Prior to the SARS-CoV-2 pandemic, antibiotic resistance was listed as the major global health care priority. Some analyses, including the O'Neill report, have predicted that deaths due to ...drug-resistant bacterial infections may eclipse the total number of cancer deaths by 2050. Although fungal infections remain in the shadow of public awareness, total attributable annual deaths are similar to, or exceeds, global mortalities due to malaria, tuberculosis or HIV. The impact of fungal infections has been exacerbated by the steady rise of antifungal drug resistant strains and species which reflects the widespread use of antifungals for prophylaxis and therapy, and in the case of azole resistance in Aspergillus, has been linked to the widespread agricultural use of antifungals. This review, based on a workshop hosted by the Medical Research Council and the University of Exeter, illuminates the problem of antifungal resistance and suggests how this growing threat might be mitigated.
Background. A paucity of data exists regarding the pharmacodynamics of caspofungin (CAS) during invasive pulmonary aspergillosis (IPA). We conducted a dosage-fractionation study to characterize the ...in vivo pharmacodynamics of CAS activity during IPA, using immunosuppressed mice inoculated intranasally with Aspergillus fumigatus. Methods. After single intraperitoneal doses (0.25, 1.0, and 4.0 mg/kg), plasma CAS concentrations were assayed by high-performance liquid chromatography. The pharmacokinetic data were analyzed by nonparametric population pharmacokinetic analysis. Three dosage groups (0.25, 1.0, and 4.0 mg/kg) fractionated into 3 different dosing intervals (q6, q24, or q48 h) were then used to evaluate the pharmacokinetic/pharmacodynamic effects (percentage of time greater than the minimum effective concentration MEC, 96-h area under the plasma concentration curve:MEC ratio, and peak concentration in plasma Cmax:MEC ratio) at clinically achievable exposures. Mice were treated for 96 h and were then euthanized, and their lungs were harvested for analysis of pulmonary fungal burden by real-time quantitative polymerase chain reaction. Results. A concentration-dependent reduction in mean pulmonary fungal burden was evident in mice in the 1 mg/kg dosage-fractionation group, with significantly lower mean pulmonary fungal burden in mice dosed q48 h versus q6 h (P < .01). A paradoxical increase in pulmonary fungal burden was observed in the highest dosage-fractionation group. Conclusions. CAS demonstrates concentration-dependent pharmacodynamics in the treatment of IPA. The Cmax:MEC ratio appears to be the parameter most closely associated with the reduction of pulmonary fungal burden.
Coding region and intronic mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17. Some of these mutations lead to an overproduction of tau isoforms with ...four microtubule-binding repeats. Here we have expressed the longest four-repeat human brain tau isoform in transgenic mice under the control of the murine Thy1 promoter. Transgenic mice aged 3 weeks to 25 months overexpressed human tau protein in nerve cells of brain and spinal cord. Numerous abnormal, tau-immunoreactive nerve cell bodies and dendrites were seen. In addition, large numbers of pathologically enlarged axons containing neurofilament- and tau-immunoreactive spheroids were present, especially in spinal cord. Signs of Wallerian degeneration and neurogenic muscle atrophy were observed. When motor function was tested, transgenic mice showed signs of muscle weakness. Taken together, these findings demonstrate that overexpression of human four-repeat tau leads to a central and peripheral axonopathy that results in nerve cell dysfunction and amyotrophy.
Veterinary Fusarioses within the United States O'Donnell, Kerry; Sutton, Deanna A; Wiederhold, Nathan ...
Journal of clinical microbiology,
11/2016, Letnik:
54, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Multilocus DNA sequence data were used to assess the genetic diversity and evolutionary relationships of 67 Fusarium strains from veterinary sources, most of which were from the United States. ...Molecular phylogenetic analyses revealed that the strains comprised 23 phylogenetically distinct species, all but two of which were previously known to infect humans, distributed among eight species complexes. The majority of the veterinary isolates (47/67 = 70.1%) were nested within the Fusarium solani species complex (FSSC), and these included 8 phylospecies and 33 unique 3-locus sequence types (STs). Three of the FSSC species (Fusarium falciforme, Fusarium keratoplasticum, and Fusarium sp. FSSC 12) accounted for four-fifths of the veterinary strains (38/47) and STs (27/33) within this clade. Most of the F. falciforme strains (12/15) were recovered from equine keratitis infections; however, strains of F. keratoplasticum and Fusarium sp. FSSC 12 were mostly (25/27) isolated from marine vertebrates and invertebrates. Our sampling suggests that the Fusarium incarnatum-equiseti species complex (FIESC), with eight mycoses-associated species, may represent the second most important clade of veterinary relevance within Fusarium Six of the multilocus STs within the FSSC (3+4-eee, 1-b, 12-a, 12-b, 12-f, and 12-h) and one each within the FIESC (1-a) and the Fusarium oxysporum species complex (ST-33) were widespread geographically, including three STs with transoceanic disjunctions. In conclusion, fusaria associated with veterinary mycoses are phylogenetically diverse and typically can only be identified to the species level using DNA sequence data from portions of one or more informative genes.
The decays
Λ
b
0
→
Λ
c
+
D
¯
(
∗
)
0
K
-
and
Λ
b
0
→
Λ
c
+
D
s
∗
-
are observed for the first time, in proton-proton collision data at
s
=
13
Te
V
, corresponding to an integrated luminosity of 5.4
...fb
-
1
collected with the LHCb detector. Their ratios of branching fractions with respect to the
Λ
b
0
→
Λ
c
+
D
s
-
mode are measured to be
B
Λ
b
0
→
Λ
c
+
D
¯
0
K
-
B
Λ
b
0
→
Λ
c
+
D
s
-
=
0.1908
-
0.0034
+
0.0036
-
0.0018
+
0.0016
±
0.0038
,
B
Λ
b
0
→
Λ
c
+
D
¯
∗
0
K
-
B
Λ
b
0
→
Λ
c
+
D
s
-
=
0.589
-
0.017
+
0.018
-
0.018
+
0.017
±
0.012
,
B
Λ
b
0
→
Λ
c
+
D
s
∗
-
B
Λ
b
0
→
Λ
c
+
D
s
-
=
1.668
±
0.022
-
0.055
+
0.061
,
where the first uncertainties are statistical, the second systematic, and the third, for the
Λ
b
0
→
Λ
c
+
D
¯
(
∗
)
0
K
-
decays, are due to the uncertainties on the branching fractions of the
D
s
-
→
K
-
K
+
π
-
and
D
¯
0
→
K
+
π
-
decay modes. The measured branching fractions probe factorization assumptions in effective theories and provide the normalization for future pentaquark searches in
Λ
b
0
→
Λ
c
+
D
¯
(
∗
)
0
K
-
decay channels.
Gliotoxin was measured in the lungs (mean, 3,976 ± 1,662 ng/g of tissue) and sera (mean, 36.5 ± 30.28 ng/ml) of mice with experimentally induced invasive aspergillosis (IA), and levels decreased with ...antifungal therapy. Gliotoxin could also be detected in the sera of cancer patients with documented (proven or probable) IA.
Aspergillus isolates (n = 103) collected from cancer patients were screened to determine the taxonomic distribution and quantity of gliotoxin production. Gliotoxin was detected in 93% of Aspergillus ...fumigatus, 75% of A. niger, 25% of A. terreus, and 4% of A. flavus cultures. Gliotoxin concentrations were highest in cultures of A. fumigatus.
Objectives
Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of ...this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis.
Methods
Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control.
Results
Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment.
Conclusions
Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation.
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