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ABSTRACT: BACKGROUND: Numerous cases of horizontal transfers (HTs) have been described for eukaryote genomes, but in contrast to prokaryote genomes, no whole genome evaluation of HTs has been carried out. This is mainly due to a lack of parametric methods specially designed to take the intrinsic heterogeneity of eukaryote genomes into account. We applied a simple and tested method based on local variations of genomic signatures to analyze the genome of the pathogenic fungus Aspergillus fumigatus. RESULTS: We detected 189 atypical regions containing 214 genes, accounting for about 1Mb of DNA sequences. However, the fraction of atypical DNA detected was smaller than the average amount detected in the same conditions in prokaryote genomes (3.1% vs 5.6%). It appeared that about one third of these regions contained no annotated genes, a proportion far greater than in prokaryote genomes. When analyzing the origin of these HTs by comparing their signatures to a home made database of species signatures, 3 groups of donor species emerged: bacteria (40%), fungi (25%), and viruses (22%). It is to be noticed that though inter-domain exchanges are confirmed, we only put in evidence very few exchanges between eukaryotic kingdoms. CONCLUSIONS: In conclusion, we demonstrated that HTs are not negligible in eukaryote genomes, bearing in mind that in our stringent conditions this amount is a floor value, though of a lesser extent than in prokaryote genomes. The biological mechanisms underlying those transfers remain to be elucidated as well as the biological functions of the transferred genes.

Research into the interaction of fungi with the host has provided significant contributions to mammalian immunology. Here, I briefly review the most notable of these contributions, starting from the time of Metchnikoff, and highlight their impact on our understanding of immunity.

When various wild strains of Penicillium lanosum and Aspergillus niger were placed in the same mild laboratory environment, their frequencies of new spontaneous mutations were clearly related to whether they had been isolated from a region of high or low microclimatic stress. In the mild environment, the total frequencies of conidial color and morphological mutations in P. lanosum, summed over all relevant loci, ranged from 0.29% to 2.4% for six strains from the north-facing, less stressful "European" slope (ES/NFS) of "Evolution Canyon" I, compared with 6.5-11.6% for five strains from the south-facing "African" slope (AS/SFS), which is a much more stressful environment, being harsher, drier, more fluctuating in temperature, and receiving up to eight times more UV radiation than the opposite slope. The corresponding figures for A. niger were 0.42-1.50% for three strains from the ES/NFS and 2.3-4.9% for six strains from the AS/SFS. The more mutagenic environment of the AS/SFS than of the ES/NFS means that, in Evolution Canyon, the mutation frequency differences between the very stressful environment and the less stressful environment are probably even larger than the 4- and 6-fold differences found here in a mild laboratory environment. The evidence from these two filamentous fungi, which have no sexual cycle, is that there are inherited differences in spontaneous mutation rates according to the levels of stress in the environment, and this feature may well be adaptive. Evolution Canyon I is at Nahal Oren, Mount Carmel, Israel.

Background. Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. Methods. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. Results. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. Conclusions. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Background. The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. Methods. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. Results. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. Conclusions. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

ABSTRACT: BACKGROUND: There are very few reports of Aspergillus fumigatus causing endogenous endophthalmitis (EAE) in immunocompetent individuals although it is well recognised in the immunocompromised. Treatment can be with intravitreal, intravenous and oral antifungal agents. The benefit of an oral agent is clear however the concentration of voriconazole in the inflamed eye after oral administration has not previously been documented. CASE PRESENTATION: We present a case of EAE in an immunocompetent 78-year-old Caucasian female who was subsequently managed with oral voriconazole. Using a bioassay, we show an appropriate voriconazole concentration in serum and vitreous samples. CONCLUSION: This case adds to the limited literature on the prevalence of endogenous endophthalmitis in immunocompetent patients and supports the use of voriconazole in such cases.

'Transplant tourism,' the practice of traveling abroad to acquire an organ, has emerged as an issue in kidney transplantation. We treated a patient who developed invasive aspergillosis of the allograft vascular anastomosis after receiving a kidney transplant in Pakistan, prompting us to review the literature of invasive mycoses among commercial organ transplant recipients. We reviewed all published cases of infections in solid organ transplant recipients who bought their organs abroad and analyzed these reports for invasive fungal infections. Including the new case reported here, 19 cases of invasive fungal infections post commercial kidney transplant occurring in 17 patients were analyzed. Infecting organisms were Aspergillus species (12/19; 63%), Zygomycetes (5/19; 26%), and other fungi (2/19; 5%). Invasive mold infections were present at the transplanted graft in 6/17 patients (35%) with graft loss or death in 13/17 (76%) of patients and overall mortality (10/17) 59%. Invasive fungal infections, frequently originating at the graft site, have emerged as a devastating complication of commercial renal transplant and are associated with high rates of graft loss and death.

