Regulation of pseurotin A biosynthesis by GliZ and zinc in Aspergillus fumigatus.

Recently, we reported that zinc regulates gliotoxin biosynthesis via ZafA, which is a zinc-responsive transcriptional activator. From an HPLC analysis of culture media of Aspergillus fumigatus, we found a trend of decreasing gliotoxin production but increasing pseurotin A and fumagillin production in proportion to the zinc concentration. The expression of the genes involved in pseurotin A biosynthesis was upregulated under high zinc concentrations. Furthermore, upregulated expression of pseurotin A biosynthetic genes and higher production of pseurotin A were observed in the zafA deletion strain. Interestingly, the deletion of gliZ, a transcriptional activator of gliotoxin biosynthesis genes, resulted in upregulated expression of pseurotin A biosynthetic genes and increased production of pseurotin A. We detected upregulation of fumR expression in the gliZ and zafA deletion mutants. The overexpression of gliZ observed in the zafA deletion mutant resulted in the failure of the mutant to increase pseurotin A production, which is a phenotype of the zafA deletion mutant. These results suggest that ZafA sequentially regulates pseurotin A biosynthesis through GliZ. Finally, we found through a murine virulence test that the gliZ and fumR double-deletion mutants showed a delayed death rate compared with the single-deletion mutants of either gliZ or fumR. Taken together, these results suggested that the biosynthesis of gliotoxin and pseurotin A are regulated in opposite ways by zinc utilization and that each secondary metabolite is synthesized when the synthesis of another secondary metabolite fails to protect it against the defense system of the host.

AfSec1 is a signal peptidase and removes signal peptides of 1,3-ß-glucanosyltransferases in Aspergillus fumigatus.

To identify the infection mechanism of Aspergillus fumigatus, which is an opportunistic fungal pathogen, we analyzed the expression profile of the whole genome of A. fumigatus during the infection of murine macrophages. A previously reported RNA-seq data analysis showed that many genes involved in cell wall synthesis were upregulated during the infection process. Interestingly, AfSec1 (3g12840), which encodes a putative signal peptidase, was upregulated dramatically, and its putative target protein Gel1, which encodes a 1,3-ß-glucanosyltransferase, was also upregulated. Instead of the AfSec1 deletion strain, the AfSec1-ΔP strain was constructed, in which the promoter region of AfSec1 was deleted, and AfSec1 expression was not detected in the AfSec1-ΔP strain. The expression of AfSec1 was recovered by the introduction of the promoter region (the AfSec1-ΔP/P strain). The nonprocessed form of Gel1 was identified in the AfSec1-ΔP strain, which lacked the promoter, but mature forms of Gel1 were found in the wild-type and in AfSec1-ΔP/P, which was the promoter complementation strain. In the plate assay, the AfSec1-ΔP strain showed higher sensitivity against caspofungin than the wild-type. However, compared with the wild-type, the deletion strain showed no difference in the sensitivity to other antifungal drugs, such as amphotericin B and voriconazole, which inhibit different targets compared with caspofungin. The AfSec1-ΔP strain exhibited ∼20% lower levels of ß-glucan in the cell wall than the wild-type. Finally, the virulence decreased when the promoter region of AfSec1 was deleted, as observed in the murine infection test and conidia-killing assay using human macrophages and neutrophils. These results suggest that AfSec1 exerts signal peptidase activity on its target Gel1 and has an important role in fungal pathogenesis.

We identified the novel signal peptidase AfSec1 from A. fumigatus. AfSec1 which removes the signal peptide of 1,3-ß-glucanosyltransferases, is a virulence factor and is a potential target for a new antifungal drug.

Regulation of Copper Metabolism by Nitrogen Utilization in Saccharomyces cerevisiae.

