Tuning of innate immunity and polarized responses by decoy receptors

After the identification of the interleukin (IL)-1 type II receptor as the prototype, decoy receptors have been identified for a number of members of the IL-1/IL-18, TNF, IL-10 and IL-13 receptor families. Moreover, the silent receptor D6 is a promiscuous decoy and scavenger receptor of inflammatory chemokines. The IL-1 decoy receptor is regulated by pro- and anti-inflammatory signals and its levels may serve as a readout of the activation of anti-inflammatory pathways, for instance by glucocorticoid hormones. Decoy receptors represent a strategy to tune inflammatory and polarized adaptive responses.     

Membrane ionic currents and properties of freshly dissociated rat brainstem neurons

It is well known that neuronal firing properties are determined by synaptic inputs and inherent membrane functions such as specific ionic currents. To characterize the ionic currents of brainstem cardio-respiratory neurons, cells from the hypoglossal (XII) nucleus and the dorsal motor nucleus of the vagus (DMX) were freshly dissociated and membrane ionic currents were studied under whole-cell voltage and current clamp. Both of these neurons showed a TTX-sensitive Na⁺ current with a much larger current density in XII than DMX neurons. This Na⁺ current had two (fast and slow) distinct inactivation decay components. The ratio of the magnitudes of the fast to slow component was roughly two-fold greater in DMX than in XII cells. Both DMX and XII neurons also showed a high voltage-activated Ca²⁺ current, but this current density was significantly greater (three-fold) in DMX than XII neurons. A relatively small amount of low-voltage activated Ca²⁺ current was also observed in DMX neurons, but not in the majority of XII cells. A transient and a sustained outward current components were observed in DMX cells, but only sustained currents were present in XII neurons. These outward currents had a reversal potential of about − 70 mV with 3 mM external K⁺ and −30 mV with 25 mM K⁺, and substitution of K⁺ with cesium and tetraethylammonium suppressed more than 90% the outward currents, indicating that most outward currents were carried by K⁺. The transient outward current consisted of two components with onesensitive to 4-aminopyridine and the other to intracellular Ca²⁺. In XII neurons, BRL 38227 (lemakalim), an ATP-sensitive K⁺ (K_ATP) channel activator, increased the sustained K⁺ currents by 10% of control, and glibenclamide, a K_ATP channel blocker, decreased the sustained K⁺ currents by 20%. Evidence for the presence of an inward rectifier K⁺ current was also obtained from both XII and DMX neurons. These results on XII and DMX neurons indicate that (1) the methods used to dissociate neurons provide a useful means to overcome voltage clamp technical difficulties; (2) ion channel characteristics such as density and biophysical properties of DMX neurons are very different from those of XII neurons; and (3) several newly discovered membrane ionic currents are present in these cells.     

Investigation of Gamma-aminobutyric acid (GABA) A receptors genes and migraine susceptibility

Background  

Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ), which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE) and type θ (GABRQ) genes and their involvement in migraine.     

Formation and specification of ventral neuroblasts is controlled by vnd in Drosophila neurogenesis

During Drosophila neural development, neuroblasts delaminate from the neuroectoderm of each hemisegment in a stereotypic orthogonal array of five rows and three columns (ventral, intermediate, and dorsal). Prevailing evidence indicates that the individual neuroblast fate is determined by the domain-specific expression of genes along the dorsoventral and anteroposterior axis. Here, we analyze the role of Vnd, a NK-2 homeodomain protein, expressed initially in the ventral neuroectoderm adjacent to the ventral midline, in the dorsoventral patterning of the neuroectoderm and the neuroblasts. We show that in vnd null mutants most ventral neuroblasts do not form and the few that form do not develop ventral fates, but instead develop intermediate-like fates. Furthermore, we demonstrate that Vnd influences the gene expression patterns in the ventral proneural clusters and neuroectoderm, and that its action in neuroblast formation includes, but is not exclusive to the activation of proneural AS-C genes. Through the use of GAL4/UAS gene-expression system we show that ectopic Vnd expression can promote ventral-like fates in intermediate and dorsal neuroblasts and can suppress certain normal characteristics of the intermediate and dorsal neuroectoderm. Our results are discussed in the context of the current evidence in dorsoventral patterning in the Drosophila neuroectoderm.     

