Class I HDACs regulate angiotensin II-dependent cardiac fibrosis via fibroblasts and circulating fibrocytes.

Fibrosis, which is defined as excessive accumulation of fibrous connective tissue, contributes to the pathogenesis of numerous diseases involving diverse organ systems. Cardiac fibrosis predisposes individuals to myocardial ischemia, arrhythmias and sudden death, and is commonly associated with diastolic dysfunction. Histone deacetylase (HDAC) inhibitors block cardiac fibrosis in pre-clinical models of heart failure. However, which HDAC isoforms govern cardiac fibrosis, and the mechanisms by which they do so, remains unclear. Here, we show that selective inhibition of class I HDACs potently suppresses angiotensin II (Ang II)-mediated cardiac fibrosis by targeting two key effector cell populations, cardiac fibroblasts and bone marrow-derived fibrocytes. Class I HDAC inhibition blocks cardiac fibroblast cell cycle progression through derepression of the genes encoding the cyclin-dependent kinase (CDK) inhibitors, p15 and p57. In contrast, class I HDAC inhibitors block agonist-dependent differentiation of fibrocytes through a mechanism involving repression of ERK1/2 signaling. These findings define novel roles for class I HDACs in the control of pathological cardiac fibrosis. Furthermore, since fibrocytes have been implicated in the pathogenesis of a variety of human diseases, including heart, lung and kidney failure, our results suggest broad utility for isoform-selective HDAC inhibitors as anti-fibrotic agents that function, in part, by targeting these circulating mesenchymal cells.

Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism.

RATIONALE: Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with associated right ventricular cardiac remodeling are poorly understood. OBJECTIVE: This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension. METHODS AND RESULTS: Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression. CONCLUSIONS: By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator standards of care.

BET acetyl-lysine binding proteins control pathological cardiac hypertrophy.

Cardiac hypertrophy is an independent predictor of adverse outcomes in patients with heart failure, and thus represents an attractive target for novel therapeutic intervention. JQ1, a small molecule inhibitor of bromodomain and extraterminal (BET) acetyl-lysine reader proteins, was identified in a high throughput screen designed to discover novel small molecule regulators of cardiomyocyte hypertrophy. JQ1 dose-dependently blocked agonist-dependent hypertrophy of cultured neonatal rat ventricular myocytes (NRVMs) and reversed the prototypical gene program associated with pathological cardiac hypertrophy. JQ1 also blocked left ventricular hypertrophy (LVH) and improved cardiac function in adult mice subjected to transverse aortic constriction (TAC). The BET family consists of BRD2, BRD3, BRD4 and BRDT. BRD4 protein expression was increased during cardiac hypertrophy, and hypertrophic stimuli promoted recruitment of BRD4 to the transcriptional start site (TSS) of the gene encoding atrial natriuretic factor (ANF). Binding of BRD4 to the ANF TSS was associated with increased phosphorylation of local RNA polymerase II. These findings define a novel function for BET proteins as signal-responsive regulators of cardiac hypertrophy, and suggest that small molecule inhibitors of these epigenetic reader proteins have potential as therapeutics for heart failure.

Comparison of Parent Questionnaires, Examiner-Led Assessment and Parents' Concerns at 14 Months of Age as Indicators of Later Diagnosis of Autism.

Parents participating in a prospective longitudinal study of infants with older siblings with autism completed an autism screening questionnaire and were asked about any concerns relating to their child's development, and children were administered an interactive assessment conducted by a researcher at 14 months. Scores on the parent questionnaire were highest for children later diagnosed with autism. Parental concerns and scores from the examiner-led assessment distinguished children with later developmental difficulties (both autism and other developmental atypicalities) from those who were developing typically. Children about whom parents expressed concern scored higher on both the questionnaire and the interactive assessment than those without concerns. There were no significant associations between total or individual item scores from the questionnaire and interactive assessment.

Attitudes of the autism community to early autism research.