To understand the relationship between carbon or nitrogen utilization and iron homeostasis, we performed an iron uptake assay with several deletion mutants with partial defects in carbon or nitrogen metabolism. Among them, some deletion mutants defective in carbon metabolism partially and the MEP2 deletion mutant showed lower iron uptake activity than the wild type. Mep2 is known as a high-affinity ammonia transporter in Saccharomyces cerevisiae. Interestingly, we found that nitrogen starvation resulted in lower iron uptake activity than that of wild-type cells without downregulation of the genes involved in the high-affinity iron uptake system FET3/FTR1. However, the gene expression of FRE1 and CTR1 was downregulated by nitrogen starvation. The protein level of Ctr1 was also decreased by nitrogen starvation, and addition of copper to the nitrogen starvation medium partially restored iron uptake activity. However, the expression of MAC1, which is a copper-responsive transcriptional activator, was not downregulated by nitrogen starvation at the transcriptional level but was highly downregulated at the translational level. Mac1 was downregulated dramatically under nitrogen starvation, and treatment with MG132, which is an inhibitor of proteasome-dependent protein degradation, partially attenuated the downregulation of Mac1. Taken together, these results suggest that nitrogen starvation downregulates the high-affinity iron uptake system by degrading Mac1 in a proteasome-dependent manner and eventually downregulates copper metabolism.

Identification of the Antidepressant Function of the Edible Mushroom Pleurotus eryngii.

Pleurotus eryngii produces various functional molecules that mediate physiological functions in humans. Recently, we observed that P. eryngii produces molecules that have antidepressant functions. An ethanol extract of the fruiting body of P. eryngii was obtained, and the extract was purified by XAD-16 resin using an open column system. The ethanol eluate was separated by HPLC, and the fraction with an antidepressant function was identified. Using LC-MS, the molecular structure of the HPLC fraction with antidepressant function was identified as that of tryptamine, a functional molecule that is a tryptophan derivative. The antidepressant effect was identified from the ethanol extract, XAD-16 column eluate, and HPLC fraction by a serotonin receptor binding assay and a cell-based binding assay. Furthermore, a forced swimming test (FST) showed that the mice treated with purified fractions of P. eryngii exhibited decreased immobility time compared with nontreated mice. From these results, we suggest that the extract of P. eryngii has an antidepressant function and that it may be employed as an antidepressant health supplement.

The Role of Zinc in Copper Homeostasis of Aspergillus fumigatus.

Copper is an essential metal ion that performs many physiological functions in living organisms. Deletion of Afmac1, which is a copper-responsive transcriptional activator in A. fumigatus, results in a growth defect on aspergillus minimal medium (AMM). Interestingly, we found that zinc starvation suppressed the growth defect of the Δafmac1 strain on AMM. In addition, the growth defect of the Δafmac1 strain was recovered by copper supplementation or introduction of the CtrC gene into the Δafmac1 strain. However, chelation of copper by addition of BCS to AMM failed to recover the growth defect of the Δafmac1 strain. Through Northern blot analysis, we found that zinc starvation upregulated CtrC and CtrA2, which encode membrane copper transporters. Interestingly, we found that the conserved ZafA binding motif 5'-CAA(G)GGT-3' was present in the upstream region of CtrC and CtrA2 and that mutation of the binding motif led to failure of ZafA binding to the upstream region of CtrC and upregulation of CtrC expression under zinc starvation. Furthermore, the binding activity of ZafA to the upstream region of CtrC was inversely proportional to the zinc concentration, and copper inhibited the binding of ZafA to the upstream region of CtrC under a low zinc concentration. Taken together, these results suggest that ZafA upregulates copper metabolism by binding to the ZafA binding motif in the CtrC promoter region under low zinc concentration, thus regulating copper homeostasis. Furthermore, we found that copper and zinc interact in cells to maintain metal homeostasis.

Response to the letter 'Absent regulation of iron acquisition by the copper regulator Mac1 in A. fumigatus'.

The answer to the letter 'Absent regulation of iron acquisition by the copper regulator Mac1 in A. fumigatus' has been prepared. We explained our data and showed supplementary information to answer the questions. And we respect the results of other groups first and explain the differences from our results.

The Role of Zinc in Gliotoxin Biosynthesis of Aspergillus fumigatus.

