ABSTRACT
Candidemia is the fourth most common kind of microbial bloodstream infection, with Candida albicans being the most common causative species. Echinocandins are employed as the first-line treatment for invasive candidiasis until the fungal species is determined and confirmed by clinical diagnosis. Echinocandins block the FKS glucan synthases responsible for embedding ß-(1,3)-d-glucan in the cell wall. The increasing use of these drugs has led to the emergence of antifungal resistance, and elevated MICs have been associated with single-residue substitutions in specific hot spot regions of FKS1 and FKS2. Here, we show for the first time the caspofungin-mediated in vivo selection of a double mutation within one allele of the FKS1 hot spot 1 in a clinical isolate. We created a set of isogenic mutants and used a hematogenous murine model to evaluate the in vivo outcomes of echinocandin treatment. Heterozygous and homozygous double mutations significantly enhance the in vivo resistance of C. albicans compared with the resistance seen with heterozygous single mutations. The various FKS1 hot spot mutations differ in the degree of their MIC increase, substance-dependent in vivo response, and impact on virulence. Our results demonstrate that echinocandin EUCAST breakpoint definitions correlate with the in vivo response when a standard dosing regimen is used but cannot predict the in vivo response after a dose escalation. Moreover, patients colonized by a C. albicans strain with multiple mutations in FKS1 have a higher risk for therapeutic failure.
Subject(s)
Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida albicans/genetics , Candidemia/drug therapy , Candidemia/microbiology , Drug Resistance, Fungal/genetics , Echinocandins/pharmacology , Echinocandins/therapeutic use , Fungal Proteins/genetics , Glucosyltransferases/genetics , Mutation/genetics , Mutation/physiology , Adult , Animals , Candida albicans/metabolism , Chitin/metabolism , DNA Fingerprinting , Female , Humans , Mice , Microbial Sensitivity Tests , Polymorphism, Single Nucleotide/genetics , Virulence/geneticsABSTRACT
BACKGROUND: Cognitive deficits are frequent in multiple sclerosis (MS) and have been associated with morphologic brain changes. Less information exists on their extent and relation to MRI findings in clinically isolated syndrome (CIS). It is also unclear if structural changes as detected by magnetization transfer (MT) imaging may provide an additional explanation for cognitive dysfunction. OBJECTIVE: To analyse the extent of cognitive deficits and their relation to MRI metrics including MT imaging in CIS compared to relapsing-remitting MS (RRMS). METHODS: Forty-four CIS and 80 RRMS patients underwent the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) and a 3 T MRI scan. RESULTS: BRB-N subtests revealed similar results in CIS and RRMS. Impaired mental processing speed was most prevalent in both groups (CIS 13.6%; RRMS 16.3%) and thus served for correlation with MRI metrics. Using stepwise linear regression analyses, the strongest predictor for decreased mental processing speed was normalized cortex volume (p < 0.001) followed by T2-lesion load (p < 0.05) in RRMS, whereas cortical MT ratio was the only MRI parameter associated with decreased mental processing speed in CIS (p < 0.005). CONCLUSION: Cognitive dysfunction occurs in CIS in a pattern similar to RRMS, with impaired mental processing speed being most prevalent. Cortical MT-ratio changes may be an early sign for tissue changes related to impaired mental processing speed in CIS while this association shifts to increased signs of cortical atrophy and lesion load in RRMS.
Subject(s)
Brain/pathology , Cognition Disorders/diagnosis , Cognition , Demyelinating Diseases/diagnosis , Magnetic Resonance Imaging , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Adult , Atrophy , Austria , Chi-Square Distribution , Cognition Disorders/etiology , Cognition Disorders/pathology , Demyelinating Diseases/pathology , Demyelinating Diseases/psychology , Disability Evaluation , Executive Function , Female , Humans , Linear Models , Male , Memory , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/pathology , Multiple Sclerosis, Relapsing-Remitting/psychology , Neuropsychological Tests , Prospective Studies , Risk Assessment , Risk Factors , Severity of Illness Index , Young AdultABSTRACT
BACKGROUND: Increased iron deposition has been implicated in the pathophysiology of multiple sclerosis (MS), based on visual analysis of signal reduction on T(2)-weighted images. R(2)* relaxometry allows to assess brain iron accumulation quantitatively. OBJECTIVE: To investigate regional brain iron deposition in patients with a clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS) and its associations with demographical, clinical, and conventional magnetic resonance imaging (MRI) parameters. METHODS: We studied 69 patients (CIS, n = 32; RRMS, n = 37) with 3T MRI and analyzed regional R(2)* relaxation rates and their correlations with age, disease duration, disability, T(2) lesion load, and normalized brain volumes. RESULTS: Basal ganglia R(2)* relaxation rates increased in parallel with age (r = 0.3-0.6; P < 0.01) and were significantly higher in RRMS than in CIS (P < 0.05). Using multivariate linear regression analysis, the rate of putaminal iron deposition was independently predicted by the patients' age, disease duration, and gray matter atrophy. CONCLUSIONS: Quantitative assessment by R(2)* relaxometry suggests increased iron deposition in the basal ganglia of MS patients, which is associated with disease duration and brain atrophy. This technique together with long-term follow-up thus appears suited to clarify whether regional iron accumulation contributes to MS morbidity or merely reflects an epiphenomenon.
