The discovery of highly potent CGRP receptor antagonists.

Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.

A relation based measure of semantic similarity for Gene Ontology annotations.

Background: Various measures of semantic similarity of terms in bio-ontologies such as the Gene Ontology (GO) have been used to compare gene products. Such measures of similarity have been used to annotate uncharacterized gene products and group gene products into functional groups. There are various ways to measure semantic similarity, either using the topological structure of the ontology, the instances (gene products) associated with terms or a mixture of both.

Technetium-99m-labelled sulesomab (LeukoScan) in the evaluation of soft tissue infections.

Objective: To perform a retrospective review of all patients receiving technetium-99m ((99m)Tc)-labelled sulesomab over a 4-year period to determine if soft tissue infections can be accurately identified.

Methods And Materials: We reviewed the results of 124 (99m)Tc-sulesomab studies performed over a 4-year period. Of these, 34 were performed for undiagnosed fever in which soft tissue infection was suspected to be the main cause.

Dissemination of Cognitive Therapy for Panic Disorder in Primary Care.

This study investigated whether brief training in cognitive therapy for panic disorder (Clark et al., 1994) can improve the outcomes that primary care therapists obtain with their patients. Seven primary care therapists treated 36 patients meeting DSM-IV (APA, 1994) criteria for panic disorder with or without agoraphobia in general practice surgeries.

The role of 99mTc-depreotide in the management of neuroendocrine tumours.

Background: In-pentetreotide scan (OctreoScan) is a widely available agent with high sensitivity for imaging neuroendocrine tumours. Negative In-pentetreotide poses diagnostic as well as therapeutic problems in terms of staging and consideration of targeted radionuclide therapy.

Aim: To assess the role of Tc-depreotide in patients with negative or weakly positive OctreoScan (Krenning score< or =1; measured on a scale range 0-4).

Electroporation of corrective nucleic acids (CNA) in vivo to promote gene correction in dystrophic muscle.

Non-viral gene transfer into skeletal muscle in vivo is enhanced by electroporation (EP) to efficiencies far beyond any other (non-EP) method reported to date. Electroporation consistently delivers high levels of transgene to muscle and has been used extensively for the delivery of therapeutic transgenes to dystrophic mouse muscle such as the mdx mouse model of human Duchenne muscular dystrophy (DMD). Since the earliest applications, electroporation has consistently and reproducibly achieved highly efficient DNA delivery to a high proportion (greater than 70%) of fibres in treated muscles.

A placebo-controlled trial of mirtazapine for the management of methamphetamine withdrawal.

Introduction And Aims: As an antidepressant with sedative and anxiolytic properties, mirtazapine may be an appropriate pharmacotherapy for methamphetamine withdrawal. This study sought to examine whether mirtazapine improves retention and alleviates methamphetamine withdrawal symptoms in an out-patient setting.

Design And Methods: An out-patient double-blind, randomised placebo-controlled trial of mirtazapine for the treatment of methamphetamine withdrawal was conducted (15 mg nocte for 2 days, 30 mg nocte for 12 days).

NHS survey: impact of conflict resolution training on working lives of healthcare staffs.

The Consumer Fraud and Security Management Service (CFSMS) is responsible for security and safety for the 1600 hospitals and other health services of England's National Health Service (NHS). Between June 2004 and May 2005, in order to counter violence directed at nurses, other caregivers and employees, SMS provided conflict resolution training (CRT) for some 250,000 NHS healthcare workers. The survey, conducted a year after the training was completed, sought to quantify the extent to which receiving CRT improved staffers' ability to deal with verbal and physical abuse.

Effective detection of corrected dystrophin loci in mdx mouse myogenic precursors.

Targeted corrective gene conversion (TCGC) holds much promise as a future therapy for many hereditary diseases in humans. Mutation correction frequencies varying between 0.0001% and 40% have been reported using chimeraplasty, oligoplasty, triplex-forming oligonucleotides, and small corrective PCR amplicons (CPA).

Evaluation of Sca-1 and c-Kit as selective markers for muscle remodelling by nonhemopoietic bone marrow cells.

Bone marrow (BM)-derived cells (BMCs) have demonstrated a myogenic tissue remodeling capacity. However, because the myoremodeling is limited to approximately 1%-3% of recipient muscle fibers in vivo, there is disagreement regarding the clinical relevance of BM for therapeutic application in myodegenerative conditions. This study sought to determine whether rare selectable cell surface markers (in particular, c-Kit) could be used to identify a BMC population with enhanced myoremodeling capacity.

Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists.

A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption.

Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: optimization of the 4-substituted piperidine.

In our continuing effort to identify CGRP receptor antagonists for the acute treatment of migraine, we have undertaken a study to evaluate alternative 4-substituted piperidines to the lead dihydroquinazolinone 1. In this regard, we have identified the piperidinyl-azabenzimidazolone and phenylimidazolinone structures which, when incorporated into the benzodiazepine core, afford potent CGRP receptor antagonists (e.g.

