmission electron microscope,there were no ultrastructure damages of corneas in both control group and voriconazole groups,either.The rabbit retinas of the 50 μg and 200 μg group have normal inner nuclear layer and photoreceptor layer,but degrees of changes in both layers were observed in the eyes of 200 μg and 400 μg group.Conclusions There is no obvious effects on rabbit corneas and retinas after single intravitreal injection of voriconazole at he dose less than or equal 100 μg.There are no obvious effects on rabbit corneas at the dose of 200 μg and 400 μg,while there are damages to the retinas in both functions and histological structures.

Relationship between letrozole administration during the luteal phase after oocyte retrieval and the early-stage ovarian hyperstimulation syndrome oocurrence / 中华妇产科杂志

Objective To investigate the effect of letrozole in decreasing the early-stage ovarian hyperstimulation syndrome (OHSS) occurrence during the luteal phase for patients of OHSS high-risk after oocyte retrieval.Methods A total of 176 high-risk OHSS patients were randomly divided into two groups after oocyte retrieval.Patients in experiment group (n=86) received 5 mg letrozole per day from the retrieval day and last for 5 days.Others in control group (n=90) received placebo.The serum concentration of FSH,LH,estradiol (E2),progesterone (P) and vascular endothelial growth factor (VEGF) from the day of hCG injection to days after injection (5 days,8 days,10 days) were measured.And the incidence of moderate and severe OHSS was observed.Results The concentration of E2 on the indicated days (5 days,8 days,10 days after hCG injection) in experiment group and control group were (5 727±2 089) versus (11 826±4 281) pmol/L,(1 613±879) versus (7 925±3 507) pmol/L,(193±90) versus (1 628±888) pmol/L; the concentration of VEGF on the indicated days in the two groups were (80± 14) versus (108± 19) ng/L,(66± 11) versus (126± 14) ng/L,(48±7) versus (148± 14) ng/L; the concentration of E2 and VEGF were lower than those in control group (all P＜0.01).The FSH concentration in experiment group were (2.1 ± 1.1) and (3.5± 1.3) U/L on the day of fifth and eighth day after hCG injection,which were significantly higher than (0.7±0.3) and (0.7±0.4) U/L in control group (P＜0.05); the LH concentration in experiment group were (0.26±0.19) and (0.72±0.60) U/L on the day of fifth and eighth day after hCG injection,which were significantly higher than (0.11 ±0.03) and (0.14±0.08) U/L in control group (P＜0.05).The incidence of moderate and severe OHSS was signicantly decreased after letrozole treatment compared with control group [2％ (2/86) versus 12％ (1 1/90),P＜0.05].Conclusion Administration of 5 mg/d letrozole for 5 days during the luteal phase can reduce the E2 and VEGF levels for the high-risk OHSS patients who needed cryopreserve all embryos,and also reduce the occurrence of early OHSS.

Effects of rizatriptan on calcitonin gene-related peptide, proenkephalin and cholecystokinin mRNA expressions in the trigeminal ganglia of a rat migraine model / 中华神经科杂志

Objective This study assesses the influence of rizatriptan on calcitonin gene-related peptide (CGRP),proenkephalin (PENK) and cholecystokinin (CCK) mRNA expressions in the trigeminal ganglia of a rat migraine model and investigates the possible mechanisms by which triptans treat migraine.Methods A total of 24 rats were randomly divided into four groups:normal control group (A),migraine model group(B),rizatriptan control group (C) and rizatriptan treatment group(D).Groups C and D were intragastrically perfused with rizatriptan,1 mg/kg per day.After 7 days,nitroglycerin was subcutaneously injected into the buttocks of the groups B and D to induce migraine.Two hours after nitroglycerin injection,the trigeminal ganglia was isolated.CGRP,PENK and CCK mRNA expressions in the trigeminal ganglia were determined using SYBR Green Ⅰ real-time quantitative PCR.Results The copy number of CGRP mRNA (× 107) in 200 ng total RNA of each group was 0.05 ±0.01,1.30 ±0.52,0.23 ±0.12,0.43 ±0.33 ; The copy number of PENK mRNA (× 103) in 200 ng total RNA of each group was 3.30 ± 1.65,0.34 ±0.14,3.91 ± 2.44,0.71 ± 0.13.The copy number of CGRP mRNA in the trigeminal ganglia of group B was significantly higher than that of group A (q =7.854,P ＜ 0.05) ; CGRP mRNA expressions were significantly lower in the trigeminal ganglia of rats in group D compared with group B (q =5.458,P ＜0.05).Compared with group A,PENK mRNA expressions in the trigeminal ganglia of rats were significantly lower in group B (q =4.478,P ＜ 0.05).PENK mRNA expressions were significantly higher in trigeminal ganglia of rats in group C compared with group D (q =4.838,P ＜ 0.05).CCK mRNA expression in trigeminal ganglia of rats was similar among groups.Conelusions Rizatriptan can decrease the expressions of CGRP in the trigeminal ganglia of the migraine rats and exhibits neurogenic inflammation triggered by CGRP.PENK expressions decrease in the trigeminal ganglia of the migraine rats,weaken the analgesic effects of enkephalin.