Zinc performs diverse physiological functions, and virtually all living organisms require zinc as an essential trace element. To identify the detailed function of zinc in fungal pathogenicity, we carried out cDNA microarray analysis using the model system of Aspergillus fumigatus, a fungal pathogen. From microarray analysis, we found that the genes involved in gliotoxin biosynthesis were upregulated when zinc was depleted, and the microarray data were confirmed by northern blot analysis. In particular, zinc deficiency upregulated the expression of GliZ, which encodes a Zn2-Cys6 binuclear transcription factor that regulates the expression of the genes required for gliotoxin biosynthesis. The production of gliotoxin was decreased in a manner inversely proportional to the zinc concentration, and the same result was investigated in the absence of ZafA, which is a zinc-dependent transcription activator. Interestingly, we found two conserved ZafA-binding motifs, 5'-CAAGGT-3', in the upstream region of GliZ on the genome and discovered that deletion of the ZafA-binding motifs resulted in loss of ZafA-binding activity; gliotoxin production was decreased dramatically, as demonstrated with a GliZ deletion mutant. Furthermore, mutation of the ZafA-binding motifs resulted in an increase in the conidial killing activity of human macrophage and neutrophil cells, and virulence was decreased in a murine model. Finally, transcriptomic analysis revealed that the expression of ZafA and GliZ was upregulated during phagocytosis by macrophages. Taken together, these results suggest that zinc plays an important role in the pathogenicity of A. fumigatus by regulating gliotoxin production during the phagocytosis pathway to overcome the host defense system.

A copper transcription factor, AfMac1, regulates both iron and copper homeostasis in the opportunistic fungal pathogen Aspergillus fumigatus.

Although iron and copper are co-ordinately regulated in living cells, the homeostatic effects of each of these metals on the other remain unknown. Here, we show the function of AfMac1, a transcriptional activator of the copper and iron regulons of Aspergillus fumigatus, on the interaction between iron and copper. In addition to the copper-specific AfMac1-binding motif 5'-TGTGCTCA-3' found in the promoter region of ctrC, the iron-specific AfMac1-binding motif 5'-AT(C/G)NN(A/T)T(A/C)-3' was identified in the iron regulon but not in the copper regulon by ChIP sequence analysis. Furthermore, mutation of the AfMac1-binding motif of sit1 eliminated AfMac1-mediated sit1 up-regulation. Interestingly, the regulation of gene expression in the iron regulon by AfMac1 was not affected by copper and vice versa AfMac1 localized to the nucleus under iron- or copper-depleted conditions, and AfMac1 was mostly detected in the cytoplasm under iron- or copper-replete conditions. Taken together, these results suggest that A. fumigatus independently regulates iron and copper homeostasis in a manner that involves AfMac1 and mutual interactions.

Efficacy of HL036 versus Cyclosporine A in the Treatment of Naturally Occurring Canine Keratoconjunctivitis Sicca.

PURPOSES: To (i) evaluate the efficacy and safety of HL036, a tumor-necrosis factor (TNF)-α-blocking protein, in the treatment of naturally occurring canine keratoconjunctivitis sicca (KCS) and (ii) compare these features with those of 1% cyclosporine A (CsA). MATERIALS AND METHODS: Dogs (n = 29) diagnosed with KCS were randomly assigned to receive one drop topical aqueous HL036 (0.2, 1, or 5 mg/mL) or 1% CsA in the affected eye(s) at 12-h intervals for 42 days. Schirmer's tear test (STT), fluorescein corneal staining (FCS), and clinical-sign scores were evaluated prior to application (day-0) and on days 14, 28, and 42 post-treatment. Of the 29 dogs enrolled, 19 (65.5%) received HL036 (HL036 group) and 10 (34.5%) received 1% CsA (CsA group). A linear mixed-effects model analysis was performed to determine score differences between groups and over time. RESULTS: After treatment, clinical-sign scores and STT values had significantly improved compared with baseline levels in dogs of both treatment groups. Decreases in total clinical-sign scores for the HL036-group were greater than those of 1% CsA group. No severe adverse reactions were noted in either group. CONCLUSIONS: Our findings suggest that topical aqueous HL036 is well-tolerated and more effective than 1% CsA for treating naturally occurring canine KCS.

