Sporadic inclusion body myositis: phenotypic variability and influence of HLA-DR3 in a cohort of 57 Australian cases.

Background And Aims: There have been few studies of the variability in the clinical phenotype in sporadic inclusion body myositis (sIBM) and it is not known whether the human leucocyte antigen (HLA) haplotype influences the phenotype and course of the disease. We studied a large cohort of patients with sIBM in order to determine the degree of phenotypic variability and different modes of presentation, as well as the influence of HLA haplotypes.

Method: A cross-sectional study of 57 biopsy-proven sIBM cases from three Australian centres was performed.

Structure of the N-terminal Mlp1-binding domain of the Saccharomyces cerevisiae mRNA-binding protein, Nab2.

Nuclear abundant poly(A) RNA-binding protein 2 (Nab2) is an essential yeast heterogeneous nuclear ribonucleoprotein that modulates both mRNA nuclear export and poly(A) tail length. The N-terminal domain of Nab2 (residues 1-97) mediates interactions with both the C-terminal globular domain of the nuclear pore-associated protein, myosin-like protein 1 (Mlp1), and the mRNA export factor, Gfd1. The solution and crystal structures of the Nab2 N-terminal domain show a primarily helical fold that is analogous to the PWI fold found in several other RNA-binding proteins.

The DEAD-box protein Dbp5 controls mRNA export by triggering specific RNA:protein remodeling events.

Messenger RNA (mRNA) export involves the unidirectional passage of ribonucleoprotein particles (RNPs) through nuclear pore complexes (NPCs), presumably driven by the ATP-dependent activity of the DEAD-box protein Dbp5. Here we report that Dbp5 functions as an RNP remodeling protein to displace the RNA-binding protein Nab2 from RNA. Strikingly, the ADP-bound form of Dbp5 and not ATP hydrolysis is required for RNP remodeling.

Activation of chloride secretion via proteinase-activated receptor 2 in a human eccrine sweat gland cell line--NCL-SG3.

Proteinase-activated receptor 2 (PAR-2) has been shown to elicit secretion in a variety of secretory epithelial cells by the transepithelial movement of chloride ions across the apical membrane. However, it is not known whether these receptors are present and/or functional in the secretory epithelial cells of the human eccrine sweat gland. To investigate this possibility mRNA analysis, Ca2+ microspectrofluorimetry and the short circuit current (Isc) technique were used to quantify electrolyte transport in a cell line (NCL-SG3) derived from human eccrine sweat gland secretory epithelia.

Apolipoprotein epsilon alleles in sporadic inclusion body myositis: a reappraisal.

Previous studies have differed as to whether APOE epsilon4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the epsilon2 allele.

Analysis of a predicted nuclear localization signal: implications for the intracellular localization and function of the Saccharomyces cerevisiae RNA-binding protein Scp160.

Gene expression is controlled by RNA-binding proteins that modulate the synthesis, processing, transport and stability of various classes of RNA. Some RNA-binding proteins shuttle between the nucleus and cytoplasm and are thought to bind to RNA transcripts in the nucleus and remain bound during translocation to the cytoplasm. One RNA-binding protein that has been hypothesized to function in this manner is the Saccharomyces cerevisiae Scp160 protein.

Limb-girdle muscular dystrophy: diagnostic evaluation, frequency and clues to pathogenesis.

We characterized the frequency of limb-girdle muscular dystrophy (LGMD) subtypes in a cohort of 76 Australian muscular dystrophy patients using protein and DNA sequence analysis. Calpainopathies (8%) and dysferlinopathies (5%) are the most common causes of LGMD in Australia. In contrast to European populations, cases of LGMD2I (due to mutations in FKRP) are rare in Australasia (3%).

The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3.

Niemann-Pick Type C (NP-C) disease, caused by mutations in either human NPC1 (hNPC1) or human NPC2 (hNPC2), is characterized by the accumulation of unesterified cholesterol in late endosomes. Although it is known that the NP-C proteins are targeted to late endosomal/lysosomal compartments, their delivery mechanisms have not been fully elucidated. To identify mechanisms regulating NP-C protein localization, we used Saccharomyces cerevisiae, which expresses functional homologs of both NP-C proteins - scNcr1p and scNpc2p.

An action research protocol to strengthen system-wide inter-professional learning and practice [LP0775514].