Risk factors and prognosis analysis of cranial nerve injury in non-acquired immune deficiency syndrome-related cryptococcal meningitis / 中国医师进修杂志

Objective To explore the risk and prognosis factor of cranial nerve injury in non acquired immune deficiency syndrome(AIDS)-related cryptococcal meningitis.Methods The clinical data of 115 patients with non-AIDS-related cryptococcal meningitis were reviewed retrospectively.Clinical characteristics,initial antifungal therapies and outcome of these patients were analyzed.The risk and prognosis factor was performed by multivariate Logistic regression.Results The incidence of cranial nerve injury was 35.7％(41/115).Among of them,the involved ratio was 48.8％ (20/41),39.0％ (16/41),24.4％ (10/41),12.2％ (5/41),7.3％ (3/41),4.9％ (2/41) in optic nerve,oculomotor nerve,acoustic nerve,abducent nerve,olfactory nerve,facial nerve.Predictive risk factor for cranial nerve injury was duration of diagnosis (OR =1.057,95％ CI 1.003-1.112),low cerebrospinal fluid cell count and intracranial hypertension were also the independent predictive factors (both P ＜ 0.05).In the follow-up peried,72.2％ (26/36) patients who had cranial nerve injury were fully recovered,with a median time of 0.5-24.0 (3.8 ±1.7) months.The independent predictors of recovery were numbers of nerve involved (OR =0.241,95 ％ CI 0.067-0.801,P =0.023) and combination therapy (OR =10.328,95 ％ CI 2.087-51.026,P =0.006).Condusions Cranial nerve injury is common in non-AIDS-related cryptococcal meningitis.Delay in diagnosis,intracranial hypertension and low cerebrospinal fluid cell count are independent predictive factors.Less cranial nerve involvement and combination therapy predicts recovery.

Aplicação curativa de fungicidas e seu efeito sobre a expansão de lesão da mancha-amarela do trigo / Curative sprays of fungicides and their effect on lesion expansion of the wheat tan spot

A mancha-amarela é uma das principais doenças foliares do trigo no Brasil, com danos de até 80% sobre o rendimento de grãos. A expansão da lesão é um importante componente da epidemia da mancha-amarela, porém ainda pouco estudado, especialmente quanto ao efeito de aplicações de fungicida em fase pós-sintoma. Para conhecer como diferentes grupos de fungicidas agem sobre a expansão da lesão, e assim otimizar o manejo da doença, quatro ensaios foram realizados na Universidade de Passo Fundo (UPF), em 2011. Os trabalhos foram organizados em delineamento de blocos casualizados, com quatro repetições, e conduzidos em câmara de crescimento com controle de temperatura e luz. Em dois deles, um fungicida triazol (propiconazol) e uma estrobilurina (azoxistrobina), bem como ambos em mistura, foram aplicados em intervalos crescentes de um até 12 dias após a inoculação das plantas dos cultivares 'Fundacep Horizonte' e 'Quartzo'. Com base em medições do tamanho da lesão, a estrobilurina não diminuiu a taxa de expansão da lesão (0,176 a 0,180 mm².dia-1) em relação à testemunha (0,175 a 0,184 mm².dia-1), enquanto o triazol (0,080 mm².dia-1) e a mistura (0,060 a 0,080 mm².dia-1) o fizeram quando aplicados em períodos inferiores a 10 ou 12 dias após a inoculação. Em outros dois ensaios, fungicidas comerciais (epoxiconazol, propiconazol, tebuconazol, azoxistrobina, piraclostrobina, ciproconazol + azoxistrobina, epoxiconazol + piraclostrobina, protioconazol + trifloxistrobina e tebuconazol + trifloxistrobina) foram aplicados às plantas aos três, cinco ou oito dias após a inoculação. Aos cinco dias, epoxiconazol, propiconazol e protioconazol + trifloxistrobina reduziram a taxa de progresso da lesão (0,07 a 0,14 mm².dia-1) em relação à testemunha (0,29 mm².dia-1). Aos oito dias, não houve diferença entre os fungicidas e a testemunha. O tamanho final das lesões foi menor (3,76 a 5,89 mm²) nas plantas tratadas com tebuconazol + trifloxistrobina, protioconazol + trifloxistrobina, tebuconazol, epoxiconazol + piraclostrobina e propiconazol, sendo maior (8,46 a 11,70 mm²) para ciproconazol + azoxistrobina, azoxistrobina, epoxiconazol e piraclostrobina, que não diferiram da testemunha. Tais resultados evidenciam a dificuldade em restringir o progresso da mancha-amarela após seu estabelecimento nas plantas e enfatiza a necessidade de estratégias de manejo preventivas.

Tan spot is one of the main diseases of wheat in Brazil reducing grain yield up to 80%. Although the lesion expansion is an important component of the epidemics, there are few studies on its control by curative sprays of fungicide. To know how different fungicides may control lesion expansion and to improve disease management, four assays were carried out at the Universidade de Passo Fundo (UPF) in 2011. All assays were organized as randomized blocks, with four replicates, inside a growth chamber with control of light and temperature. In two assays a triazole (propiconazole) and a strobylurin (azoxystrobin) fungicides, as well as their mixture, were sprayed from one to 12 day intervals after inoculation of the wheat cultivars 'Fundacep Horizonte' and 'Quartzo'. Based upon measurements of the lesion size, the strobylurin did not reduce the rate of lesion growth (0.176 to 0.180 mm².day-1) in comparison to the non-sprayed control (0.175 to 0.184 mm².day-1), whereas the triazole (0.080 mm².day-1) and the fungicide mix (0.060 to 0.080 mm².day-1) did it if sprayed within 10 or 12 days after inoculation. In two other assays, commercial fungicides (epoxiconazole, propiconazole, tebuconazole, azoxystrobin, pyraclostrobin, cyproconazole + azoxystrobin, epoxiconazole + pyraclostrobin, protioconazole + trifloxystrobin and tebuconazole + trifloxystrobin) were sprayed onto plants at three, five and eight days after inoculation. Spraying of the fungicides epoxiconazole, propiconazole, and protioconazole + trifloxystrobin at five days reduced the rate of lesion expansion (0.07 to 0.14 mm².day-1) over the control non-sprayed plants (0.29 mm².day-1). Fungicide applications eight days had no effect on the rate of progress of lesions. The final lesion size was smaller (3.76 to 5.89 mm²) on plants sprayed with tebuconazole + trifloxystrobin, protioconazole + trifloxystrobin, tebuconazol, epoxiconazole + pyraclostrobin, and propiconazole, but higher (8.46 to 11.70 mm²) for cyproconazole + azoxystrobin, azoxystrobin, epoxiconazole, and pyraclostrobin, which did not differ from the non-sprayed control. These results show how difficult is to limit tan spot increase after disease establishment and indicate that is management requires the adoption of preventive control strategies.

Triazoles: a valuable insight into recent developments and biological activities / 中国天然药物

In recent years, heterocyclic compounds, analogs, and derivatives have attracted strong interest due to their useful biological and pharmacological properties. The small and simple triazole nucleus is present in compounds aimed at evaluating new entities that possess anti-microbial, anti-tumor, antitubercular, anti-convulsant, anti-depressant, antimalarial, and anti-inflammatory activities. Triazoles display a broad range of biological activities and are found in many potent, biologically active compounds, such as trazodone (antidepressant drug), rizatriptan (antimigrane drug), hexaconazole (antifungal drug) and alprazolam (hyptonic, sedative and tranquilizer drug). So far, modifications of the triazole ring have proven highly effective with improved potency and lesser toxicity. The present review highlights the recently synthesized triazoles possessing important biological activities.

Cranial nerve impairment in cryptococcal meningitis: predictors and prognosis / 中华传染病杂志

Objective To understand the predictors and prognostic significance of cranial nerve impairment in non-acquired immune deficiency syndrome (AIDS) patients with cryptococcal meningitis.Methods A total of 145 non-AIDS patients with cryptococcal meningitis admitted to Huashan Hospital,Fudan University from Jan 2000 to Dec 2010 were reviewed retrospectively.Clinical characteristics,initial antifungal therapies and outcome of these patients were analyzed.Continuous variables were analyzed using t test and categorical variables were compared by x2 test or Fisher's exact test.Multivariate analysis was performed by binary Logistic regressions.Results Out of 145 patients,52 (35.9％) patients had cranial nerve impairment at enrollment.Optic (25/52,48.1％) and oculomotor (22/52,42.3％) nerves were the most commonly involved,followed by auditory (12/52,23.1％),abducens (6/52,11.5％),olfactory (4/52,7.7％) and facial (3/52,5.8％) nerves.The best predictive factor of cranial nerve injury was duration of diagnosis (OR =1.056,95％ CI:1.002-1.111).The risk of cranial injury would increase by 5.6％ with one-week delay of diagnosis.Intracranial hypertension and low cerebrospinal fluid cell count were also the independent predictive factors (both P＜0.05).In the follow-up period,73.3％ patients who had cranial nerve injuries were fully recovered,with a median time of 3 (0.5-24.0) months.The independent predictors of recovery were numbers of nerve involved (OR =0.230,95 ％ CI:0.066-0.800,P=0.021) and amphotericin B (AmB) plus 5-fluorocytosine,triazole antifungal agent therapy (OR=10.317,95％CI:2.086-51.025,P=0.004).Conclusions Cranial nerve impairment occurs in one-third of non-AIDS patients with cryptococcal meningitis.Delay in diagnosis,intracranial hypertension and low cerebrospinal fluid cell count are independent predictive factors.Less cranial nerve involvement and AmB plus triazole therapy predict recovery.

Design, synthesis and antifungal activity of novel 2,5-disubstituted 1,3,4-oxadiazoles / 第二军医大学学报

Objective To study the in vitro antifungal activity of novel 2,5-disubstituted 1,3,4-oxadiazoles. MethodsSixteen novel 2,5-disubstituted 1,3,4-oxadiazoles compounds have been designed, synthesized and characterized by 1HNMR, LC-MS spectra. Their antifungal activities were evaluated with six tested pathogenic fungi in vitro. Results All the title compounds exhibited potent antifungal activities against Candida albicans, Cryptococcus neoformans, Candida parapsilosis, Candida tropicalis, and Trichophyton rubrum, but not Aspergillus fumigatus. The activities of compound 14, 17 and 18 against Candida atbicans and Cryptococcus neoformans (with the MIC80 0.25 μg/ml) were similar to that of fluconazole. The activities of compound 14 and 17 against Trichophyton rubrum (with the MIC80 0.25 μg/ml) were 2 times as high as that of fluconazole and were similar to that of ketoconazole. Conclusion The 1,2,3-triazole can be efficiently introduced to 1,3,4-oxadiazoles compounds by intermolecular 1,3-dipolar cycloaddition. All the title compounds exhibit certain antifungal activities with broad spectrum. The substituent of the benzene plays an important role in improving the antifungal activity of the compound.

Synthesis and antifungal activity of 1-(1H-1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanol / 第二军医大学学报

Objective: To study the antifungal activity of triazole alcohols by introduction of n-butyl and triazole as side chains. Methods: A total of 16 compounds of 1-(1H-1, 2, 4-triazole-1-yl)-2-(2, 4-difluorophenyl)-3-substituted-2-propanol were synthesized and characterized by 1HNMR and LC-MS. The in vitro antifungal activities of the compounds were determined by tests with 8 human pathogenic fungi. Results: It was found that all the 16 title compounds exhibited antifungal activities, and compounds 7b, 7d, 7e and 7i had antifungal activities stronger than fluconazole, similar to itraconazole. Conclusion: Introduction of n-butyl and triazole side chain can confer antifungal activities to the compounds.

