Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation.

Purpose Of Review: This review describes current knowledge of ganciclovir (GCV) and valganciclovir (ValGCV) pharmacokinetic/pharmacodynamic characteristics, highlighting the likely contribution from host genetic factors to interpatient variability. The evidence and challenges surrounding optimization of drug dosing through therapeutic drug monitoring (TDM) are examined, with recommendations made.

Recent Findings: Pharmacokinetic studies of current dosing guidelines have shown high interindividual and intraindividual variability of GCV concentrations.

Culture-Free Phylogenetic Analysis of Legionella pneumophila Using Targeted CRISPR/Cas9 Next-Generation Sequencing.

Currently available methods for the laboratory investigation of Legionella pneumophila outbreaks require organism culture. The ability to sequence L. pneumophila directly from clinical samples would significantly reduce delays.

A 12-Year Retrospective Study of Invasive Amoebiasis in Western Sydney: Evidence of Local Acquisition.

In Australia, amoebiasis is thought to occur in travellers, immigrants from endemic areas, and among men who have sex with men. Prevalence of amoebiasis in communities with immigrants from -endemic countries is unknown. The present study is a retrospective case series analysis of patients with laboratory-confirmed amoebiasis from Western Sydney Local Health District, Australia, between years 2005 and 2016.

Hypertrophy and dietary tyrosine ameliorate the phenotypes of a mouse model of severe nemaline myopathy.

Nemaline myopathy, the most common congenital myopathy, is caused by mutations in genes encoding thin filament and thin filament-associated proteins in skeletal muscles. Severely affected patients fail to survive beyond the first year of life due to severe muscle weakness. There are no specific therapies to combat this muscle weakness.

Mosaic caveolin-3 expression in acquired rippling muscle disease without evidence of myasthenia gravis or acetylcholine receptor autoantibodies.

Inherited rippling muscle disease is an autosomal dominant disorder usually associated with caveolin-3 mutations. Rare cases of acquired rippling muscle disease with abnormal caveolin-3 localisation have been reported, without primary caveolin-3 mutations and in association with myasthenia gravis and acetylcholine receptor autoantibodies, or thymoma. We present three new patients with electrically-silent muscle rippling and abnormal caveolin-3 localisation, but without acetylcholine receptor autoantibodies, or clinical or electrophysiological evidence of myasthenia gravis.

In vitro analysis of rod composition and actin dynamics in inherited myopathies.

Rods are the pathological hallmark of nemaline myopathy, but they can also occur as a secondary phenomenon in other disorders, including mitochondrial myopathies such as complex I deficiency. The mechanisms of rod formation are not well understood, particularly when rods occur in diverse disorders with very different structural and metabolic defects. We compared the characteristics of rods associated with abnormalities in structural components of skeletal muscle thin filament (3 mutations in the skeletal actin gene ACTA1) with those of rods induced by the metabolic cell stress of adenosine triphosphate depletion.

Cap disease due to mutation of the beta-tropomyosin gene (TPM2).

Cap disease or cap myopathy is a form of congenital myopathy in which peripheral, well-demarcated 'caps' of disorganised thin filaments are seen in muscle fibres. Mutation of the TPM2 gene, that encodes beta-tropomyosin, is the first reported genetic cause. In this paper, we describe a further case of cap disease due to a mutation in TPM2, confirming the importance of this genetic association.

Disease severity and thin filament regulation in M9R TPM3 nemaline myopathy.

The mechanism of muscle weakness was investigated in an Australian family with an M9R mutation in TPM3 (alpha-tropomyosin(slow)). Detailed protein analyses of 5 muscle samples from 2 patients showed that nemaline bodies are restricted to atrophied Type 1 (slow) fibers in which the TPM3 gene is expressed. Developmental expression studies showed that alpha-tropomyosin(slow) is not expressed at significant levels until after birth, thereby likely explaining the childhood (rather than congenital) disease onset in TPM3 nemaline myopathy.

Mechanisms underlying intranuclear rod formation.

Specific mutations within the alpha-skeletal actin gene (ACTA1) result in intranuclear rod myopathy (IRM), characterized by rod-like aggregates containing actin and alpha-actinin-2 inside the nucleus of muscle cells. The mechanism leading to formation of intranuclear aggregates containing sarcomeric proteins and their impact on cell function and contribution to disease pathogenesis is unknown. In this study, we transfected muscle and non-muscle cells with mutants of alpha-skeletal actin (Val163Leu, Val163Met) associated with intranuclear rod myopathy.

Intranuclear rod myopathy: molecular pathogenesis and mechanisms of weakness.

Objective: Mutations in the alpha-skeletal actin gene (ACTA1) result in a variety of inherited muscle disorders characterized by different pathologies and variable clinical phenotypes. Mutations at Val163 in ACTA1 result in pure intranuclear rod myopathy; however, the molecular mechanisms by which mutations at Val163 lead to intranuclear rod formation and muscle weakness are unknown.

Methods And Results: We investigated the effects of the Val163Met mutation in ACTA1 in tissue culture and Drosophila models, and in patient muscle.

An alphaTropomyosin mutation alters dimer preference in nemaline myopathy.

Nemaline myopathy is a human neuromuscular disorder associated with muscle weakness, Z-line accumulations (rods), and myofibrillar disorganization. Disease-causing mutations have been identified in genes encoding muscle thin filament proteins: actin, nebulin, slow troponin T, betaTropomyosin, and alphaTropomyosin(slow). Skeletal muscle expresses three tropomyosin (Tm) isoforms from separate genes: alphaTm(fast)(alphaTm, TPM1), betaTm (TPM2), and alphaTm(slow) (gammaTm, TPM3).

Evidence for a dominant-negative effect in ACTA1 nemaline myopathy caused by abnormal folding, aggregation and altered polymerization of mutant actin isoforms.

We have studied a cohort of nemaline myopathy (NM) patients with mutations in the muscle alpha-skeletal actin gene (ACTA1). Immunoblot analysis of patient muscle demonstrates increased gamma-filamin, myotilin, desmin and alpha-actinin in many NM patients, consistent with accumulation of Z line-derived nemaline bodies. We demonstrate that nebulin can appear abnormal secondary to a primary defect in actin, and show by isoelectric focusing that mutant actin isoforms are present within insoluble actin filaments isolated from muscle from two ACTA1 NM patients.