Background: Inter-professional learning (IPL) and inter-professional practice (IPP) are thought to be critical determinants of effective care, improved quality and safety and enhanced provider morale, yet few empirical studies have demonstrated this. Whole-of-system research is even less prevalent. We aim to provide a four year, multi-method, multi-collaborator action research program of IPL and IPP in defined, bounded health and education systems located in the Australian Capital Territory (ACT).

Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis.

Objectives: To describe first dose and steady state antiretroviral drug exposure in the female genital tract.

Design: Non-blinded, single center, open-label pharmacokinetic study in HIV-infected women.

Method: Twenty-seven women initiating combination antiretroviral therapy underwent comprehensive blood plasma and cervicovaginal fluid sampling for drug concentrations during the first dose of antiretroviral therapy and at steady-state.

Cognitive tutor: applied research in mathematics education.

For 25 years, we have been working to build cognitive models of mathematics, which have become a basis for middle- and high-school curricula. We discuss the theoretical background of this approach and evidence that the resulting curricula are more effective than other approaches to instruction. We also discuss how embedding a well specified theory in our instructional software allows us to dynamically evaluate the effectiveness of our instruction at a more detailed level than was previously possible.

An interaction between two RNA binding proteins, Nab2 and Pub1, links mRNA processing/export and mRNA stability.

mRNA stability is modulated by elements in the mRNA transcript and their cognate RNA binding proteins. Poly(U) binding protein 1 (Pub1) is a cytoplasmic Saccharomyces cerevisiae mRNA binding protein that stabilizes transcripts containing AU-rich elements (AREs) or stabilizer elements (STEs). In a yeast two-hybrid screen, we identified nuclear poly(A) binding protein 2 (Nab2) as being a Pub1-interacting protein.

Recognition of polyadenosine RNA by zinc finger proteins.

Messenger RNA transcripts are coated from cap to tail with a dynamic combination of RNA binding proteins that process, package, and ultimately regulate the fate of mature transcripts. One class of RNA binding proteins essential for multiple aspects of mRNA metabolism consists of the poly(A) binding proteins. Previous studies have concentrated on the canonical RNA recognition motif-containing poly(A) binding proteins as the sole family of poly(A)-specific RNA binding proteins.

Simultaneous determination of 17 antiretroviral drugs in human plasma for quantitative analysis with liquid chromatography-tandem mass spectrometry.

This work describes a sensitive method for the simultaneous determination of 17 antiretroviral drugs including nucleoside analog reverse transcriptase inhibitors, non-nucleoside analog reverse transcriptase inhibitors, protease inhibitors and a nucleotide analog reverse transcriptase inhibitor in 50 microL of human plasma. This method employed high-performance liquid chromatography-tandem mass spectrometry with electrospray ionization. The analytes were monitored in multiple reaction monitoring mode and the polarity was switched from positive to negative to positive to detect all compounds after a single injection.

The absence of apoeccrine glands in the human axilla has disease pathogenetic implications, including axillary hyperhidrosis.

Background: The existence of a third type of sweat gland in human axillary skin, the apoeccrine gland, with a capacity to produce much higher sweat output than the eccrine gland, was proposed from examination of microdissected glands. However, previous studies of axillary skin glands did not examine the entire individual glandular structure via serial sections and the markers used to identify the different glands gave conflicting results and, hence, the existence of the apoeccrine gland remains controversial.

Objectives: To investigate human axillary sweat glands by serial section histology and immunofluorescence.

A preliminary study of the short circuit current (Isc) responses of sweat gland cells from normal and anhidrotic horses to purinergic and adrenergic agonists.

The causal factors of equine anhidrosis have not yet been elucidated but defective electrolyte transport mechanisms in the gland are likely to be involved. To investigate this possibility, experiments were performed on cultured equine sweat gland epithelia from five free-sweating UK horses (3 intact males, 2 mares, aged 2-4 years) and from three free-sweating Singapore horses (1 intact male, 2 mares, aged 3-5 years) and three anhidrotic (Singapore) horses (1 intact male, 1 gelding, 1 mare, aged 3-6 years). Cultured cells from each animal were grown on permeable supports and loaded into Ussing chambers to quantify transepithelial resistance and agonist-induced electrolyte transport by the short circuit current (Isc) technique.

Designing a holographic modal wavefront sensor for the detection of static ocular aberrations.