BACKGROUND: Aspergillus fumigatus is associated with both invasive and allergic pulmonary diseases, in different hosts. The organism is inhaled as a spore, which, if not cleared from the airway, germinates into hyphal morphotypes that are responsible for tissue invasion and resultant inflammation. Hyphae secrete multiple products that function as antigens, evoking both a protective (T(H)1-T(H)17) and destructive allergic (T(H)2) immunity. How Aspergillus allergens (Asp f proteins) participate in the development of allergic sensitization is unknown. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether Asp f proteins are strictly associated with T(H)2 responses, or represent soluble hyphal products recognized by healthy hosts, human T cell responses to crude and recombinant products were characterized by ELISPOT. While responses (number of spots producing IFN-gamma, IL-4 or IL-17) to crude hyphal antigen preparations were weak, responses to recombinant Asp f proteins were higher. Recombinant allergens stimulated cells to produce IFN-gamma more so than IL-4 or IL-17. Volunteers exhibited a diverse CD4+ and CD8+ T cell antigen recognition profile, with prominent CD4 T(H)1-responses to Asp f3 (a putative peroxismal membrane protein), Asp f9/16 (cell wall glucanase), Asp f11 (cyclophilin type peptidyl-prolyl isomerase) and Asp f22 (enolase). Strong IFN-gamma responses were reproduced in most subjects tested over 6 month intervals. CONCLUSIONS: Products secreted after conidial germination into hyphae are differentially recognized by protective T cells in healthy, non-atopic individuals. Defining the specificity of the human T cell repertoire, and identifying factors that govern early responses may allow for development of novel diagnostics and therapeutics for both invasive and allergic Aspergillus diseases.

F-9775A and F-9775B are cathepsin K inhibitors that arise from a chromatin remodelling deletant strain of Aspergillus nidulans. A polyketide synthase gene has been determined to be responsible for their formation and for the simpler, archetypical polyketide orsellinic acid. We have discovered simple culture conditions that result in the production of the three compounds, and this facilitates analysis of the genes responsible for their synthesis. We have now analysed the F9775/orsellinic acid gene cluster using a set of targeted deletions. We find that the polyketide synthase alone is required for orsellinic acid biosynthesis and only two additional genes in the cluster are required for F9775 A and B synthesis. Our deletions also yielded the bioactive metabolites gerfelin and diorcinol.

Fifteen species of Aspergillus were screened for occurrence of lectins. Nine of them (A. sydowii, A. candidus, A. allahabadi, A. terricola, A. ficuum, A. sparsus, A. carneus, A. pulvinus and A. aculeatus) were found to possess lectin activity. None of the species elaborated lectin in culture supernatant. All the lectins agglutinated rat, pig and rabbit erythrocytes. A. sydowii, A. candidus, A. allahabadi, A. terricola, A. ficuum, A. sparsus, A. carneus and A. aculeatus lectins agglutinated all human type erythrocytes equally, while A. pulvinus lectin specifically agglutinated human type A and O erythrocytes. Neuraminidase and protease treatment to erythrocytes substantially augmented lectin titres manyfold. Lectins showed specificity to mucin and asialofetuin and all of them were specific to L-arabinose except that of A. carneus. Lectins from A. sydowii, A. ficuum, A. sparsus and A. carneus displayed remarkable specificities to D-xylose. Maximum lectin activity was expressed by 11 day old cultures of A. sydowii (titre 32), A. ficuum (titre 64) and A. sparsus (titre 1024). Lectins from A. aculeatus, A. candidus and A. terricola were expressed by 7-10 days, 6-9 days and 5-11 days old cultures, respectively. A. allahabadi cultures exhibited maximum lectin activity (titre 32) after 8-10 days of cultivation. A. carneus and A. pulvinus expressed optimal titres of 32 and 8, respectively on the 9th day.

Earlier articles

The syndrome of allergic bronchopulmonary aspergillosis is exceedingly rare in the United States. We have studied a 9-year-old child who fulfills all of the clinical and laboratory criteria of this syndrome, and who is believed to be the first patient in the pediatric age range reported in this country. Clinical and laboratory features include wheezing with fever, transient pulmonary infiltrates, eosinophilia of blood and sputum, septate hyphae and positive culture for Aspergillus fumigatus in the sputum, and skin-sensitizing antibody and precipitating antibody to Aspergillus fumigatus. Successful treatment included administration of corticosteroids orally and of amphotericin B by aerosol.

