Role of Tris-CaEDTA as an adjuvant with nebulised tobramycin in cystic fibrosis patients with Pseudomonas aeruginosa lung infections: A randomised controlled trial

BackgroundWe tested if disrupting iron utilisation by P. aeruginosa by adding the Tris-buffered chelating agent CaEDTA to nebulised tobramycin would enhance bacterial clearance and improve lung function in CF patients.MethodsIn this double-blind, randomised controlled trial, 26 episodes (25 patients) with P. aeruginosa infection admitted to two CF centres for treatment of an acute pulmonary exacerbation were randomly assigned to receive either 75 mg CaEDTA in Tris-buffered saline or placebo (Tris-buffered saline) nebulised in combination with 250 mg tobramycin twice daily for six weeks followed with four week safety follow-up. Primary endpoints were safety, tolerability, and bacterial density of P. aeruginosa. A secondary endpoint was lung function.ResultsThe study drug was well tolerated with adverse events comparable in both groups. The mean (SD) reduction in sputum P. aeruginosa count (log₁₀ CFU/g) in the CaEDTA vs placebo group was 2·05 (2·57) vs 0·82 (2·71) at two weeks relative to admission (p = 0·39). The mean improvement in ppFEV₁ was 16 vs 5 (p = 0·16); 11 vs 2 (p = 0·28); and 6 vs 2 percentage points (p = 0·47) at two, six, and ten weeks in CaEDTA and placebo groups, respectively.ConclusionsIn this pilot study in CF patients, an increase in the reduction of sputum density of P. aeruginosa and an increase in ppFEV₁ was observed in the group of patients who received Tris-CaEDTA added to inhaled tobramycin compared to the group who received inhaled tobramycin alone, although these differences were not statistically significant. The treatment was also shown to be safe.     

Gender Variance in Children and Adolescents with Neurodevelopmental and Psychiatric Conditions from Australia

Archives of Sexual Behavior - Gender variance is a broad term used to describe gender non-conforming behaviors. Past studies have used the parental response to Child Behavior Checklist (CBCL) Item...     

Depression,anxiety, and loneliness among adolescents and young adults with IBD in the UK: the role of disease severity,age of onset,and embarrassment of the condition

Quality of Life Research - Adolescents and young adults (AYA) with Inflammatory Bowel Disease (IBD) report higher depressive symptoms and anxiety compared to healthy controls, with disease severity...     

Transforming proteins of fujinami and PRCII avian sarcoma viruses have different subcellular locations

The subcellular locations of transforming proteins encoded by the related avian sarcoma viruses, PRCII and Fujinami sarcoma virus (FSV), were compared by cell fractionation and by indirect immunofluorescence. Whereas both viruses encode gag-fps proteins associated with tyrosine-specific kinase activity, FSV is more highly tumorigenic than PRCII in vivo. Cell fractionation studies showed that the PRCII transforming protein, P105, became associated with the high-speed particulate fraction shortly after synthesis. However, PRCII P105 did not fractionate with the plasma membrane marker, but rather with high-density membranes. It is unique in this subcellular localization among viral tyrosine kinases. This membrane association was found to be relatively insensitive to salt concentration and did not require divalent cations. Immunofluorescent studies, using anti-fps serum, showed that the PRCII protein was present in discrete, large, cytoplasmic patches, as well as in a juxtanuclear location. In contrast, FSV-encoded P130 was found to fractionate with the plasma membrane marker when cells were analyzed in low salt in the presence of magnesium. However, at higher salt concentrations and in the absence of magnesium, the bulk of P130 was found to be soluble. Immunofluorescent staining of FSV P130 revealed a diffuse, cytoplasmic pattern that was distinct from that of the PRCII product. The observed difference in the subcellular localization of these transforming proteins may be the cause of the difference in tumorigenicity between the two viruses.     

The Effects of Permeation Enhancers on the Surface Morphology of the Rat Nasal Mucosa: A Scanning Electron Microscopy Study

A rat model has been developed to compare relative morphological changes in the nasal mucosa after exposure to potential membrane permeation enhancers. Scanning electron microscopy was used to characterize gross structural and specific cellular changes following exposure. Micrographs of the rat nasal mucosa were scored in four categories: (1) mucosal surface integrity, (2) ciliary morphology, (3) mucus/extracellular debris, and (4) presence of red blood cells. The order of increasing morphological damage resulting from a 5-min exposure to each surfactant was 0.5% Solulan C-24 0.5% Solulan C-24/0.5% sodium tauro-24,25-dihydrofusidate (STDHF) < 0.5% STDHF < 1.0% STDHF 1.0% Laureth-9 < 1.0% sodium taurodeoxycholate 1.0% sodium deoxycholate. The changes observed in the mucosal morphology after exposure to the various surfactants are in general agreement with data in the literature. This model is able to compare rapidly the relative morphological effects on the mucosal membrane of different nasal formulations.     