The extent to which holographic modal wavefront sensing can be applied to the detection of ocular aberrations was investigated. First, the idea of extending the dynamic range of the sensor by increasing the mask bias and the collection area of the pinhole detectors used in the sensor is reviewed. Errors in the detection of single-mode aberrations owing to reduced coherence from retinal scattering, photon, readout, and quantization noise are evaluated.

Feminist-informed participatory action research: a methodology of choice for examining critical nursing issues.

Identifying a methodology to guide a study that aims to enhance service delivery can be challenging. Participatory action research offers a solution to this challenge as it both informs and is informed by critical social theory. In addition, using a feminist lens helps acquiesce this approach as a suitable methodology for changing practice.

Oral administration of Ginkgo biloba extract, EGb-761 inhibits thermal hyperalgesia in rodent models of inflammatory and post-surgical pain.

Background And Purpose: Studies in vitro suggest that the standardised extract of Ginkgo biloba, EGb-761 has anti-inflammatory properties and modulatory effects on key pain-related molecules. This study investigated the analgesic and anti-inflammatory effects of EGb-761 on carrageenan-induced inflammatory and hindpaw incisional pain.

Experimental Approach: Adult male Wistar rats (n=6-10/group; 250-420 g) were injected intradermally with carrageenan into the left hindpaw or anaesthetised with isoflurane (2%) and a longitudinal 1 cm incision was made through the skin, fascia and plantaris muscle of the hindpaw.

Enteropathogenic Escherichia coli Tir is an SH2/3 ligand that recruits and activates tyrosine kinases required for pedestal formation.

Enteropathogenic Escherichia coli (EPEC) cause intestinal inflammation, severe diarrhoea and mortality, particularly among children in developing nations. Upon attachment to intestinal epithelial cells, EPEC induces actin-filled membrane protrusions called 'pedestals' and disrupts microvilli to form attaching and effacing (A/E) lesions. EPEC also disrupts epithelial barrier function and causes colitis.

Unofficial policy: access to housing, housing information and social services among homeless drug users in Hartford, Connecticut.

Background: Much research has shown that the homeless have higher rates of substance abuse problems than housed populations and that substance abuse increases individuals' vulnerability to homelessness. However, the effects of housing policies on drug users' access to housing have been understudied to date. This paper will look at the "unofficial" housing policies that affect drug users' access to housing.

Extensive sequence variation exists among isolates of murine cytomegalovirus within members of the m02 family of genes.

Murine cytomegalovirus (MCMV) is a widely used model for human cytomegalovirus (HCMV) and has facilitated many important discoveries about the biology of CMVs. Most of these studies are conducted using the laboratory MCMV strains Smith and K181. However, wild-derived isolates of MCMV, like HCMV clinical isolates, exhibit genetic variation from laboratory strains, particularly at the ends of their genomes in areas containing known or putative immune-evasion and tropism genes.

AP endonuclease paralogues with distinct activities in DNA repair and bacterial pathogenesis.

Oxidative stress is a principal cause of DNA damage, and mechanisms to repair this damage are among the most highly conserved of biological processes. Oxidative stress is also used by phagocytes to attack bacterial pathogens in defence of the host. We have identified and characterised two apurinic/apyrimidinic (AP) endonuclease paralogues in the human pathogen Neisseria meningitidis.

Functional overlap between conserved and diverged KH domains in Saccharomyces cerevisiae SCP160.

The K homology (KH) domain is a remarkably versatile and highly conserved RNA-binding motif. Classical KH domains include a characteristic pattern of hydrophobic residues, a Gly-X-X-Gly (GXXG) segment, and a variable loop. KH domains typically occur in clusters, with some retaining their GXXG sequence (conserved), while others do not (diverged).

Successful resuscitation of an ASA 3 patient following ropivacaine-induced cardiac arrest.

A patient with severe myocardial disease and acute-on-chronic renal failure was undergoing a brachial plexus block for formation of an arteriovenous fistula when accidental intravascular injection of ropivacaine resulted in ventricular fibrillation. Cardiopulmonary resuscitation was instituted immediately and the advanced life support algorithm was followed until the return of sinus rhythm. Although, in comparison with bupivacaine, ropivacaine appears to be a safer local anaesthetic agent in the setting of intravenous injection, the emphasis on safety should remain a priority.