Impact of rapid, culture-independent diagnosis of candidaemia and invasive candidiasis in a community health system.

Background: Delay in treatment of candidaemia and invasive candidiasis remains a cause of significant morbidity and mortality in high-risk patients. Widespread empirical utilization of antifungal therapy often occurs in an effort to minimize this risk. Objectives: This study assessed the impact of the T2Candida Panel in a multi-hospital community health system on time to initiation of antifungal therapy in candidaemic patients as well as the utilization of micafungin. Methods: Outcomes were compared between those patients with candidaemia prior to T2Candida implementation and those after implementation. Micafungin utilization for patients with suspected candidaemia/invasive candidiasis was compared with that for patients with a negative T2Candida Panel post-implementation. Results: There was a significant decrease in time to appropriate therapy in the post-T2Candida group (34 versus 6 h, P = 0.0147). Empirical antifungal therapy was avoided in 58.4% of T2Candida-negative patients. Conclusions: These results support the implementation of T2Candida to improve time to appropriate therapy for candidaemic patients while simultaneously expanding antimicrobial stewardship efforts to appropriately utilize antifungals.

An electronic quantum eraser.

The quantum eraser is a device that illustrates the quantum principle of complementarity and shows how a dephased system can regain its lost quantum behavior by erasing the "which-path" information already obtained about it. Thus far, quantum erasers were constructed predominantly in optical systems. Here, we present a realization of a quantum eraser in a mesoscopic electronic device. The use of interacting electrons, instead of noninteracting photons, allows control over the extracted information and a smooth variation of the degree of quantum erasure. The demonstrated system can serve as a first step toward a variety of more complex setups.

Controlled dephasing of an electron interferometer with a path detector at equilibrium.

Controlled dephasing of electrons, via "which path" detection, involves, in general, coupling a coherent system to a current driven noise source. However, here we present a case in which a nearly isolated electron puddle within a quantum dot, at thermal equilibrium and in millikelvin range temperature, fully dephases the interference in a nearby electronic interferometer. Moreover, the complete dephasing is accompanied by an abrupt π phase slip, which is robust and nearly independent of system parameters. Attributing the robustness of the phenomenon to the Friedel sum rule--which relates a system's occupation to its scattering phases--proves the universality of this powerful rule. The experiment allows us to peek into a nearly isolated quantum dot, which cannot be accessed via conductance measurements.

JunB is a gatekeeper for B-lymphoid leukemia.

Loss of JunB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JunB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JunB-deficient (junB(Delta/Delta)) cells induced leukemia in RAG2(-/-) mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junB(Delta/Delta) tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junB(Delta/Delta) cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16(INK4a). These alterations were due to irreversible reprogramming of the cell, because - once established - accelerated disease induced by junB(Delta/Delta) cells was not reverted by re-introducing JunB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JunB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.

The selectivity filter of the voltage-gated sodium channel is involved in channel activation.

Amino acids located in the outer vestibule of the voltage-gated Na+ channel determine the permeation properties of the channel. Recently, residues lining the outer pore have also been implicated in channel gating. The domain (D) IV P-loop residue alanine 1529 forms a part of the putative selectivity filter of the adult rat skeletal muscle (mu1) Na+ channel. Here we report that replacement of alanine 1529 by aspartic acid enhances entry to an ultra-slow inactivated state. Ultra-slow inactivation is characterized by recovery time constants on the order of approximately 100 s from prolonged depolarizations and by the fact that entry to this state can be reduced by binding to the pore of a mutant mu-conotoxin GIIIA, suggesting that ultra-slow inactivation may reflect a structural rearrangement of the outer vestibule. The voltage dependence of ultra-slow inactivation in DIV-A1529D is U-shaped, with a local maximum near -60 mV, whereas activation is maximal only above -20 mV. Furthermore, a train of brief depolarizations produces more ultra-slow inactivation than a single maintained depolarization of the same duration. These data suggest that ultra-slow inactivation emanates from "partially activated" closed states and that the P-loop in DIV may undergo a conformational change during channel activation, which is accentuated by DIV-A1529D.

