DOMINANTLY INHERITED JUVENILE OPTIC ATROPHY

Until recently, the separate existence and nature of the juvenile form of dominantly inherited optic atrophy have been generally overlooked. Yet the condition has a characteristic clinical picture. Individual features of this clinical picture, but in no instance all of them, are common to other diseases, especially tobacco-alcohol amblyopia and glaucoma. Theoretical assessment of the site of the basic lesion is frustrated by contradictions between the known facts. The condition is common, and is one of which all optometrists should be aware.     

Replacement of Tyr-SO3H by a p-carboxymethyl-phenylalanine in a CCK8-derivative preserves its high affinity for CCK-B receptor

The sulfated tyrosine present in the sequence of CCK₈ Asp²⁶-Tyr(SO₃H)-Met-Gly-Trp-Met-Asp-PheNH₂, seems to play a critical role in the recognition of CCK-A binding sites. In this work, we have investigated whether the presence of an anionic charge on the tyrosine moiety is strictly necessary and whether the sulfate moiety interacts with a divalent cation in the receptor subsite. For this purpose, the novel amino acids (l,d ) Phe(p-CH₂CO₂H) and (l,d ) Phe(p-CH₂CONHOH), as well as their l -resolved forms were introduced into the sequence of Ac[X²⁷, Nle²⁸, Nle³¹]-CCK_27-33 by solid phase method. The biological activities of these new derivatives were compared to two almost equiactive analogues of CCK₈, Ac[Phe(p-CH2SO₃H)²⁷, Nle²⁸, Nle³¹]-CCK_27-33 and Boc[Nle²⁸, Nle³¹]-CCK₂₇-3₃ (BDNL) and to the nonsulfated analogue of the latter peptide (BDNL NS). All these new CCK-related analogues behave as agonists in stimulating pancreatic amylase release and display high affinity for brain binding sites (K₁～ 3-11 nm ) but the only peptides which retain affinity for CCK-A receptors (K₁～ 20 nm ) are those containing a p-caiboxymethyl phenylalanine. Thus, introduction of this amino acid under an esterified form on the side chain, into specific and potent CCK-B agonists could allow compounds endowed with good bioavailabilities to be obtained.     

High Resolution Computed Tomography in the Evaluation of Glomus Tumours of the Petrous Temporal Bone.

Recent advances in surgery have made it possible to resect virtually all glomus tumours involving the petrous temporal bone. The surgical approach depends on the extent of the tumour and the degree of involvement of the intrapetrous portion of the internal carotid artery. High resolution computed tomography offers an accurate means of staging these tumours and of distinguishing them from an aberrant internal carotid artery. The CT scans of eighteen patients thought clinically to have glomus tumours of the temporal bone were reviewed. The final diagnoses in our series included twelve glomus turnours, three aberrant internal carotid arteries, two carcinoid tumours and one meningioma.     

Humoral responses in mice following vaccination with DNA encoding glutathione S-transferase of Fasciola hepatica: effects of mode of vaccination and the cellular compartment of antigen expression

The humoral responses in mice following vaccination with DNA constructs encoding Fasciola hepatica glutathione S-transferase (GST) have been evaluated. GST47 cDNA was subcloned into two DNA vaccine vectors, VR1012 and VR1020, which direct expression to the cytoplasmic and extracellular compartments, respectively. Expression was confirmed by transfection into COS 7 cells. Groups of mice were vaccinated with these constructs, by either intramuscular injection with the VR1012-or VR1020-based constructs, or intradermal vaccination (with a gene gun) with the VR1020-based construct. Vaccination with the construct designed for secretion resulted in an increased humoral response compared to vaccination with the nonsecretory construct. The level of the total humoral response after vaccination with the secretion construct was not dependent on the route of vaccination. However, the isotype profile of the response differed between the groups; intramuscular vaccination with the construct directing cytoplasmic expression yielded an immuoglobulin (Ig)G2a dominant (Th1-type) response, intradermal vaccination with the secretory construct a IgG1/IgE dominant (Th2-type) response, and intramuscular vaccination with the secretory construct a mixed isotype response. These results demonstrate that the immunogenicity of a DNA vaccine based on Fasciola GST, as well as the isotype of the response against GST, is determined by the mode of vaccine administration.     

Solid phase synthesis of the retro viral nucleocapsid protein NCp10 of Moloney Murine Leukaemia virus and related “zinc-fingers” in free SH forms

The core of retroviruses contains a highly conserved, low molecular weight, basic protein that binds nucleic acids and is essential for genomic RNA packaging. The 56 amino acid protein, NCp10, of Moloney Murine Leukaemia virus (MoMuLV) has the CysX₂CysX⁴HisX⁴Cys zinc finger-like motif shared by all retrovirus nucleocapsid proteins. The native protein and five modified peptides containing the zinc binding domain were synthesized by solid phase in order to investigate the structural and biochemical role of Zn²⁺ chelation in MoMuLV NCp10 activity. The purity of the synthetic molecules was verified by HPLC and their sequences were confirmed by amino acid analysis and sequencing in the case of NCp10. Thiol dosage agreed with the theoretical value of free cysteine for all these molecules. Fluorescence measurements performed on synthetic NCp10 and zinc finger fragments showed that the tryptophan quantum yield was Zn²⁺ -dependent allowing a 1:1 stoichiometry for the complex to be determined. The apparent affinity constant of NCp10 for the metal was estimated to be superior to 10⁶ M^-1. The synthetic protein, in the presence of Zn²⁺ ions, possesses all the biological properties of NCp10 isolated from virions. It catalyzes both the MoMuLV RNA dimerization and the annealing of the replication primer tRNA^Pro onto MoMuLV RNA.     

Overdose deaths following previous non‐fatal heroin overdose: Record linkage of ambulance attendance and death registry data

Introduction and Aims. Experiencing previous non‐fatal overdoses have been identified as a predictor of subsequent non‐fatal overdoses; however, few studies have investigated the association between previous non‐fatal overdose experiences and overdose mortality. We examined overdose mortality among injecting drug users who had previously been attended by an ambulance for a non‐fatal heroin overdose. Design and Methods. Using a retrospective cohort design, we linked data on non‐fatal heroin overdose cases obtained from ambulance attendance records in Melbourne, Australia over a 5‐year period (2000–2005) with a national death register. Results. 4884 people who were attended by ambulance for a non‐fatal heroin overdose were identified. One hundred and sixty‐four overdose deaths occurred among this cohort, with an average overdose mortality rate of 1.20 per 100 person‐years (95% CI, 1.03–1.40). Mortality rate decreased 10‐fold after 2000 coinciding with widely reported declines in heroin availability. Being male, of older age (>35 years) and having been attended multiple times for previous non‐fatal overdoses were associated with increased mortality risk. Discussion and Conclusions. As the first to show a direct association between non‐fatal overdose and subsequent overdose mortality, this study has important implications for the prevention of overdose mortality. This study also shows the profound effect of macro‐level heroin market dynamics on overdose mortality.[Stoové MA, Dietze PM, Jolley D. Overdose deaths following previous non‐fatal heroin overdose: Record linkage of ambulance attendance and death registry data. Drug Alcohol Rev 2009;28:347–352]