Sinonasal characteristics and quality of life by SNOT-22 in adult patients with cystic fibrosis.

The prevalence of chronic sinus disease in cystic fibrosis (CF) has gradually increased. Sinonasal involvement may have influence on pulmonary exacerbations and can have a negative impact on the quality of life. To evaluate nasal characteristics and quality of life in adult patients with CF; to establish an association and determine the predictors in SNOT-22 questionnaire. Cross- sectional study with prospective data collection was performed to evaluate adult CF patients. Patients underwent clinical evaluation, lung function tests, nasal endoscopy, and paranasal sinuses CT scan. All the patients answered the SNOT-22 questionnaire. RESULTS: A total of 91 patients were allocated, of which, 45.1% were male. Patients were divided into three groups by SNOT-22. A high average age, late age of diagnosis, rhinitis symptoms, and clinical criteria for rhinosinusitis were observed more frequently in patients with high SNOT-22 scores (p < 0.05). Overall, 84.6% patients had abnormal CT findings, with aplasia/hypoplasia of the sphenoid sinus being the most common finding. In multiple regression model, age, female gender, and Pseudomonas aeruginosa in the sputum were associated with high SNOT-22 scores in the nasal domain. Hyposmia and lack of medial bulging of lateral nasal wall were variables associated with high SNOT-22 scores in the quality of life domain. In total score, there was a positive association with age and the presence of P. aeruginosa in sputum. Despite high prevalence of abnormal tomographic findings, patients reported mild intensity of sinonasal symptoms. Advanced age and the presence of P. aeruginosa were associated with higher SNOT-22 scores.

Physical interaction between Sit1 and Aft1 upregulates FOB uptake activity by inhibiting protein degradation of Sit1 in Saccharomyces cerevisiae.

Previously, we reported that Aft1 regulates Sit1 by modulating the ubiquitination of Sit1 in Saccharomyces cerevisiae. Here, we report the function of the physical interaction between Sit1 and Aft1 in ferrioxamine B (FOB) uptake. The interaction between Sit1 and Aft1 induced protein localization of Sit1 to the plasma membrane, and more Sit1 was detected in the plasma membrane when Sit1 and Aft1 were coexpressed compared with Sit1 expression alone. The MSN5-deletion mutant, which failed to translocate Aft1 to the cytosolic compartment, showed lower FOB uptake activity than the wild type. However, higher free iron uptake activity was detected in the MSN5-deletion mutant. Furthermore, the strain transformed with AFT1-1(up) plasmid, which failed to regulate Aft1 via iron concentration and accumulated Aft1 in the nucleus, showed lower FOB uptake activity. The Aft1 Y179F mutant, which contained a tyrosine residue that was changed to phenylalanine, failed to interact physically with Sit1 and showed more degradation of the Sit1 and, ultimately, lower FOB uptake activity. Additionally, we found that MG132 and PMSF, which are inhibitors of proteasomes and serine proteases, respectively, increased the Sit1 protein level. Taken together, these results suggest that the protein-protein interaction between Sit1 and Aft1 is an important factor in the FOB uptake activity of Sit1.

Chronic rhinosinusitis and nasal polyposis in cystic fibrosis: update on diagnosis and treatment.

Although cystic fibrosis (CF) is an irreversible genetic disease, advances in treatment have increased the life expectancy of CF patients. Upper airway involvement, which is mainly due to pathological changes in the paranasal sinuses, is prevalent in CF patients, although many are only mildly symptomatic (with few symptoms). The objective of this literature review was to discuss the pathophysiology and current therapeutic management of chronic rhinosinusitis (CRS) in CF patients. The review was based on current evidence, which was classified in accordance with the Oxford Centre for Evidence-Based Medicine criteria. When symptomatic, CRS with nasal polyps can affect quality of life and can lead to pulmonary exacerbations, given that the paranasal sinuses can be colonized with pathogenic bacteria, especially Pseudomonas aeruginosa. Infection with P. aeruginosa plays a crucial role in morbidity and mortality after lung transplantation in CF patients. Although clinical treatment of the upper airways is recommended as initial management, this recommendation is often extrapolated from studies of CRS in the general population. When sinonasal disease is refractory to noninvasive therapy, surgery is indicated. Further studies are needed in order to gain a better understanding of upper airway involvement and improve the management of CRS in CF patients, with the objective of preserving lung function and avoiding unnecessary invasive procedures.

