Explore the vast range of titles available.

Surgeries to correct nasal airway obstruction (NAO) often have less than desirable outcomes, partly due to the absence of an objective tool to select the most appropriate surgical approach for each patient. Computational fluid dynamics (CFD) models can be used to investigate nasal airflow, but variables need to be identified that can detect surgical changes and correlate with patient symptoms. CFD models were constructed from pre- and post-surgery computed tomography scans for 10 NAO patients showing no evidence of nasal cycling. Steady-state inspiratory airflow, nasal resistance, wall shear stress, and heat flux were computed for the main nasal cavity from nostrils to posterior nasal septum both bilaterally and unilaterally. Paired t-tests indicated that all CFD variables were significantly changed by surgery when calculated on the most obstructed side, and that airflow, nasal resistance, and heat flux were significantly changed bilaterally as well. Moderate linear correlations with patient-reported symptoms were found for airflow, heat flux, unilateral allocation of airflow, and unilateral nasal resistance as a fraction of bilateral nasal resistance when calculated on the most obstructed nasal side, suggesting that these variables may be useful for evaluating the efficacy of nasal surgery objectively. Similarity in the strengths of these correlations suggests that patient-reported symptoms may represent a constellation of effects and that these variables should be tracked concurrently during future virtual surgery planning.

Quantal neurotransmitter release at excitatory synapses depends on glutamate import into synaptic vesicles by vesicular glutamate transporters (VGLUTs). Of the three known transporters, VGLUT1 and VGLUT2 are expressed prominently in the adult brain, but during the first two weeks of postnatal development, VGLUT2 expression predominates. Targeted deletion of VGLUT1 in mice causes lethality in the third postnatal week. Glutamatergic neurotransmission is drastically reduced in neurons from VGLUT1-deficient mice, with a specific reduction in quantal size. The remaining activity correlates with the expression of VGLUT2. This reduction in glutamatergic neurotransmission can be rescued and enhanced with overexpression of VGLUT1. These results show that the expression level of VGLUTs determines the amount of glutamate that is loaded into vesicles and released and thereby regulates the efficacy of neurotransmission.

Synaptotagmin 1 likely acts as a Ca2+ sensor in neurotransmitter release by Ca2+-binding to its two C2 domains. This notion was strongly supported by the observation that a mutation in the C2A domain causes parallel decreases in the apparent Ca2+ affinity of synaptotagmin 1 and in the Ca2+ sensitivity of release. However, this study was based on a single loss-of-function mutation. We now show that tryptophan substitutions in the synaptotagmin 1 C2 domains act as gain-of-function mutations to increase the apparent Ca2+ affinity of synaptotagmin 1. The same substitutions, when introduced into synaptotagmin 1 expressed in neurons, enhance the Ca2+ sensitivity of release. Mutations in the two C2 domains lead to comparable and additive effects in release. Our results thus show that the apparent Ca2+ sensitivity of release is dictated by the apparent Ca2+ affinity of synaptotagmin 1 in both directions, and that Ca2+ binding to both C2 domains contributes to Ca2+ triggering of release.

Summary Objectives To evaluate the dose–response relationship of tarafenacin, an antimuscarinic agent in development phase, for efficacy and safety, at daily doses of 0.2 and 0.4 mg for the treatment of overactive bladder (OAB) Patients and methods This multicentre, placebo‐controlled, randomised, double‐blind, phase 2b study was conducted. Patients were randomised to tarafenacin 0.2 mg, tarafenacin 0.4 mg or placebo daily for 12 weeks. Adult patients with OAB for at least 6 months, with an average of ≥ 8 micturitions per day and ≥ 3 incontinence episodes or a total of ≥ 6 urgency episodes per 3 days were enrolled. The primary objective was to compare the mean changes in the number of micturitions per 24 h of the two doses of tarafenacin compared with placebo from baseline to 12 weeks after treatment. Results A total of 334 patients were screened, of whom 235 patients were randomised. The mean decrease in the number of micturitions per 24 h from baseline to 12 weeks was statistically higher in the tarafenacin 0.4 mg group (−2.43 ± 2.21 times per day, p = 0.033) and non‐statistically significant in the tarafenacin 0.2 mg group (−1.92 ± 2.45 times per day, p = 0.393) when compared with the placebo group (−1.77 ± 2.95 times per day). There were no statistically significant differences in the mean change of urgency episodes per 24 h among three groups. The most common adverse event was dry mouth. There were no significant differences in blurred vision and constipation compared with placebo. Conclusions Tarafenacin 0.4 mg decreased the number of micturitions in patients with OAB after 12 weeks compared with placebo, and the dose–response relationship of tarafenacin 0.2 and 0.4 mg was confirmed. Both dose levels of tarafenacin were well tolerated.