SOX5: Lamb–Shaffer syndrome—A case series further expanding the phenotypic spectrum

To delineate further the clinical phenotype of Lamb–Shaffer Syndrome (LSS) 16 unpublished patients with heterozygous variation in SOX5 were identified either through the UK Decipher database or the study team was contacted by clinicians directly. Clinical phenotyping tables were completed for each patient by their responsible clinical geneticist. Photos and clinical features were compared to assess key phenotypes and genotype–phenotype correlation. We report 16 SOX5 variants all of which meet American College of Medical Genetics/Association for Clinical Genomic Science ACMG/ACGS criteria class IV or V. 7/16 have intragenic deletions of SOX5 and 9/16 have single nucleotide variants (including both truncating and missense variants). The cohort includes two sets of monozygotic twins and parental gonadal mosaicism is noted in one family. This cohort of 16 patients is compared with the 71 previously reported cases and corroborates previous phenotypic findings. As expected, the most common findings include global developmental delay with prominent speech delay, mild to moderate intellectual disability, behavioral abnormalities and sometimes subtle characteristic facial features. We expand in more detail on the behavioral phenotype and observe that there is a greater tendency toward lower growth parameters and microcephaly in patients with single nucleotide variants. This cohort provides further evidence of gonadal mosaicism in SOX5 variants; this should be considered when providing genetic counseling for couples with one affected child and an apparently de novo variant.     

Selective incorporation of111In-labeled PHOTOFRIN™ by glioma tissuein vivo

The use of PHOTOFRIN for photodynamic therapy of human gliomas has been studied by i.v. administration and laser photosensitization. Defining the uptake of PHOTOFRIN in the patient's tumor in comparison with the surrounding normal brain tissue is highly desirable for patient selection and study ofin vivo kinetics. We utilized a non-invasive approach to the detection of PHOTOFRIN uptake in brain tumors with¹¹¹In-oxine radiolabeled PHOTOFRIN and external imaging and quantitation using a gamma camera. Biodistribution of¹¹¹In-labeled PHOTOFRIN in 13 organs was determined in four dogs and 15 mice with gliomas.^99mTc-DTPA was used as a control for nonspecific uptake. The greatest concentration of¹¹¹In-PHOTOFRIN in the brain tumor occurred at 24 hours post i.v. administration. The brain tumor PHOTOFRIN uptake was seven times greater than that of normal brain. The decreased blood background at 72 hours made this the optimum time for imaging. Specific tumor tissue uptake of¹¹¹In-PHOTOFRIN occurred, well beyond that resulting from blood-brain-barrier (BBB) breakdown.     

Disposition in mice of 7-hydroxystaurosporine,a protein kinase inhibitor with antitumor activity

UCN-01, a hydroxylated derivative of staurosporine, was selected for study because of its promising antitumor activity. For mice dosed intravenously, subcutaneously, or by oral gavage with this compound, the maximum tolerated doses (MTD) were 20, 10, and >100 mg/kg, respectively. UCN-01 was stable in mouse and dog plasma, but in human plasma it was converted to a metabolite in a process not inhibited by standard protease and esterase inhibitors. Following n intravenous dose of 10 mg/kg UCN-01, the half-lives for the initial (t _1/2) and terminal (t _1/2) exponential phases of elimination were 10 and 85 min, respectively; the area under the plasma concentration-time curve (AUC value) was 117 g min ml^–1. In mice dosed by oral gavage with 10 mg/kg, the calculated value for the half-life of the elimination phase was 150 min. The AUC value was 15 g min ml^–1, giving a value for bioavailability of 13%. After subcutaneous dosing with 10 mg/kg, the calculated values for half-lives for the distribution and elimination phases were 23 and 130 min, respectively; the AUC value was 113 g min ml^–1. Since this value is equivalent to that obtained for intravenous dosing, administration of UCN-01 by the subcutaneous route may be an alternative to intravenous dosing in preclinical and clinical trials.This work was supported by contract NO1-CM-27710 (National Cancer Institute, National Institutes of Health, Department of Health and Human Services)     

The enhancement of nerve regeneration using growth factors: a brief review

The management of peripheral nerve injuries continues to challenge the surgeon. Despite advances in surgical technique, return of normal function is uncommon after the repair of a transected nerve. It is now possible to enhance the process of nerve regeneration in animals using growth factors carried in silicone nerve guides. In this article the biological process of nerve regeneration is described and contemporary research involving the use of growth factor implants to facilitate nerve regeneration is reviewed.