A fibrose cística (FC) é uma doença genética irreversível, mas os avanços no tratamento têm aumentado a expectativa de vida dos pacientes. O acometimento das vias aéreas superiores, principalmente por alterações patológicas dos seios paranasais, é prevalente nesses pacientes, embora muitos apresentem poucos sintomas. O objetivo desta revisão é discutir a fisiopatologia e o manejo terapêutico atual da rinossinusite crônica (RSC) na FC. A revisão fundamentou-se nas evidências mais recentes, classificadas em conformidade com os critérios do Oxford Centre for Evidence-Based Medicine. Quando sintomática, a RSC com pólipos nasais pode afetar a qualidade de vida e as exacerbações pulmonares, já que os seios paranasais podem ser colonizados por bactérias patogênicas, principalmente a Pseudomonas aeruginosa. Essa bactéria tem papel crucial na morbidade e mortalidade após o transplante pulmonar em pacientes com FC. Embora o tratamento clínico das vias aéreas superiores seja indicado no manejo inicial, a indicação é muitas vezes extrapolada de estudos sobre RSC na população geral. A cirurgia é a alternativa quando o quadro nasossinusal é refratário à terapia não invasiva. Mais estudos são necessários para compreender melhor o acometimento das vias aéreas superiores e melhorar o manejo da RSC na FC, a fim de preservar a função pulmonar e evitar procedimentos invasivos desnecessários.

Chronic rhinosinusitis and nasal polyposis in cystic fibrosis: update on diagnosis and treatment / Rinossinusite crônica e polipose nasossinusal na fibrose cística: atualização sobre diagnóstico e tratamento

Although cystic fibrosis (CF) is an irreversible genetic disease, advances in treatment have increased the life expectancy of CF patients. Upper airway involvement, which is mainly due to pathological changes in the paranasal sinuses, is prevalent in CF patients, although many are only mildly symptomatic (with few symptoms). The objective of this literature review was to discuss the pathophysiology and current therapeutic management of chronic rhinosinusitis (CRS) in CF patients. The review was based on current evidence, which was classified in accordance with the Oxford Centre for Evidence-Based Medicine criteria. When symptomatic, CRS with nasal polyps can affect quality of life and can lead to pulmonary exacerbations, given that the paranasal sinuses can be colonized with pathogenic bacteria, especially Pseudomonas aeruginosa. Infection with P. aeruginosa plays a crucial role in morbidity and mortality after lung transplantation in CF patients. Although clinical treatment of the upper airways is recommended as initial management, this recommendation is often extrapolated from studies of CRS in the general population. When sinonasal disease is refractory to noninvasive therapy, surgery is indicated. Further studies are needed in order to gain a better understanding of upper airway involvement and improve the management of CRS in CF patients, with the objective of preserving lung function and avoiding unnecessary invasive procedures.

A fibrose cística (FC) é uma doença genética irreversível, mas os avanços no tratamento têm aumentado a expectativa de vida dos pacientes. O acometimento das vias aéreas superiores, principalmente por alterações patológicas dos seios paranasais, é prevalente nesses pacientes, embora muitos apresentem poucos sintomas. O objetivo desta revisão é discutir a fisiopatologia e o manejo terapêutico atual da rinossinusite crônica (RSC) na FC. A revisão fundamentou-se nas evidências mais recentes, classificadas em conformidade com os critérios do Oxford Centre for Evidence-Based Medicine. Quando sintomática, a RSC com pólipos nasais pode afetar a qualidade de vida e as exacerbações pulmonares, já que os seios paranasais podem ser colonizados por bactérias patogênicas, principalmente a Pseudomonas aeruginosa. Essa bactéria tem papel crucial na morbidade e mortalidade após o transplante pulmonar em pacientes com FC. Embora o tratamento clínico das vias aéreas superiores seja indicado no manejo inicial, a indicação é muitas vezes extrapolada de estudos sobre RSC na população geral. A cirurgia é a alternativa quando o quadro nasossinusal é refratário à terapia não invasiva. Mais estudos são necessários para compreender melhor o acometimento das vias aéreas superiores e melhorar o manejo da RSC na FC, a fim de preservar a função pulmonar e evitar procedimentos invasivos desnecessários.

