Antifungal Resistance and New Strategies to Control Fungal Infections

Despite improvement of antifungal therapies over the last 30 years, the phenomenon of antifungal resistance is still of major concern in clinical practice. In the last 10 years the molecular mechanisms underlying this phenomenon were extensively unraveled. In this paper, after a brief overview of currently available antifungals, molecular mechanisms of antifungal resistance will be detailed. It appears that major mechanisms of resistance are essential due to the deregulation of antifungal resistance effector genes. This deregulation is a consequence of point mutations occurring in transcriptional regulators of these effector genes. Resistance can also follow the emergence of point mutations directly in the genes coding antifungal targets. In addition we further describe new strategies currently undertaken to discover alternative therapy targets and antifungals. Identification of new antifungals is essentially achieved by the screening of natural or synthetic chemical compound collections. Discovery of new putative antifungal targets is performed through genome-wide approaches for a better understanding of the human pathogenic fungi biology

Local regularity for parabolic nonlocal operators

Weak solutions to parabolic integro-differential operators of order $\alpha \in (\alpha_0, 2)$ are studied. Local a priori estimates of H\"older norms and a weak Harnack inequality are proved. These results are robust with respect to $\alpha \nearrow 2$. In this sense, the presentation is an extension of Moser's result in 1971.Comment: 31 pages, 3 figure

An analysis of the production-regeneration system in the coastal upwelling area off N.W. Africa based on oxygen, nitrate and ammonium distributions

Using the hydrographic and nutrient data from the R/V Jean Charcot CINECA-V cruise and Broenkow\u27s (1965) mixing model, we have calculated the biologically induced changes in the oxygen, nitrate and ammonium distribution patterns of the upwelling system off Cape Blanc, N .W. Africa...

Anomalous Fermion Number Non-Conservation on the Lattice

The anomaly for the fermion number current is calculated on the lattice in a simple prototype model with an even number of fermion doublets.Comment: 6 pages, CERN-TH.6717/92. Contribution to the Amsterdam Lattice '92 Conferenc

Sub-Gaussian short time asymptotics for measure metric Dirichlet spaces

This paper presents estimates for the distribution of the exit time from balls and short time asymptotics for measure metric Dirichlet spaces. The estimates cover the classical Gaussian case, the sub-diffusive case which can be observed on particular fractals and further less regular cases as well. The proof is based on a new chaining argument and it is free of volume growth assumptions

On the total curvatures of a tame function

Given a definable function f, enough differentiable, we study the continuity of the total curvature function t --> K(t), total curvature of the level {f=t}, and the total absolute curvature function t-->|K| (t), total absolute curvature of the level {f=t}. We show they admits at most finitely many discontinuities

The W_N minimal model classification

We first rigourously establish, for any N, that the toroidal modular invariant partition functions for the (not necessarily unitary) W_N(p,q) minimal models biject onto a well-defined subset of those of the SU(N)xSU(N) Wess-Zumino-Witten theories at level (p-N,q-N). This permits considerable simplifications to the proof of the Cappelli-Itzykson-Zuber classification of Virasoro minimal models. More important, we obtain from this the complete classification of all modular invariants for the W_3(p,q) minimal models. All should be realised by rational conformal field theories. Previously, only those for the unitary models, i.e. W_3(p,p+1), were classified. For all N our correspondence yields for free an extensive list of W_N(p,q) modular invariants. The W_3 modular invariants, like the Virasoro minimal models, all factorise into SU(3) modular invariants, but this fails in general for larger N. We also classify the SU(3)xSU(3) modular invariants, and find there a new infinite series of exceptionals.Comment: 25 page

