Recognition and Clinical Presentation of Invasive Fungal Disease in Neonates and Children

AW and JK are supported by the Wellcome Trust Strategic Award (grant 097377) and the MRC Centre for Medical Mycology (grant MR/N006364/1) at the University of AberdeenPeer reviewedPublisher PD

Potential Microbiological Effects of Higher Dosing of Echinocandins

The antifungal "paradoxical effect” has been described as the reversal of growth inhibition at high doses of echinocandins, most usually caspofungin. This microbiological effect appears to be a cellular compensatory response to cell wall damage, resulting in alteration of cell wall content and structure as well as fungal morphology and growth. In vitro studies demonstrate this reproducible effect in a certain percentage of fungal isolates, but animal model and clinical studies are less consistent. The calcineurin and Hsp90 cell signaling pathways appear to play a major role in regulating these cellular and structural changes. Regardless of the clinical relevance of this paradoxical growth effect, understanding the specific actions of echinocandins is paramount to optimizing their use at either standard or higher dosing schemes, as well as developing future improvements in our antifungal arsena

Antifungal activity of compounds targeting the Hsp90-calcineurin pathway against various mould species

Objectives Invasive mould infections are associated with a high mortality rate and the emergence of MDR moulds is of particular concern. Calcineurin and its chaperone, the heat shock protein 90 (Hsp90), represent an important pathway for fungal virulence that can be targeted at different levels. We investigated the antifungal activity of compounds directly or indirectly targeting the Hsp90-calcineurin axis against different mould species. Methods The in vitro antifungal activity of the anticalcineurin drug FK506 (tacrolimus), the Hsp90 inhibitor geldanamycin, the lysine deacetylase inhibitor trichostatin A and the Hsp70 inhibitor pifithrin-μ was assessed by the standard broth dilution method against 62 clinical isolates of Aspergillus spp. and non-Aspergillus moulds (Mucoromycotina, Fusarium spp., Scedosporium spp., Purpureocillium/Paecilomyces spp. and Scopulariopsis spp.) Results FK506 had variable antifungal activity against different Aspergillus spp. and was particularly active against Mucor spp. Geldanamycin had moderate antifungal activity against Fusarium spp. and Paecilomyces variotii. Importantly, trichostatin A had good activity against the triazole-resistant Aspergillus ustus and the amphotericin B-resistant Aspergillus terreus as well as the MDR Scedosporium prolificans. Moreover, trichostatin A exhibited synergistic interactions with caspofungin against A. ustus and with geldanamycin against Rhizopus spp. for which none of the other agents showed activity. Pifithrin-μ exhibited little antifungal activity. Conclusions Targeting the Hsp90-calcineurin axis at different levels resulted in distinct patterns of susceptibility among different fungal species. Lysine deacetylase inhibition may represent a promising novel antifungal strategy against emerging resistant mould

Frecuencia de factores asociados a ideación suicida en pacientes con fibromialgia en dos hospitales de Lambayeque 2015

Objetivo: determinar la frecuencia de los factores asociados a ideación suicida en pacientes con fibromialgia en dos hospitales de Lambayeque, 2015. Material y Métodos: estudio descriptivo transversal con análisis exploratorio. Se entrevistó a pacientes con fibromialgia de consultorios externos de los hospitales Regional Lambayeque (Hospital 1) y Almanzor Aguinaga Asenjo de Chiclayo (Hospital 2). Se aplicaron 5 cuestionarios: la escala del centro de estudios epidemiológicos para depresión, escala de Zung para ansiedad, índice de calidad de sueño de Pittsburgh, escala de valoración análoga del dolor y la escala de ideación suicida de Beck, adaptada a población Lambayecana. Se realizó análisis univariado y bivariado exploratorio. Resultados: Se entrevistaron 125 pacientes, 61 del hospital 1 y 64 del Hospital 2; 87%, fueron mujeres. Hubieron 73,6% malos dormidores, 68% tuvieron depresión, 22,4% ansiedad, 24,8% dolor corporal difuso moderado-severo y 30,4% ideación suicida, 27,9% y 32,8% en el primer y segundo hospital, respectivamente. En los pacientes con Ideación suicida la frecuencia fue: mala calidad del sueño 81,6% (p=0,1), depresión 71%(p=0,5), ansiedad 42% (0,001) y dolor corporal difuso (DCD) de moderado a severo 26,3% (p=0,005). En el multivariado, ansiedad, rp= 1,4 IC95%= 1,14-1,7, p= 0,006 y ser mal dormidor, rp= 1,2, IC95%= 1,0-1,4, p=0,01 se asociaron a Ideación suicida. Conclusiones: la frecuencia de ideación suicida es elevada en estos pacientes. El factor más frecuente fue mala calidad de sueño. Ansiedad y ser mal dormidor se asociaron a ideación suicida.Tesi

Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry.

BACKGROUND: Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. METHODS: Clinical data from patients with candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis. RESULTS: The incidence of candidemia caused by non-Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P CONCLUSIONS: The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen

Tumoral calcinosis: radiologic-pathologic correlation

Tumoral calcinosis is a frequently misdiagnosed disorder. This study details the radiologic and pathologic characteristics of tumoral calcinosis that distinguish it from most other entities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46807/1/256_2004_Article_BF00204854.pd

Localization and activity of the calcineurin catalytic and regulatory subunit complex at the septum is essential for hyphal elongation and proper septation in Aspergillus fumigatus: Analysis of the calcineurin complex in Aspergillus fumigatus

Calcineurin, a heterodimer composed of the catalytic (CnaA) and regulatory (CnaB) subunits, plays key roles in growth, virulence, and stress responses of fungi. To investigate the contribution of CnaA and CnaB to hyphal growth and septation, ΔcnaB and ΔcnaA ΔcnaB strains of A. fumigatus were constructed. CnaA co-localizes to the contractile actin ring early during septation and remains at the center of the mature septum. While CnaB's septal localization is CnaA-dependent, CnaA's septal localization is CnaB-independent but CnaB is required for CnaA's function at the septum. Catalytic null mutations in CnaA caused stunted growth despite septal localization of the calcineurin complex, indicating the requirement of calcineurin activity at the septum. Compared to the ΔcnaA and ΔcnaB strains, the ΔcnaA ΔcnaB strain displayed more defective growth and aberrant septation. While three Ca2+-binding motifs in CnaB were sufficient for its association with CnaA at the septum, the amino-terminal arginine-rich domains (16-RRRR-19 and 44-RLRKR-48) are dispensable for septal localization, yet required for complete functionality. Mutation of the 51-KLDK-54 motif in CnaB causes its mislocalization from the septum to the nucleus, suggesting it is a nuclear export signal sequence. These findings confirm a cooperative role for calcineurin complex in regulating hyphal growth and septation

Plasma Membrane Localization Is Required for RasA-Mediated Polarized Morphogenesis and Virulence of Aspergillus fumigatus

ABSTRACT Ras is a highly conserved GTPase protein that is essential for proper polarized morphogenesis of filamentous fungi. Localization of Ras proteins to the plasma membrane and endomembranes through posttranslational addition of farnesyl and palmitoyl residues is an important mechanism through which cells provide specificity to Ras signal output. Although the Aspergillus fumigatus RasA protein is known to be a major regulator of growth and development, the membrane distribution of RasA during polarized morphogenesis and the role of properly localized Ras signaling in virulence of a pathogenic mold remain unknown. Here we demonstrate that Aspergillus fumigatus RasA localizes primarily to the plasma membrane of actively growing hyphae. We show that treatment with the palmitoylation inhibitor 2-bromopalmitate disrupts normal RasA plasma membrane association and decreases hyphal growth. Targeted mutations of the highly conserved RasA palmitoylation motif also mislocalized RasA from the plasma membrane and led to severe hyphal abnormalities, cell wall structural changes, and reduced virulence in murine invasive aspergillosis. Finally, we provide evidence that proper RasA localization is independent of the Ras palmitoyltransferase homolog, encoded by erfB , but requires the palmitoyltransferase complex subunit, encoded by erfD . Our results demonstrate that plasma membrane-associated RasA is critical for polarized morphogenesis, cell wall stability, and virulence in A. fumigatus