An experimental model of chronic rhinosinusitis in rabbits without bacterial inoculation.

PURPOSE: Evaluate and compare two different experimental techniques of maxillary sinus ostium occlusion using N-butyl cyanoacrylate in developing chronic histological findings without the inoculation of pathogenic bacteria among rabbits. METHODS: In a randomized study, sixteen New Zealand rabbits were assigned for occlusion of the right maxillary sinus through a transmaxillary approach or through the roof of the nasal cavity. The contralateral sinus served as a control. After 12 weeks, the animals were sacrificed for blinded histopathological analysis of the maxillary sinus mucosa. RESULTS: Histopathological changes consistent with CRS were found in eight (100%) of the maxillary sinuses approached transmaxillary and three of those through the roof of the nasal cavity (37.5%), p 0.008 and 0.250, respectively, comparing with the control side. Chronic mucosal changes were significantly better induced using the transmaxillary approach (p 0.026). CONCLUSION: It is possible to induce a model of chronic sinusitis among rabbits with transmaxillary sinus occlusion without bacterial inoculation. This model can be replicated for future cellular studies.

An experimental model of chronic rhinosinusitis in rabbits without bacterial inoculation

PURPOSE: Evaluate and compare two different experimental techniques of maxillary sinus ostium occlusion using N-butyl cyanoacrylate in developing chronic histological findings without the inoculation of pathogenic bacteria among rabbits. METHODS: In a randomized study, sixteen New Zealand rabbits were assigned for occlusion of the right maxillary sinus through a transmaxillary approach or through the roof of the nasal cavity. The contralateral sinus served as a control. After 12 weeks, the animals were sacrificed for blinded histopathological analysis of the maxillary sinus mucosa. RESULTS: Histopathological changes consistent with CRS were found in eight (100%) of the maxillary sinuses approached transmaxillary and three of those through the roof of the nasal cavity (37.5%), p 0.008 and 0.250, respectively, comparing with the control side. Chronic mucosal changes were significantly better induced using the transmaxillary approach (p 0.026). CONCLUSION: It is possible to induce a model of chronic sinusitis among rabbits with transmaxillary sinus occlusion without bacterial inoculation. This model can be replicated for future cellular studies. .

Sinonasal alterations in computed tomography scans in cystic fibrosis: a literature review of observational studies.

BACKGROUND: Almost all cystic fibrosis (CF) patients reveal upper airway involvement in computed tomography (CT) scans. Sinonasal pathology has become a challenging issue because there are few studies to guide appropriate management. The objective of this study was to provide information about paranasal sinus CT manifestations in CF patients, mainly in adulthood. METHODS: We performed a literature review of descriptive studies about CT sinonasal findings in CF patients using the following databases: MEDLINE, EMBASE, Web of Science, LILACS, Scielo, and Cochrane. RESULTS: Eighteen articles were included in this review. There was a high variability in methodological aspects for most of the studies. The most prevalent findings reported were opacification of sinuses, presence of frontal and sphenoidal aplasia or hypoplasia, underdevelopment of paranasal sinuses, and medial bulging of the lateral nasal wall in CT scans. CONCLUSION: There are few studies in the CF adult population regarding sinonasal CT alterations. Many studies report specific pathological features in CF upper airways that could help in the diagnosis of doubtful cases.

Rinossinusite fúngica invasiva aguda com desfecho favorável / Acute invasive fungal rhinosinusitis with favorable outcome

A rinossinusite fúngica invasiva aguda é uma patologia que afeta principalmente pacientes imunocomprometidos, tendo morbidade e mortalidade elevadas.Apresentamos um caso de aspergilose invasiva aguda em paciente imunocomprometido, que apresentou bom desfecho pelo diagnóstico precoce e rápida intervenção. Relato de caso: Menina de 13 anos com diagnóstico de leucemia mieloide aguda interna por neutropenia febril após quimioterapia. TCseios da face mostrou opacificação parcial dos seios à esquerda. Leucograma revelou contagem de 880 leucócitos totais. À endoscopia nasal, constatou-se corneto médio isquêmico à esquerda. Levada de urgência ao bloco cirúrgico e realizado debridamento amplo. Anatomopatológico revelou áreas de necrose isquêmica e estruturas fúngicas angioinvasivas, compatíveis com aspergilose.Exame de cultura de fungo confirmou Aspergillus flavus. Iniciado tratamento com voriconazol. Paciente realiza acompanhamento com a Oncologia Pediátrica,mantendo-se em remissão oncológica e sem recidiva fúngica. A frequência das infecções micóticas do nariz e seios paranasais vem aumentando nas últimas décadas. Há um quadro febril, com ou sem sintomas nasais, sem resposta a antibióticos. Endoscopia nasal é o exame mais importante. O corneto médio costuma ser mais acometido. Não há sinais patognomônicos na TC, servindo mais como um instrumento de diagnóstico diferencial, planejamento emonitoramento pós-terapêutico. A correção concomitante de qualquer distúrbio metabólico ou imunológico subjacente é o fator prognóstico mais importante.Deve ser introduzida terapia antifúngica associada ao debridamento cirúrgico. O risco de contaminação fúngica pode ser minimizado com cuidados de exposição do paciente neutropênico e com a implantação de unidades de internação com filtros HEPA.

Acute invasive fungal sinusitis is a disease that affects primarily immunocompromised patients causing high morbidity and mortality. We present a case of acute invasive aspergillosis in an immunocompromised patient that evolved with a good outcome resulting from early diagnosis and rapid intervention. Case report: a thirteen year-old girl diagnosed with acute myeloid leukemia admitted for febrile neutropenia after chemotherapy. Sinus CT revealed partial opacification of left sinuses. Blood tests showed a number of total leukocytes, count 880. In the nasal endoscopy, we found a left middle turbinate ischemia. Patient was taken to surgical emergency and submitted to extensive debridement. Pathological examination revealed areas of ischemic necrosis and angioinvasive fungal structures consistent with aspergillosis. Examination confirmed Aspergillus flavus; Voriconazole was introduced. Follow-up was performed by pediatric oncology; cancer kept in remission without fungal recurrence. The incidence of fungal infections of the nose and paranasal sinuses has been increasing in recent decades. Fever unresponsive to antibiotics,with or without nasal symptoms, is the most suggestive sign of this disease that typically affects the middle turbinate. Nasal endoscopy is its most effective diagnostic test. There are no pathognomonic signs using CT, which serves moreas a post-treatment tool for differential diagnosis, planning, and monitoring.Concomitant correction of any underlying metabolic or immune disorder is the most important prognostic factor. Antifungal therapy should be introduced and associated with surgical debridement. Risk of fungal contamination can be minimized with care of exposure of neutropenic patients, and with the implantation of hospitalization units with HEPA filters.

Effect of clinical pathways on the management of acute asthma in the emergency department: five years of evaluation.

There is a wide variability in clinical practice for treating acute asthma (AA) in the emergency department (ED), interfering in the quality of care. The purpose of this study was to evaluate the impact of a clinical pathway on the management of AA in the ED. We conducted a prospective before-after study of patients presenting with AA to the adult ED, during five separate periods (from January to March): in 2001 (pre-protocol group), 2002, 2003, 2004, and 2005 (6 months without educational reinforcement). We evaluated the effects of the recommendations on objective assessment of severity, diagnostic resource utilization, use of recommended and non-recommended therapy, and outcomes. The 2001, 2002, 2003, 2004, and 2005 groups comprised, respectively: 108, 96, 97, 98, and 101 patients. There was a significant increase in the use of pulse oximetry (8.3%, 77.1%, 88.7%, 95.9%, and 97.0%, respectively; p < 0.001). There was an increase in the use of peak expiratory flow rate from 2001 to 2004 (4.6%, 20.8%, 28.9%, and 48.0%) and a decrease after a period without educational efforts (29.7%, p < 0.001). Although the overall use of systemic corticosteroids was not changed, there was a significant increase in the use of oral steroids (p < 0.001). There was a decrease in aminophylline utilization (p = 0.005). Length of stay in the ED was significantly reduced (p = 0.04). There was no effect on hospital admission or emergency discharge (p = 0.193). The AA clinical pathway applied in the ED was associated with a positive effect on improving the quality of care.