C-peptide, Na+,K+-ATPase, and Diabetes

Na+,K+-ATPase is an ubiquitous membrane enzyme that allows the extrusion of three sodium ions from the cell and two potassium ions from the extracellular fluid. Its activity is decreased in many tissues of streptozotocin-induced diabetic animals. This impairment could be at least partly responsible for the development of diabetic complications. Na+,K+-ATPase activity is decreased in the red blood cell membranes of type 1 diabetic individuals, irrespective of the degree of diabetic control. It is less impaired or even normal in those of type 2 diabetic patients. The authors have shown that in the red blood cells of type 2 diabetic patients, Na+,K+-ATPase activity was strongly related to blood C-peptide levels in non–insulin-treated patients (in whom C-peptide concentration reflects that of insulin) as well as in insulin-treated patients. Furthermore, a gene-environment relationship has been observed. The alpha-1 isoform of the enzyme predominant in red blood cells and nerve tissue is encoded by the ATP1A1 gene.Apolymorphism in the intron 1 of this gene is associated with lower enzyme activity in patients with C-peptide deficiency either with type 1 or type 2 diabetes, but not in normal individuals. There are several lines of evidence for a low C-peptide level being responsible for low Na+,K+-ATPase activity in the red blood cells. Short-term C-peptide infusion to type 1 diabetic patients restores normal Na+,K+-ATPase activity. Islet transplantation, which restores endogenous C-peptide secretion, enhances Na+,K+-ATPase activity proportionally to the rise in C-peptide. This C-peptide effect is not indirect. In fact, incubation of diabetic red blood cells with C-peptide at physiological concentration leads to an increase of Na+,K+-ATPase activity. In isolated proximal tubules of rats or in the medullary thick ascending limb of the kidney, C-peptide stimulates in a dose-dependent manner Na+,K+-ATPase activity. This impairment in Na+,K+-ATPase activity, mainly secondary to the lack of C-peptide, plays probably a role in the development of diabetic complications. Arguments have been developed showing that the diabetesinduced decrease in Na+,K+-ATPase activity compromises microvascular blood flow by two mechanisms: by affecting microvascular regulation and by decreasing red blood cell deformability, which leads to an increase in blood viscosity. C-peptide infusion restores red blood cell deformability and microvascular blood flow concomitantly with Na+,K+-ATPase activity. The defect in ATPase is strongly related to diabetic neuropathy. Patients with neuropathy have lower ATPase activity than those without. The diabetes-induced impairment in Na+,K+-ATPase activity is identical in red blood cells and neural tissue. Red blood cell ATPase activity is related to nerve conduction velocity in the peroneal and the tibial nerve of diabetic patients. C-peptide infusion to diabetic rats increases endoneural ATPase activity in rat. Because the defect in Na+,K+-ATPase activity is also probably involved in the development of diabetic nephropathy and cardiomyopathy, physiological C-peptide infusion could be beneficial for the prevention of diabetic complications

Evaluation of the BD Phoenix™ CPO Detect Test for the detection of carbapenemase producers.

Becton-Dickinson recently developed the Phoenix™ CPO (carbapenemase-producing organism) Detect Test, a growth-based test embedded in Gram-negative (GN) panels for the detection and confirmation of bacteria producing class A, B and D carbapenemases. This study aimed to (a) determine the performance of the CPO test, and (b) assess its added value in routine diagnostic workflows. The performance of the BD Phoenix CPO test was analysed retrospectively on a collection of 185 molecularly characterized strains, including 92 CPOs, and prospectively on 135 and 160 routine isolates with and without CPO suspicion, respectively. In the retrospective study the CPO test exhibited 92.4% accuracy (95%CI 87.6-95.8), 97.8% sensitivity (95%CI 92.4-99.7) and 87.1% specificity (95%CI 78.6-93.2) for carbapenemase detection. The CPO test provided a classification to class A, B, and D for 81.3% of detected carbapenemases with 94.6% accuracy (95%CI 86.7-98.5). In the prospective study the CPO test detection performance showed 77.8% accuracy (95%CI 68.8-84.5), 100% sensitivity (95%CI 91.2-100) and 67.8% specificity (95%CI 57.3-77.1) with 135 CPO-suspicious isolates and 98.8% accuracy and specificity (95%CI 95.6-99.9) with 160 non-CPO-suspicious isolates. Compared to routine testing, the implementation of the CPO test allowed a mean reduction of 21.3 h (95%CI 17.6-25) in turnaround time, 16.8 min (95%CI 13.4-20.2) in hands-on time, and 20.6 CHF (95%CI 16.5-24.8) in costs. The CPO test is reliable for the detection of CPO with a high sensitivity. However, the relatively low detection specificity required the use of additional confirmatory methods. The carbapenemase classification accuracy is robust in providing preliminary results before molecular characterization. Finally, the implementation of the test in routine workflows allowed a significant reduction in turnaround time, hands-on time and cost compared to the conventional approach