Adjuvant drugs for peripheral nerve blocks: The role of nmda antagonists, neostigmine, epinephrine, and sodium bicarbonate

The potential for misuse, overdose, and chronic use has led researchers to look for other methods to decrease opioid consumption in patients with acute and chronic pain states. The use of peripheral nerve blocks for surgery has gained increasing popularity as it minimizes peripheral pain signals from the nociceptors of local tissue sustaining trauma and inflammation from surgery. The individualization of peripheral nerve blocks using adjuvant drugs has the potential to improve patient outcomes and reduce chronic pain. The major limitations of peripheral nerve blocks are their limited duration of action and dose-dependent adverse effects. Adjuvant drugs for peripheral nerve blocks show increasing potential as a solution for postoperative and chronic pain with their synergistic effects to increase the duration of action and decrease the required dosage of local anesthetic. N-methyl-d-aspartate (NMDA) receptor antagonists are a viable option for patients with opioid resistance and neuropathic pain due to their affinity to the neurotransmitter glutamate, which is released when patients experience a noxious stimulus. Neostigmine is a cholinesterase inhibitor that exerts its effect by competitively binding at the active site of acetylcholinesterase, which prevents the hydrolysis of acetylcholine and subsequently retaining acetylcholine at the nerve terminal. Epinephrine, also known as adrenaline, can potentially be used as an adjuvant to accelerate and prolong analgesic effects in digital nerve blocks. The theorized role of sodium bicarbonate in local anesthetic preparations is to increase the pH of the anesthetic. The resulting alkaline solution enables the anesthetic to more readily exist in its un-ionized form, which more efficiently crosses lipid membranes of peripheral nerves. However, more research is needed to show the efficacy of these adjuvants for nerve block prolongation as studies have been either mixed or have small sample sizes

Parental Genome Dosage Imbalance Deregulates Imprinting in Arabidopsis

In mammals and in plants, parental genome dosage imbalance deregulates embryo growth and might be involved in reproductive isolation between emerging new species. Increased dosage of maternal genomes represses growth while an increased dosage of paternal genomes has the opposite effect. These observations led to the discovery of imprinted genes, which are expressed by a single parental allele. It was further proposed in the frame of the parental conflict theory that parental genome imbalances are directly mirrored by antagonistic regulations of imprinted genes encoding maternal growth inhibitors and paternal growth enhancers. However these hypotheses were never tested directly. Here, we investigated the effect of parental genome imbalance on the expression of Arabidopsis imprinted genes FERTILIZATION INDEPENDENT SEED2 (FIS2) and FLOWERING WAGENINGEN (FWA) controlled by DNA methylation, and MEDEA (MEA) and PHERES1 (PHE1) controlled by histone methylation. Genome dosage imbalance deregulated the expression of FIS2 and PHE1 in an antagonistic manner. In addition increased dosage of inactive alleles caused a loss of imprinting of FIS2 and MEA. Although FIS2 controls histone methylation, which represses MEA and PHE1 expression, the changes of PHE1 and MEA expression could not be fully accounted for by the corresponding fluctuations of FIS2 expression. Our results show that parental genome dosage imbalance deregulates imprinting using mechanisms, which are independent from known regulators of imprinting. The complexity of the network of regulations between expressed and silenced alleles of imprinted genes activated in response to parental dosage imbalance does not support simple models derived from the parental conflict hypothesis

Preparedness of the CTSA's Structural and Scientific Assets to Support the Mission of the National Center for Advancing Translational Sciences (NCATS)

The formation of the National Center for Advancing Translational Sciences (NCATS) brings new promise for moving basic and discoveries to clinical practice, ultimately improving the health of the nation. The CTSA sites, now housed with NCATS, are organized and prepared to support in this endeavor. The CTSAs provide a foundation for capitalizing on such promise through provision of a disease-agnostic infrastructure devoted to C&T science, maintenance of training programs designed for C&T investigators of the future, by incentivizing institutional reorganization and by cultivating institutional support