Avaliação prognóstica precoce da asma aguda na sala de emergência / Early prognosis of acute asthma in the emergency room

OBJETIVO: Estudar medidas clínicas e funcionais pulmonares utilizadas nos primeiros quinze minutos de manejo da asma aguda em um serviço de emergência, para predição prognóstica. MÉTODOS: Estudo de coorte, prospectivo, que incluiu pacientes consecutivos com asma aguda, com idades entre doze e 55 anos e medida do pico de fluxo expiratório menor ou igual a 50 por cento do previsto. Realizaram-se avaliações na admissão, aos quinze minutos e em quatro horas após o início do tratamento. O tratamento incluiu salbutamol e ipratrópio, administrados por aerossol dosimetrado com espaçador, e 100 mg de hidrocortisona intravenosa. O desfecho favorável foi definido pelo pico de fluxo expiratório maior ou igual a 50 por cento do previsto após a quarta hora de tratamento, e o desfecho desfavorável pelo pico de fluxo expiratório menor que 50 por cento do previsto. RESULTADOS: Tiveram desfecho favorável 27 pacientes e desfavorável 24. A análise multivariada identificou o pico de fluxo expiratório em porcentagem do previsto aos quinze minutos como variável mais preditiva. O pico de fluxo expiratório maior ou igual a 40 por cento aos quinze minutos mostrou significativa contribuição em predizer desfecho favorável (sensibilidade = 0,74, especificidade = 1,00 e valor preditivo positivo = 1,00). O pico de fluxo expiratório menor que 30 por cento aos quinze minutos contribuiu para predizer desfecho desfavorável (sensibilidade = 0,54, especificidade = 0,93 e valor preditivo positivo = 0,87). CONCLUSÃO: O estudo sugeriu que a medida do pico de fluxo expiratório aos quinze minutos do manejo da asma aguda em um serviço de emergência é um instrumento útil para avaliação prognóstica.

Early prognosis of acute asthma in the emergency room.

OBJECTIVE: To evaluate clinical and pulmonary function measurements taken in the first fifteen minutes of the assessment of acute asthma in the emergency room and used for prognostic purposes. METHODS: A prospective cohort study involving consecutive patients with acute asthma. Only patients who were between the ages of 12 and 55 and presented peak expiratory flow rates < or = 50% of predicted were included. Evaluations were performed upon admission, then again at 15 minutes and 4 hours after the initiation of treatment. Treatment included albuterol and ipratropium delivered by metered-dose inhaler with a spacer, together with 100 mg of intravenous hydrocortisone. Favorable outcomes were defined as peak expiratory flow > or = 50% of predicted after 4 hours of treatment, and unfavorable outcomes were defined as peak expiratory flow < 50% after 4 hours of treatment. RESULTS: Favorable outcomes were seen in 27 patients, and unfavorable outcomes were seen in 24 patients. In the multivariate analysis, peak expiratory flow as percentage of predicted was identified as the variable with the highest predictive value. A peak expiratory flow > or = 40% after 15 minutes of treatment showed significant power in predicting a favorable outcome (sensitivity = 0.74, specificity = 1.00, and positive predictive value = 1.00). A peak expiratory flow < 30% after 15 minutes of treatment was predictive of a poor outcome (sensitivity = 0.54, specificity = 0.93, and positive predictive value = 0.87). CONCLUSION: Our results suggest that measuring peak expiratory flow after 15 minutes of management in the emergency room is a useful tool for predicting outcomes in cases of acute asthma.