Bladder leiomyoma: Advantages of sonography over computed tomography

The complementary use of sonography in the evaluation of a bladder-base leiomyoma is reported. Sonography, as compared to computed tomography, was able to document the solid nature of the tumor, its submucosal location, and determined the site of origin and exact relationship to adjacent organs by virtue of the ability to image in multiple planes. The sonographic appearance of a submucosal, solid lobulated bladder-base mass is suggestive of a leiomyoma.     

Pharmacokinetics and tissue disposition of the biological response modifier BAY i 7433 (copovithane) in patients with cancer

Summary Copovithane is an uncharged, water-soluble, synthetic polymer with an average molecular weight of 5800 daltons. It demonstrates antitumor activity in vivo against a variety of tumors in animal models but is inactive in vitro. This agent has been found to have immunorestorative activity in man. In concert with its phase I clinical trial, copovithane concentrations were analyzed by HPLC in plasma, urine, and autopsy and in tumor biopsy specimens obtained from patients. Copovithane was cleared from plasma biphasically with a mean t_1/2 of 11.1±4 min and a t_1/2 of 246±78 min at the dose of 1 g/m², while the plasma half-lives increased to 57.7±12 and 718±149 for the alpha and beta phases, respectively, at the 10 g/m² dose, demonstrating clear, dose-dependent pharmacokinetics. There were no significant differences between dose 1 and dose 4 pharmacokinetics. The apparent volume of distribution (V_d) was 14.5±1. at the 1 g/m² dose and increased to 73 1. at the 33 g/m² dose. The calculated mean clearance rate for copovithane in plasma was between 2.4 and 5.4 mg/kg x min and did not appear to be dose-dependent. The urinary excretion of copovithane was approximately 5% of the administered dose over 120 h at the 1 g/m² dose and decreased to 1% at the 33 g/m² dose. In seven tumor biopsy samples, concentrations of drug in tumor varied from 1- to 1000-fold higher than that found in concurrent plasma samples. In three autopsy samples, the highest concentrations were found in kidney, intestine, and liver, in decreasing order. These studies show that copovithane exhibits dose-dependent changes in pharmacokinetics at doses between 1 and 33 g/m². However, copovithane does penetrate well to tumor tissues, achieving high tumor/plasma ratios. In addition, copovithane concentrations were highest in kidney tissue, which may be a site for potential organ toxicity.     

Beyond empathy decline: Do the barriers to compassion change across medical training?

Advances in Health Sciences Education - Background: Despite being a mandated, foundational value in healthcare, research on compassion remains limited. Studying the individual, patient, clinical,...     

Gastrointestinal Contributions to the Postprandial Experience

Food ingestion induces homeostatic sensations (satiety, fullness) with a hedonic dimension (satisfaction, changes in mood) that characterize the postprandial experience. Both types of sensation are secondary to intraluminal stimuli produced by the food itself, as well as to the activity of the digestive tract. Postprandial sensations also depend on the nutrient composition of the meal and on colonic fermentation of non-absorbed residues. Gastrointestinal function and the sensitivity of the digestive tract, i.e., perception of gut stimuli, are determined by inherent individual factors, e.g., sex, and can be modulated by different conditioning mechanisms. This narrative review examines the factors that determine perception of digestive stimuli and the postprandial experience.     

Digitale Gesundheitsanwendungen (DiGA) in der ärztlichen und psychotherapeutischen Versorgung. Chancen und Herausforderungen aus Sicht der Leistungserbringer

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Versicherte haben seit 2019 einen gesetzlichen Anspruch auf Verordnung von digitalen Gesundheitsanwendungen (DiGA). Die...