In vitro and in vivo antifungal activity of a triadimenol compound / 第二军医大学学报

Objective: To observe the in vitro and in vivo antifungal activity of a triadimenol compound SL-130. Methods: The M27-A project recommended by the National Committee for Clinical Laboratory Standard (NCCLS) in 1997 was used in the present study. The minimum inhibitory concentrations (MIC80) of SL-130 were determined for candidal and non-candidal strains with different susceptibilities to fluconazole. Agar disk diffusion test, time-kill curves test and mouse survival rate were employed to examine the antifungal activity of SL-130. Results: The results indicated that SL-130 had stronger in vitro antifungal activity than fluconazole, and similar in vivo activity to fluconazole. Conclusion: The structure of SL-130 is quite unique and it has in vitro and in vivo antifungal activity: further study is warranted on the compound.

Synthesis of 1-(1H-1, 2, 4-triazole-1-yl)-2-(2, 4-difluoro-phenyl)-3- N-cyclopropyl-N-substituted amino-2-propanols and test of its antifungal activity / 第二军医大学学报

Objective: To study the antifungal activity of triazole alcohols by introduction of cyclopropyl as side chain. Methods: Nine title compounds were synthesized and characterized by 1 HNMR, MS spectra and element analysis. Eight fungi were used for in vitro anti-fungal test. Results: All of the title compounds showed antifungal activities of different extents, especially to the deep infection ones,and they had a MIC value < 0.125 μg/ml against Candida albicans,showing an anti-fungal activity 4 times higher than that of fluconzole and similar to that of totraconazaole. Conclusion: 1-(1H-1,2,4-triazole-1-yl)-2-(2, 4-difluoro-phenyl)-3-[N-cyclopropyl-N-(3,4-dichlorobenzyl) amino]-2-propanols (6f) has a better activity ratio and is worth further studying.

Design, synthesis, and antifungal activity of 3-substituted triazole derivatives / 第二军医大学学报

Objective: To study the in vitro antifungal activity of triazole alcohols by introduction of 1, 2, 3-triazole as the side chain. Methods: Twenty-one novel triazole alcohol compounds were designed, synthesized, and characterized by 1HNMR and MS spectra. The in vitro antifungal activities of the compounds were evaluated using eight kinds of pathogenic fungi. Results: All the synthesized compounds exhibited certain antifungal activities. The MIC 80 value of compound 7 1-(1H-1, 2, 4-triazole-1-yl)-2-(2, 4-difluorophenyl)-3-[N,N-(1-substituted-benzyl-4-methylene-1H-1,2,3-triazole)] against Candida albicans was 0.25 μg/ml, with its activity being 4 times that of fluconazole. The MIC80 value of compound VI 1-(1H-1,2,4-triazole- 1-yl)-2-(2,4-difluorophenyl)-3-(N,N-dipropargyl)-2-propanols against Candida albicans was 0.0156μg/ml, with its activity being 64 times that of fluconazole and 4 times that of itraconazole. Conclusion: The 1,2,3-triazole can be efficiently introduced by intermolecular 1,3-dipolar cycloaddition. Large side chains may be a disadvantage for improving the antifungal activity of the title compounds.

Effect of letrozole on EM rat models and influence on the reproductive system / 中国医师杂志

Objection To study the effect of letrozole on EM rat models and influence on the reproductive system. Methods Surgically transplanted autologous uterine tissues to ectopic site beside the uterines in rats were used as animal models to study endometriosis. 20 EM model rats were random divided into letrozole-treated group and saline solution-treated control group. The change of ectopic lesion volume in each group was compared before and after treatment. Apoptotic cells were assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick-end labeling (TUNEL) assay, and the uterian horn and ovary were weighted and observed by optical microscopy to study the change of morphology. Results The volumes of the endometriotic tissues of letrozole group reduced more than that in control group[ ( 28. 75 ± 2.28 )mm3 vs ( 108.39 ±9. 98)mm3, P <0.01 ]. The apoptotic rate in letrozole group [ (5.52 ±2. 81 )% ]was higher than control group[ (2.11 ± 1.70)%, P <0. 01 ]. The ovarian weights in letrozole-treated group increased significantly[ (25.25 ± 9. 89) mg/100g vs ( 13. 10 ± 2. 70 ) mg/100g, P < 0. 01 ], arid the ovaries showed polycyst. The uterian weights in letrozole-treated group[ (41.46 ± 15.81 ) mg/100g vs (94. 81 ±18.00) mg/100g, P <0. 05 ] significantly decreased, and the endometriums presented atrophy. Conclusion Letrozole treated EM by means of increasing the apoptosis of the ectopic tissues. Letrozole would give ovarian over stimulating and the uterian weighting decreased as well as endometriums atrophy.