Calcineurin Is Required for Pseudohyphal Growth, Virulence, and Drug Resistance in <em>Candida lusitaniae</em>

<div><p><em>Candida lusitaniae</em> is an emerging fungal pathogen that infects immunocompromised patients including HIV/AIDS, cancer, and neonatal pediatric patients. Though less prevalent than other <em>Candida</em> species, <em>C. lusitaniae</em> is unique in its ability to develop resistance to amphotericin B. We investigated the role of the calcium-activated protein phosphatase calcineurin in several virulence attributes of <em>C. lusitaniae</em> including pseudohyphal growth, serum survival, and growth at 37°C. We found that calcineurin and Crz1, a <em>C. albicans</em> Crz1 homolog acting as a downstream target of calcineurin, are required for <em>C. lusitaniae</em> pseudohyphal growth, a process for which the underlying mechanism remains largely unknown in <em>C. lusitaniae</em> but hyphal growth is fundamental to <em>C. albicans</em> virulence. We demonstrate that calcineurin is required for cell wall integrity, ER stress response, optimal growth in serum, virulence in a murine systemic infection model, and antifungal drug tolerance in <em>C. lusitaniae</em>. To further examine the potential of targeting the calcineurin signaling cascade for antifungal drug development, we examined the activity of a calcineurin inhibitor FK506 in combination with caspofungin against echinocandin resistant <em>C. lusitaniae</em> clinical isolates. Broth microdilution and drug disk diffusion assays demonstrate that FK506 has synergistic fungicidal activity with caspofungin against echinocandin resistant isolates. Our findings reveal that pseudohyphal growth is controlled by the calcineurin signaling cascade, and highlight the potential use of calcineurin inhibitors and caspofungin for emerging drug-resistant <em>C. lusitaniae</em> infections.</p> </div

Eddies Induced in Cylindrical Containers by a Rotating End Wall

The flow generated in a viscous liquid contained in a cylindrical geometry by a rotating end wall is considered. Recent numerical and experimental work has established several distinct phases of the motion when fluid inertia plays a significant role. The current paper, however, establishes the nature of the flow in the thus far neglected low Reynolds number regime. Explicitly, by employing biorthogonality relations appropriate to the current geometry, it is shown that a sequence of exponentially decaying eddies extends outward from the rotating end wall. The cellular structure is a manifestation of the dominance of complex eigensolutions to the homogeneous problem and arises as the result of nonlinear forcing associated with an inertial correction to the Stokes flow

Calcineurin inhibitor exhibits synergistic antifungal activity with caspofungin against <i>C. lusitaniae</i> wild-type and echinocandin-resistant strains.

<p>Disk diffusion assays were used to determine synergistic antifungal activity with caspofungin against clinical echinocandin-resistant <i>C. lusitaniae</i> strains. Cells were grown overnight at 30°C, and 0.1 OD₆₀₀ (in 100 µl) was spread on the surface of RPMI media lacking or containing FK506 (1 µg/ml). A disk was placed on the surface of the medium and 12.5 µg caspofungin (5 µl of 2.5 mg/ml) was added to each disk. The plates were incubated at 30°C for 48 h and photographed. S = caspofungin-sensitive; R = caspofungin-resistant (less susceptible). Scale bar = 6 mm.</p

Proposed roles of calcineurin and Crz1 in core stress responses in <i>C. lusitaniae</i>.

<p><i>C. lusitaniae</i> core stress responses including pseudohyphal growth, drug tolerance, virulence, serum growth, cell membrane and wall integrity, ER stress, and Ca²⁺ homeostasis are controlled by either calcineurin-dependent or -independent signaling cascades. The pseudohyphal development, serum growth, and virulence are controlled by Crz1-mediated calcineurin signaling, while cell wall integrity and echinocandin tolerance are governed by Crz1-independent calcineurin signaling (green shading). Crz1 also exhibits calcineurin-independent functions to: 1) negatively regulate cell membrane integrity, ER stress, and azole tolerance; 2) positively regulate Ca²⁺ tolerance (red shading).</p