Although computed tomography (CT) of the thorax has been compared to plain chest radiography and bronchography for demonstration of central bronchiectasis (CB) in allergic bronchopulmonary aspergillosis (ABPA), the CT presentation of the disease is yet to be highlighted. With this in view, the CT appearances in 23 patients with ABPA were evaluated. The scans were assessed for bronchial, parenchymal and pleural abnormalities. Central bronchiectasis was identified in all patients, involving 114 (85%) of the 134 lobes and 210 (52%) of the 406 segments studied. Other bronchial abnormalities such as dilated and totally occluded bronchi (11 patients), air-fluid levels within dilated bronchi (five patients), bronchial wall thickening (10 patients) and parallel-line shadows (seven patients) were also observed. Parenchymal abnormalities, which had a predilection for upper lobes, included consolidation in 10 (43%) patients, collapse in four (17%) patients and parenchymal scarring in 19 (83%) patients. A total of six cavities were seen in three (13%) patients, and an emphysematous bullae was detected in one (4%) patient. The pleura was involved in 10 (43%) patients. Ipsilateral pleural effusion with collapse was observed in one patient, while in nine other patients, parenchymal, lesions extended up to the pleura. Concomitant allergic Aspergillus sinusitis (AAS) was also detected in three (13%) of the 23 patients. Computed tomography of the thorax in patients with ABPA provides a sensitive method for the assessment of bronchial, parenchymal and pleural abnormalities, and should constitute a part of the diagnostic work of the disease.

Allergic bronchopulmonary aspergillosis (ABPA) complicates asthma and cystic fibrosis. The survival factors in Aspergillus fumigatus that support saprophytic growth in bronchial mucus are not understood. Prednisone remains the most definitive treatment but need not be administered indefinitely. MHC II -restricted CD4(+) T( H)2 clones have been derived from patients with ABPA. The total serum IgE concentration is elevated sharply but is "nonspecific. " IgE serum isotypic antibodies to A fumigatus are useful in diagnosis; this is in contrast to the situation for patients with asthma without ABPA. High-resolution computed tomography of the chest demonstrates multiple areas of bronchiectasis in most patients with ABPA and is a useful radiologic tool. Some asthma control patients might have a few bronchiectatic airways, but not to the extent seen in or of the same character as those in ABPA. This review discusses clinical, radiologic, investigational, pathogenetic, and treatment issues of ABPA.

OBJECTIVE: Allergic bronchopulmonary aspergillosis (ABPA) occurs in cases of atopic asthma and may result in important lung disease. Early diagnosis is essential as this disease is responsive to steroids. However, while asthma is common, ABPA is infrequently diagnosed. CT allows precision in the diagnosis of central bronchiectasis (which is virtually pathognomonic of ABPA) and may enable earlier diagnosis. DESIGN: A prospective evaluation of 255 patients with asthma for ABPA, using skin prick testing (SPT) for Aspergillus fumigatus (AF) as a screening tool and incorporating CT into the diagnostic algorithm. SETTING: Asthma clinic, Green Lane Hospital, Auckland, New Zealand. PARTICIPANTS: Patients with asthma. INTERVENTIONS: ABPA was diagnosed using "essential" criteria (ie, asthma, SPT positivity to AF, elevated serum total IgE, elevated serum AF-specific IgE, and pulmonary infiltrates seen on chest radiography or central bronchiectasis seen on CT scan) and "minimal essential" criteria (ie, asthma, SPT positivity, and central bronchiectasis). MEASUREMENTS AND RESULTS: Two hundred fifty-five consecutive patients with asthma who consented to SPT were studied: 218 of 255 patients (86.8%) were atopic; and 47 of 255 patients (21.6%) were AF-positive, of whom 35 accepted further evaluation including CT scanning. A secure diagnosis of ABPA, satisfying all essential criteria, was evident in 9 of 35 patients (25.7%), a proportion that increased to 13 of 35 patients (37.1%) by using the minimal essential diagnostic criteria. CONCLUSIONS: SPT positivity to AF was present in approximately 20% of patients in the asthma clinic. A diagnosis of ABPA is disclosed by CT in 25 to 40% of SPT-positive patients, depending on the selection of diagnostic criteria. These findings support the use of SPT as a screening tool in the asthma clinic and indicate that a routine CT scan is warranted in SPT-positive patients.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a disease that presents with diverse clinicoradiologic manifestations. High-attenuation mucus (HAM) is a characteristic radiologic finding seen in patients with ABPA; however, the clinical significance of the entity remains unknown. AIMS AND OBJECTIVES: To describe the outcome of patients with ABPA who were demonstrated to have HAM, and compare with the outcome of patients without HAM. METHODS: All consecutive patients with asthma presenting to the Chest Clinic of this institute over a 4-year period were screened with an Aspergillus skin test. Patients with positive findings were further investigated, and the diagnosis of ABPA was confirmed based on predefined criteria. The patients were further classified into two groups based on the presence of HAM on HRCT scan. RESULTS: During the study period, 755 patients were screened for ABPA using the Aspergillus skin test; 291 patients (38.5%) had positive findings, and ABPA was diagnosed in 155 patients (mean age, 33.98 years; 76 women). Twenty-nine patients (18.7%) with ABPA were identified to have HAM on HRCT scans at presentation. The baseline characteristics were similar between the two groups, but patients with HAM had higher mean eosinophil counts, higher mean serum total IgE, and higher Aspergillus fumigatus-specific IgE levels. On multivariate analysis, both the severity of bronchiectasis and HAM predicted relapse of ABPA (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.13 to 1.42; and OR, 3.61; 95% CI, 1.23 to 10.61, respectively). Failure to achieve complete remission was influenced by the severity of bronchiectasis but not by HAM (OR, 1.55; 95% CI, 1.29 to 1.85; and OR, 3.41; 95% CI, 0.89 to 13.1, respectively). CONCLUSIONS: HAM impaction in ABPA is associated with initial serologic severity and frequent relapses but does not seem to influence complete remission.