Intertumoural variability in functional imaging within patients suffering from neuroendocrine tumours. An observational, cross-sectional study.

(123)I mIBG (meta-iodobenzylguanidine) and (111)In pentetreotide scintigraphy imaging modalities are useful in demonstrating neuroendocrine tumours. Although (111)In pentetreotide is generally held to be a more superior imaging agent than (123)I mIBG for neuroendocrine tumours, we noted a differential uptake of the two agents by different tumour sites within individual patients. In some cases, the two tracers appeared to demonstrate different lesions within the same patient.

Non-peptide calcitonin gene-related peptide receptor antagonists from a benzodiazepinone lead.

High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor-acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor K(i)=44nM and IC(50)=38nM.

DNA electroporation in vivo targets mature fibres in dystrophic mdx muscle.

Non-viral gene transfer into skeletal muscle is enhanced by electroporation and myotoxin preconditioning of muscle following plasmid injection. We investigated in vivo delivery of naked DNA to mdx mouse muscle, utilising enhanced green fluorescent protein reporter vector (pEGFP) and a corrective nucleic acid to promote targeted corrective gene conversion at the mutant mdx mouse dystrophin (DMDmdx) locus. Electroporation, myoablation with bupivacaine and a combined protocol, were applied to mdx muscle.

Biochemical and structural characterization of a novel class of inhibitors of the type 1 insulin-like growth factor and insulin receptor kinases.

The type 1 insulin-like growth factor receptor (IGF-1R) is often overexpressed on tumor cells and is believed to play an important role in anchorage-independent proliferation. Additionally, cell culture studies have indicated that IGF-1R confers increased resistance to apoptosis caused by radiation or chemotherapeutic agents. Thus, inhibitors of the intracellular kinase domain of this receptor may have utility for the clinical treatment of cancer.

Diagnostic screening of mitochondrial DNA mutations in Australian adults 1990-2001.

Background: Many diverse pathogenic mitochondrial DNA (mtDNA) mutations have been described since 1988. The Melbourne Neuromuscular Research Institute (MNRI) has undertaken diagnostic detection of selected mtDNA mutations since 1990. MtDNA mutations screened have included point mutations associated with Leber's hereditary optic neuropathy (LHON; G3460A, G11778A and T14484C), mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS; A3243G), myoclonus epilepsy and ragged red fibres (MERRF; A8344G) and Leigh's syndrome/neuropathy ataxia retinitis pigmentosa (LS/NARP; T8993C/G).

Characteristics, retention and readmissions of opioid-dependent clients treated with oral naltrexone.

The aims of this study were to examine the retention rates of opioid-dependent clients treated with oral naltrexone and identify factors that influence retention in treatment of 981 opioid-dependent clients at a public out-patient clinic in Perth, Western Australia. The average retention period for all clients was 9.0 weeks.

CD45 fraction bone marrow cells as potential delivery vehicles for genetically corrected dystrophin loci.

Targeted correction of mutations in muscle can be delivered by direct i.m. injection of corrective DNA to the dystrophic muscle or by autologous injection of cells that have been genetically corrected after isolation from the individual with the dystrophic muscle.

Targeted gene correction in the mdx mouse using short DNA fragments: towards application with bone marrow-derived cells for autologous remodeling of dystrophic muscle.

In muscle, mutant genes can be targeted and corrected directly by intramuscular (i.m.) injection of corrective DNA, or by ex vivo delivery of DNA to myogenic cells, followed by cell transplantation.

A novel clinical phenotype of myopathy, sensorimotor neuropathy, infertility, and hypogonadism with multiple mitochondrial DNA deletions.

We describe a patient with myopathy, sensorimotor neuropathy, hypogonadism, and infertility with abnormal sperm mobility and morphology. Analysis of the deltoid muscle DNA revealed a G to A change at nt 1102 in the twinkle gene and multiple mitochondrial DNA deletions. Histochemistry revealed "ragged-red" fibers and many cytochrome-c oxidase negative fibers (32%) that lacked the mitochondrial encoded respiratory chain subunits I and II and the nuclear encoded subunit VIc.

In vivo and in vitro correction of the mdx dystrophin gene nonsense mutation by short-fragment homologous replacement.

Targeted genetic correction of mutations in cells is a potential strategy for treating human conditions that involve nonsense, missense, and transcriptional splice junction mutations. One method of targeted gene repair, single-stranded short-fragment homologous replacement (ssSFHR), has been successful in repairing the common deltaF508 3-bp microdeletion at the cystic fibrosis transmembrane conductance regulator (CFTR) locus in 1% of airway epithelial cells in culture. This study investigates in vitro and in vivo application of a double-stranded method variant of SFHR gene repair to the mdx mouse model of Duchenne muscular dystrophy (DMD).

2-Arylindole-3-acetamides: FPP-competitive inhibitors of farnesyl protein transferase.

A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed.