Morphological and biochemical studies of a mouse mutant (fro/fro) with bone fragility.

The mutation fragilitas ossium (fro) was discovered in a random-bred stock of mice during an experiment aimed at detecting recessive lethal mutations after treatment of the postmeiotic germ cells of male mice with tris (1-aziridinyl)phosphine sulphide. The affected mice were moderately runted and had deformities in all four limbs. The radiological and histological findings indicate that the mutant is similar to human osteogenesis imperfecta. The ash content of long bones was lower in the mutant. A defect of type I collagen could not be detected. The electrophoretic patterns of alpha bands of type I and V collagen and CB derived peptides of type I collagen from bone and skin showed no abnormalities. The total collagen synthesis and secretion in cultures of dermal fibroblasts, as well as the gel electrophoresis of procollagen and collagen chains synthesized, and of their CB peptides, were the same as those found in the controls. The percentage of type I and type V collagen synthesized was similar; that of type III was lower in the mutants. Bone osteonectin was found to be decreased by 30% and bone sialoprotein by 5%. The mRNA level for osteonectin was decreased in the fibroblasts of the mutant by about 50%. Whether the defective expression of the osteonectin in fro/fro mice is due to a mutation in the gene itself or its regulatory site(s), or is secondary to other factors remains to be established. The fro/fro mouse may represent a model for some forms of human bone fragility without collagen abnormalities.     

Pharmacological study of the chicken's monocular optokinetic nystagmus: effects of GABAergic agonist and antagonists.

When injected into the chicken open eye, the GABA-agonist THIP and the GABA-antagonists bicuculline and picrotoxin induced spontaneous eye movements in nasal-temporal (N-T) and in temporal-nasal (T-N) direction, respectively. These spontaneous movements were scarcely modulated by optokinetic stimulation, irrespective of the direction of stimulation. It is suggested that they are due to the suppression of directional selectivity of retinal ganglion cells. When injected into the closed eye, GABAergic drugs did not produce spontaneous nystagmus. THIP provoked a reduction of the N-T component, without modifying the T-N one, while GABA antagonists induced a significant increase in OKN performance, especially for the N-T direction of stimulation. In these conditions, picrotoxin also provoked an increase in the duration of both components of optokinetic after nystagmus, indicating a direct effect of the drug upon the velocity-storage system.     

Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1)

Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. In the most common subtype (TD1), femurs are curved, while in TD2, straight femurs are associated with cloverleaf skull. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene were identified in both subtypes. While TD2 was accounted for by a single recurrent mutation in the tyrosine kinase 2 domain, TD1 resulted from either stop codon mutations or missense mutations in the extracellular domain of the gene. Here, we report the identification of FGFR3 mutations in 25/26 TD cases. Two novel missense mutations (Y373C and G370C) were detected in 8/26 and 1/26 TD1 cases respectively. Both mutations created cysteine residues in the juxta extramembrane domain of the receptor. Sixteen cases carried the previously reported R248C (9/26 cases), S249C (2/26 cases) or stop codon FGFR3 mutations (5/26 cases). Our results suggest that TD1 is a genetically homogeneous condition and give additional support to the view that newly created cysteine residues in the extracellular domain of the protein play a key role in the severity of the disease.      

Electronic Structure and Surface Properties of Copper Thiocyanate: A Promising Hole Transport Material for Organic Photovoltaic Cells

Considering the significance of hexagonal copper thiocyanate (β-CuSCN) in several optoelectronic technologies and applications, it is essential to investigate its electronic structure and surface properties. Herein, we have employed density functional theory (DFT) calculations to characterise the band structure, density of states, and the energy-dependent X-ray photoelectron (XPS) valence band spectra at variable excitation energies of β-CuSCN. The surface properties in the absence and presence of dimethyl sulfoxide (DMSO), a solvent additive for improving perovskite solar cells’ power conversion efficiency, have also been systematically characterised. β-CuSCN is shown to be an indirect band gap material (E_g = 3.68 eV) with the valence band edge demonstrated to change from being dominated by Cu-3d at soft X-ray ionisation photon energies to Cu-3p at hard X-ray ionisation photon energies. The adsorption energy of dimethyl sulfoxide (DMSO) on the (100) and (110) β-CuSCN surfaces is calculated at −1.12 and −0.91 eV, respectively. The presence of DMSO on the surface is shown to have a stabilisation effect, lowering the surface energy and tuning the work function of the β-CuSCN surfaces, which is desirable for organic solar cells to achieve high power conversion efficiencies.     

Reduction in length of stay for patients undergoing oesophageal and gastric resections with implementation of enhanced recovery packages

Introduction

The high mortality and morbidity associated with resection for oesophagogastric malignancy has resulted in a conservative approach to the postoperative management of this patient group. In August 2009 we introduced an enhanced recovery after surgery (ERAS) pathway tailored to patients undergoing resection for oesophagogastric malignancy. We aimed to assess the impact of this change in practice on standard clinical outcomes.

