The 364 exon TTN gene encodes titin (TTN), the largest known protein, which plays key structural, developmental, mechanical, and regulatory roles in cardiac and skeletal muscles. Prior to next-generation sequencing (NGS), routine analysis of the whole TTN gene was impossible due to its giant size and complexity. Thus, only a few TTN mutations had been reported and the general incidence and spectrum of titinopathies was significantly underestimated. In the last months, due to the widespread use of NGS, TTN is emerging as a major gene in human-inherited disease. So far, 127 TTN disease-causing mutations have been reported in patients with at least 10 different conditions, including isolated cardiomyopathies, purely skeletal muscle phenotypes, or infantile diseases affecting both types of striated muscles. However, the identification of TTN variants in virtually every individual from control populations, as well as the multiplicity of TTN isoforms and reference sequences used, stress the difficulties in assessing the relevance, inheritance, and correlation with the phenotype of TTN sequence changes. In this review, we provide the first comprehensive update of the TTN mutations reported and discuss their distribution, molecular mechanisms, associated phenotypes, transmission pattern, and phenotype-genotype correlations, alongside with their implications for basic research and for human health.

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.

BackgroundPhase III clinical studies have confirmed that enoxaparin is superior to standard heparin in reducing the rate of recurrent ischaemic events in patients with non-ST elevation acute coronary syndromes. Patients with moderate to severe renal impairment were, however, excluded from these studies. Due to the hydrophilic disposition of enoxaparin, accumulation is likely in patients with renal dysfunction, thereby increasing the risk of haemorrhagic complications if standard weight adjusted treatment doses are used. Arbitrary dose reduction has been repor ted to increase the risk of ischaemic events, presumably due to inadequate enoxaparin concentrations. AimThe aims of this study were to investigate the influence of glomerular filtration rate (GFR) on the pharmacokinetics of subcutaneously administered enoxaparin, and to develop a practical dosing algorithm in renal impairment that can easily be used at the bedside. MethodsThirty-eight patients, median age 78 years (range 44-87), mean GFR 32 ml min -1 (range 16-117) and mean weight 69 kg (range 32-95), presenting with acute coronary syndrome were recruited into the study. Approximately 10 anti-Xa concentrations were taken per patient over their period of therapy. A population pharmacokinetic model was developed using non linear mixed effects modelling techniques, utilizing the software NONMEM. Stochastic simulations were performed to identify the most suitable dosing regimen. ResultsThree hundred and thirteen anti-Xa concentrations were collected. A two compar tment, first order input model was identified as the best baseline model. Covariates found to improve model fitting were GFR as a linear function on clearance (CL) and weight as a linear function on the central volume compartment (V c ). The fraction of drug excreted unchanged ( F u ) was estimated at 71%. CL and V c from the final covariate model were estimated as; CL (l h -1 ) = 0.681 per 4.8 l hr -1 (GFR) + 0.229 V c (l) = 5.22 per 80 kg (total body weight) Correspondence Bruce Green,

Background: The solubility of dental pulp tissue in sodium hypochlorite has been extensively investigated but results have been inconsistent; due most likely to variations in experimental design, the volume and/or rate of replenishment of the solutions used and the nature of the tissues assessed. Traditionally, the sodium hypochlorite solutions used for endodontic irrigation in Australia have been either Milton or commercial bleach, with Milton being the most common. Recently, a range of Therapeutic Goods Administration (TGA) approved proprietary sodium hypochlorite solutions, which contain surfactant, has become available. Some domestic chlorine bleaches now also contain surfactants. The purpose of this study was to perform new solubility assessments, comparing Milton with new TGA approved products, Hypochlor 1% and Hypochlor 4% forte, and with a domestic bleach containing surfactant (White King). Methods: Ten randomly assigned pulp samples of porcine dental pulp of approximately equal dimensions were immersed in the above solutions, as well as representative concentrations of sodium hydroxide. Time to complete dissolution was measured and assessed statistically. Results: White King 4% showed the shortest dissolution time, closely followed by Hypochlor 4% forte. White King 1% and Hypochlor 1% each took around three times as long to completely dissolve the samples of pulp as their respective 4% concentrations, while Milton took nearly 10 times as long. The sodium hydroxide solutions showed no noticeable dissolution of the pulp samples. Conclusions:The composition and content of sodium hypochlorite solutions had a profound effect on the ability of these solutions to dissolve pulp tissue in vitro. Greater concentrations provided more rapid dissolution of tissue. One per cent solutions with added surfactant and which contained higher concentrations of sodium hydroxide were significantly more effective in dissolution of pulp tissue than Milton.

Various types of alcoholics have been described and heredity has been shown to be involved in some of these types. An important role of the mesolimbic dopamine system has been suggested in the reinforcing effects of alcohol and recent molecular genetic studies are implicating the gene for the D2 dopamine receptor (DRD2) in alcoholism. In a double-blind study, bromocriptine, a DRD2 agonist, or placebo was administered to alcoholics with either the A1 (A1/A1 and A1/A2 genotypes) or only the A2 (A2/A2 genotype) allele of the DRD2 gene. The greatest improvement in craving and anxiety occurred in the bromocriptine-treated A1 alcoholics and attrition was highest in the placebo-treated A1 alcoholics. The feasibility of a pharmacogenetic approach in treating certain types of alcoholics is suggested.

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Pregnancy and delivery are critical times for women with bleeding disorders, with mothers, and possibly their affected infants, being exposed to a variety of haemostatic challenges. Management of women with bleeding disorders during pregnancy involves a multidisciplinary team including, but not limited to, an obstetrician, an anaesthetist and a haematologist. This consensus document from the Australian Haemophilia Centre Directors’ Organisation (AHCDO) provides practical information for clinicians managing women with bleeding disorders during pregnancy. Included are: the expected physiological response in pregnancy in such women; management of pregnancy, labour and delivery, as well as obstetric anaesthesia issues, postpartum care, and reducing and treating postpartum haemorrhage; and management of infants at risk of a bleeding disorder and of bleeding in neonates. The guidelines were developed after extensive consultation, face‐to‐face meetings and revisions. The final document represents a consensus opinion of all AHCDO members. Where evidence is lacking, recommendations are based on clinical experience and consensus opinion.