For the first time, an immunodominant Aspergillus nidulans antigen (ASPND1) consistently reactive with serum samples from aspergilloma patients has been purified and characterized, and its coding gene (aspnd1) has been cloned and sequenced. ASPND1 is a glycoprotein with four N-glycosidically-bound sugar chains (around 2.1 kDa each) which are not necessary for reactivity with immune human sera. The polypeptide part is synthesized as a 277-amino-acid precursor of 30.6 kDa that after cleavage of a putative signal peptide of 16 amino acids, affords a mature protein of 261 amino acids with a molecular mass of 29 kDa and a pI of 4.24 (as deduced from the sequence). The ASPND1 protein is 53.1% identical to the AspfII allergen from Aspergillus fumigatus and 48% identical to an unpublished Candida albicans antigen. All of the cysteine residues and most of the glycosylation sites are perfectly conserved in the three proteins, suggesting a similar but yet unknown function. Analysis of the primary structure of the ASPND1 coding gene (aspnd1) has allowed the establishment of a clear relationship between several previously reported A. fumigatus and A. nidulans immunodominant antigens.

A novel dipeptidyl-peptidase (DPP V) was purified from the culture medium of Aspergillus fumigatus. This is the first report of a secreted dipeptidyl-peptidase. The enzyme had a molecular mass of 88 kDa and contained approximately 9 kDa of N-linked carbohydrate. The expression and secretion of dipeptidyl-peptidase varied with the growth conditions; maximal intra- and extracellular levels were detected when the culture medium contained only proteins or protein hydrolysates in the absence of sugars. The gene of DPP V was cloned and showed significant sequence homology to other eukaryotic dipeptidyl-peptidase genes. Unlike the other dipeptidyl-peptidases, which are all intracellular, DPP V contained a signal peptide. Like the genes of other dipeptidyl-peptidases, that of DPP V displayed the consensus sequences of the catalytic site of the nonclassical serine proteases. The biochemical properties of native and recombinant DPP V obtained in Pichia pastoris were unique and were characterized by a substrate specificity limited to the hydrolysis of X-Ala, His-Ser, and Ser-Tyr dipeptides at a neutral pH optimum. In addition, we showed that DPP V is identical to one of the two major antigens used for the diagnosis of aspergillosis.

No abstract. Opening sentences: Mucoid impaction of the bronchi is a clinical syndrome manifested by inspissated mucus plugs of the second-order bronchi. It occurs predominantly in patients who have a history of asthma or obstructive bronchitis and live in low-humidity, warm geographic areas.

A review of the records of 17 patients with stage V (fibrotic stage) allergic bronchopulmonary aspergillosis observed since initial diagnosis (mean observation period, 4.9 years) demonstrated that, of the 11 surviving patients, four have very severe respiratory impairment. The other seven patients have mild or moderate functional impairment, but most of these have not shown clinical deterioration during the observation period. The occurrence of new roentgenographic infiltrates after the time of diagnosis was observed in only one patient in this series. Serum IgE and IgG levels against Aspergillus fumigatus, when compared with those of a control pool of serum samples from asthmatic patients with immediate cutaneous reactivity to Aspergillus, were the most useful immunologic studies diagnostically. Lung biopsy specimens obtained in five patients were of relatively little diagnostic value. All patients have required long-term prednisone therapy for control of asthma. Those patients whose forced expiratory volume in 1 s (FEV1) remained less than or equal to 0.8 L after initial corticosteroid treatment demonstrated a poor prognosis. When only moderate lung damage has occurred at the time of diagnosis, a stable subsequent course may be expected even in patients with stage V disease.

(N.B. The Aspergillus website used to maintain a bibliographic database which was compiled from Medline and Web of Science (GRAsp), but as all users now have access to the former free of charge via the NCBI website and most will have access to Web of Science via their own libraries this resource is currently not being updated. It contains papers dating up to 7th October 2002. Search the GRASp Database here.)