[Central presynaptic receptors]. / Zentrale präsynaptische Rezeptoren.

Experiments on two different inhibitory presynaptic receptor systems are presented. 1. Superfused and electrically stimulated brain slices are a widely used experimental model to study the release of noradrenaline and its modulation by inhibitory alpha-2 adrenoceptors. By using a minisuperfusion chamber we succeeded in studying the simplest case of autoinhibition, i.e. the release of transmitter induced by a single pulse and two consecutive pulses, respectively. When electrical stimulation is performed using a single pulse, no autoinhibition is possible, whereas following stimulation with two pulses the transmitter released by the first pulse will inhibit the effect of the second pulse. By systemically varying the time interval between the two pulses the minimal time requirement for development of autoinhibition was determined to be 100 ms. Short pulse trains of high frequency such as 4 pulses within 30 ms circumvent autoinhibition and cause inhibition-free release by each applied pulse. The release of transmitter evoked in this way is not only free from autoinhibition but, in addition, easily measurable, which makes this method of stimulation very suitable for analyses at presynaptic receptors. By using this approach it became possible, for the first time, to determine dissociation constants of antagonists and agonists at the central presynaptic alpha-2 adrenoceptor without the distortion introduced by autoinhibition occurring during release. 2. There is a substantial body of evidence for a role of medullary serotonergic nerve cells in the regulation of blood pressure and heart rate. It is hypothesized that the serotonergic neurons project to the thoracic spinal cord exerting a tonic excitatory influence on presynaptic sympathetic neurons of the intermediolateral cell column. Experiments were performed in pentobarbital anaesthetized rats to reduce this excitatory tone by activating inhibitory autoreceptors which are located on the perikarya and dendrites on the serotonergic cells and which have been shown to belong to the 5-HT1A subtype. Local stereotactic injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) caused a decrease in mean arterial blood pressure (MAP) and heart rate (HR). The effects were blocked by pretreatment of the animals with the 5-HT1A antagonist spiroxatrine. Moreover, neurochemical lesioning of serotonergic neurons by intracisternal injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) abolished the effects of 8-OH-DPAT. Bilateral intraspinal injection of 5,7-DHT, which interrupts the medullo-spinal serotonergic pathway, markedly attenuated the effects of local intramedullary injection of 8-OH-DPAT.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of urapidil and 8-OH-DPAT on brain 5-HT turnover and blood pressure in rats.

The effects of urapidil, of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and of the alpha 2-adrenoceptor agonist clonidine on the in vivo rate of synthesis of 5-hydroxytryptamine (5-HT) were determined in rat brain cortex and hypothalamus. Urapidil (10 mg/kg), 8-OH-DPAT (0.3 mg/kg) or clonidine (0.3 mg/kg; all drugs i.p.) caused significant reductions in 5-HT synthesis rate. Pretreatment with the selective 5-HT1A receptor antagonist spiroxatrine (SPX; 1 mg/kg s.c.) or the nonselective 5-HT1 receptor antagonist metitepine (1 mg/kg i.p.) abolished the effects of urapidil and 8-OH-DPAT, but not of clonidine. The effects of urapidil and 8-OH-DPAT on mean arterial blood pressure (MAP) and heart rate (HR) of pentobarbital-anesthetized, normotensive rats were measured following stereotaxic microinjection into the B1/B3 cell region of the ventral medulla. The mean percentage decreases induced by urapidil (3 micrograms) and 8-OH-DPAT (0.2 micrograms) amounted to (MAP/HR) -13%/-6% and -19%/-25%, respectively. The following pretreatments markedly attenuated or prevented the effects of intramedullary injections of urapidil or 8-OH-DPAT: (a) SPX (1 mg/kg s.c., 60 min): (b) intracisternal injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 0.2 mg; 7-10 days); (c) bilateral injection of 5,7-DHT at the cervical level of the spinal cord (each side 5 micrograms; 7-10 days). The present results are compatible with an action of urapidil as agonist at central 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)