Pediatric patients receiving hematopoietic stem cell transplantation undergo regular administration of intravenous busulfan as a conditioning regimen. Once-daily regimen of busulfan has been proposed as a more convenient alternative to the traditional regimen, but it may increase the risk of toxicity such as veno-occlusive disease (VOD). The study aims to evaluate the pharmacokinetics (PKs) of once-daily regimens and investigate appropriate intravenous infusion times to reduce the risk of toxicity. Once-daily busulfan dosing regimens for pediatric patient were reviewed and selected including EMA- and FDA-based once-daily dosing regimens. We generated busulfan PK data of virtual pediatric patients using a previously developed population PK model. PK profiles and proportion of patients achieving the referenced maximum concentration (Cmax) and exposure to busulfan were used to evaluate the appropriateness of both infusion time and dosing regimens. Predicted PK profiles and exposure of busulfan showed relatively similar distributions for all once-daily dosing regimens. Most patients exceeded the referenced Cmax possibly associated with a high risk of VOD with all once-daily regimens when applied with 3 hours of infusion. While intravenous infusion of once-daily busulfan is typically administered over 3 hours, our findings emphasize the necessity of considering sufficient infusion times to ensure safe drug utilization and prevent toxicity, which will aid in optimal busulfan use in pediatric oncology.

The transcription factor TCF4 was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing Tcf4 in forebrain ( Tcf4 tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed Tcf4 tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 ( Tcf4Ex4δ +/− ) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of Tcf4 tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in Tcf4 tg mice and enhanced long-term potentiation in Tcf4Ex4δ +/− mice indicating specific gene-dosage effects. Tcf4 tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.

To facilitate the selection of multiple gene integrants in Hansenula polymorpha, a rapid and copy-number-controlled selection system was developed using a vector containing a telomeric autonomous replication sequence and the bacterial aminoglycoside 3-phosphotransferase (APH) gene. Direct use of the unmodified APH gene as a dominant selectable marker resulted in the extremely slow growth of transformants and the frequent selection of spontaneous resistance. For the proper performance of the APH gene, a set of deleted glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoters of H. polymorpha were fused to the APH gene. The fusion construct with the 578-bp GAPDH promoter conferred G418 resistance sufficient to allow rapid growth of transformants, and thus facilitated the selection of transformants with up to 15 tandem copies of the vector. To increase further the integration copy number within the gene-dose-dependent range, the GAPDH promoter was serially deleted down to the -61 nucleotide. With this weak expression cassette, the integration copy number could easily be controlled between 1 and 50. Tandemly integrated copies of plasmids near the end of the chromosome were mitotically stable over 150 generations. The dosage-dependent selection system of this study would provide a powerful tool for the development of H. polymorpha as an industrial strain to produce recombinant proteins.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Synaptic vesicles are loaded with neurotransmitter by means of specific vesicular transporters. Here we show that expression of BNPI, a vesicle-bound transporter associated with sodium-dependent phosphate transport 1 , 2 , 3 , results in glutamate uptake by intracellular vesicles. Substrate specificity and energy dependence are very similar to glutamate uptake by synaptic vesicles. Stimulation of exocytosis—fusion of the vesicles with the cell membrane and release of their contents—resulted in quantal release of glutamate from BNPI-expressing cells. Furthermore, we expressed BNPI in neurons containing GABA (γ-aminobutyric acid) and maintained them as cultures of single, isolated neurons that form synapses to themselves. After stimulation of these neurons, a component of the postsynaptic current is mediated by glutamate as it is blocked by a combination of the glutamate receptor antagonists, but is insensitive to a GABA A receptor antagonist. We conclude that BNPI functions as vesicular glutamate transporter and that expression of BNPI suffices to define a glutamatergic phenotype in neurons.

Plaster of Paris (PoP) impregnated bandages have been used to maintain the position of bones and joints for over a century. Classically, wool dressing is applied to the limb before the PoP, which can then be moulded to the desired shape. A modification of this practice is to wrap the PoP bandages circumferentially in cotton before wetting and applying to the patient in an attempt to reduce inhalation of plaster dust and reduce mess. However, this may affect the water content of the cast and therefore also its setting properties and strength. This study compared the setting properties of PoP casts when used with and without cotton wrapping. Sixty specimens, compliant with the American Society for Testing and Materials standards for three-point bending tests, were prepared, with thirty wrapped in cotton. All were weighed before and after water immersion, and wrapped around a plastic cylinder to mimic limb application. Bending stiffness and yield strength was measured on a servohydraulic materials testing machine at 2, 6, 12, 24, 48 and 72 hours. The water content of cotton-wrapped plaster was significantly higher (50%) than that of standard plaster. It had significantly lower strength up to 24 hours and significantly lower stiffness up to 72 hours. The initial decrease in strength and stiffness of the cast wrapped in cotton may comprise the ability of the backslab to hold the joint or bone in an optimal position. Any modification of the standard plaster slab application technique should allow for the potential adverse effects on the plaster setting properties.

Lactobacillus delbrueckii subsp. delbrueckii KCTC 1047, grown in de Man, Rogosa and Sharpe (MRS) or soymilk media, completely hydrolyzed the isoflavone glucosides, genistin and daidzin at 50 μg ml^sup -1^, into their respective aglycones, genistein and daidzein within 30 min. Other lactic acid bacteria did not produce β-glucosidase, the enzyme responsible for the hydrolysis of isoflavone glucosides, when cultured in MRS medium. Glucoside-hydrolyzing activity was induced in some lactic acid bacteria when cultured in soymilk medium. These strains hydrolyzed 70-80% of genistin into genistein and 25-40% of daidzin into daidzein.[PUBLICATION ABSTRACT]