Methods

Two cohorts were studied of patients undergoing resection for oesophagogastric malignancy before (August 2008 – July 2009) and after (August 2009 – July 2010) the implementation of the ERAS pathway. Data were collected on demographics, interventions, length of stay, morbidity and in-hospital mortality.

Results

There were 53 and 55 oesophagogastric resections undertaken respectively for malignant disease in each of the study periods. The median length of stay for both gastric and oesophageal resection decreased from 15 to 11 days (Mann– Whitney U, p<0.001) following implementation of the ERAS pathway. There was no significant increase in morbidity (gastric resection 23.1% vs 5.3% and oesophageal resection 25.9% vs 16.7%) or mortality (gastric resection no deaths and oesophageal resection 1.8% vs 3.6%) associated with the changes. There was a significant decrease in the number of oral contrast studies used following oesophageal resection, with a reduction from 21 (77.8%) in 2008–2009 to 6 (16.7%) in 2009–2010 (chi-squared test, p<0.0001).

Conclusions

The introduction of an enhanced recovery programme following oesophagogastric surgery resulted in a significant decrease in length of median patient stay in hospital without a significant increase in associated morbidity and mortality.     

A switch from GnRH agonist to GnRH antagonist in castration-resistant prostate cancer patients leads to a low response rate on PSA

Purpose

At the time of castration resistance, it is recommended to realize hormonal manipulations before chemotherapy. We evaluated the impact of a switch from GnRH agonist to antagonist in patients with castration-resistant prostate cancer on PSA and testosterone levels at 3 months.

Methods

Retrospectively, 17 patients from 5 different centers undergoing androgen deprivation therapy and presenting rising PSA confirmed on 3 blood samples 2 weeks apart and despite a castrate testosterone level (<0.5 ng/ml) were reviewed. Antiandrogen withdrawal syndrome had been tested before the switch. Degarelix was administered as followed: 240 mg for the first injection and then 80 mg every month, subcutaneously. We evaluated the PSA and testosterone level variation 3 months after the switch. Patients who experienced a variation in PSA of less than 10% compared to the baseline or who had a more than 10% PSA decrease were defined as responders.

Results

Mean PSA level at the switch was 34.3 ± 50.3 ng/ml, with a mean testosterone level of 0.21 ± 0.13 ng/ml. Three months after the switch, mean PSA level was 59.9 ± 81.6 ng/ml (P = 0.061), with a mean testosterone level of 0.19 ± 0.08 ng/ml (P = 0.086). At 3 months, 4 patients (23%) responded to therapy. Thirteen patients (77%) experienced a rise in PSA of more than 10% compared to baseline; 41% of patients decreased their testosterone level. The limitations of this study are its retrospective nature and the limited number of patients.

Conclusion

Switch from an agonist to an antagonist of GnRH has a limited impact on PSA at 3 months in castration-resistant prostate cancer patients.     

Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat

Relaxin-3 (RLX3) is a newly identified member of the relaxin/insulin peptide family that is highly conserved across a range of species from fish to mammals and is highly expressed in rat, mouse and human brain. Extensive pharmacological studies have demonstrated that RLX3 is a high affinity, selective ligand for G-protein-coupled receptor-135 (GPCR135, now classified as relaxin family peptide-3 receptor; RXFP3). In ongoing studies to understand the physiological functions of RLX3, the distribution of RLX3-containing neuronal elements in rat brain was determined by immunohistochemistry, using an affinity-purified polyclonal antiserum raised against a conserved segment of the RLX3 C-peptide (AS-R3(85-101)). Consistent with the distribution of RLX3 mRNA, neurons containing RLX3-like immunoreactivity (LI) were observed in the pontine nucleus incertus and the majority of these cells, which are known to express corticotropin-releasing factor receptor-1, were shown to express glutamic acid decarboxylase-65-immunoreactivity, suggesting a GABA phenotype. Nerve fibers and terminals containing RLX3-LI were observed adjacent to cells in the nucleus incertus and in various forebrain regions known to receive afferents from the nucleus incertus, including cortex, septum, hippocampus, thalamus, hypothalamus and midbrain. Regions that contained highest densities of RLX3-positive fibers included the medial septum, lateral preoptic area, lateral hypothalamus/medial forebrain bundle and ventral hippocampus; and additional fibers were observed in olfactory bulb and olfactory and frontal/cingulate cortices, bed nucleus of the stria terminalis, dorsal endopiriform, intergeniculate, and supramammillary nuclei, and the periaqueductal gray and dorsal raphe. The RLX3-positive network overlapped the regional distribution of GPCR135 mRNA and specific binding sites for an [125I]-GPCR135-selective, chimeric peptide. These anatomical findings further support the proposition that RLX3 is the endogenous ligand for GPCR135 in rat brain and provide evidence for broad modulatory activity of RLX3 in behavioral activation relating to autonomic and neuroendocrine control of metabolism and reproduction and higher-order processes such as stress and cognition.