Investigation into the earliest signs of autism in infants has become a significant sub-field of autism research. This work invokes specific ethical concerns such as use of 'at-risk' language, communicating study findings to parents and the future perspective of enrolled infants when they reach adulthood. This study aimed to ground this research field in an understanding of the perspectives of members of the autism community. Following focus groups to identify topics, an online survey was distributed to autistic adults, parents of children with autism and practitioners in health and education settings across 11 European countries. Survey respondents (n = 2317) were positively disposed towards early autism research, and there was significant overlap in their priorities for the field and preferred language to describe infant research participants. However, there were also differences including overall less favourable endorsement of early autism research by autistic adults relative to other groups and a dislike of the phrase 'at-risk' to describe infant participants, in all groups except healthcare practitioners. The findings overall indicate that the autism community in Europe is supportive of early autism research. Researchers should endeavour to maintain this by continuing to take community perspectives into account.

AKT network of genes and impaired myocardial contractility during murine acute Chagasic myocarditis.

Chagasic disease is associated with high morbidity in Latin America. Acute Chagasic myocarditis is consistently found in acute infections, but little is known about its contribution to chronic cardiomyopathy. The aim of the study was to phenotypically characterize two strains of mice with differential Chagas infection susceptibility and correlate strain myocarditis phenotypes with heart tissue gene expression. C57BL/6J and Balb/c mice were injected intraperitoneally with 0 or 150-200 tissue-derived trypomastigotes (Tulahuen strain). Echocardiograms, brain natriuretic peptide, and troponin were measured. Heart tissue was harvested for histopathological analysis and gene expression profiling on microarrays. Genes differently expressed between infected Balb/c and C57BL/6J mice were identified. Echocardiograms showed differences in Balb/c versus C57BL/6J infected mice in heart rate (413 versus 476 beats per minute; P = 0.0001), stroke volume (31.9 ± 9.3 versus 39.2 ± 5.5 µL; P = 0.03), and cardiac output (13.1 ± 3.5 versus 18.7 ± 3.2 µL/min; P = 0.002). Gene expression at 4 weeks analysis showed 32 statistically significant (q value < 0.05) differentially expressed genes between infected Balb/c and C57BL/6J mice that were enriched for genes related to the protein kinase B (AKT) pathway. These specific phenotypic features of cardiac response during acute Chagasic myocarditis may, in part, be related to host AKT network regulation.

The physiotherapy management of patients undergoing coronary artery surgery: A questionnaire survey.

The current physiotherapy management of patients undergoing coronary artery surgery in 22 public and 13 private hospitals across Australia and New Zealand was examined using a questionnaire survey. Respondents were asked to identify assessment and treatment techniques used in the pre- and post-operative management. An 83 per cent response from physiotherapists was obtained. Ninety-four per cent of respondents reported that pre-operative assessment was performed routinely. Eighty-nine per cent of respondents indicated that all patients were treated routinely by physiotherapists in the post-extubation period. Positioning and deep breathing exercises were the most commonly used techniques for patients post-extubation. Factors determining treatment choice and the impact of research on current physiotherapy practice are discussed.

Nurse-led management of hypertrophic and keloid scars.

Keloid and hypertrophic scars are difficult to treat, and their management requires a structured approach with input from a multidisciplinary team. Typically, patients are treated in busy, general clinics--an environment that is not suitable for these patients, whose treatment can take considerable time and requires emotional support. The development of a dedicated, nurse-led keloid scar clinic covering scar management and skin camouflage is described, the benefits of which have been evaluated. Results to date show that it is cost-effective, that it has reduced the non-attendance rate at the clinic, and that it improves compliance and has led to better resolution of scars in a shorter time than previously.

Atypical audiovisual speech integration in infants at risk for autism.

The language difficulties often seen in individuals with autism might stem from an inability to integrate audiovisual information, a skill important for language development. We investigated whether 9-month-old siblings of older children with autism, who are at an increased risk of developing autism, are able to integrate audiovisual speech cues. We used an eye-tracker to record where infants looked when shown a screen displaying two faces of the same model, where one face is articulating/ba/and the other/ga/, with one face congruent with the syllable sound being presented simultaneously, the other face incongruent. This method was successful in showing that infants at low risk can integrate audiovisual speech: they looked for the same amount of time at the mouths in both the fusible visual/ga/- audio/ba/and the congruent visual/ba/- audio/ba/displays, indicating that the auditory and visual streams fuse into a McGurk-type of syllabic percept in the incongruent condition. It also showed that low-risk infants could perceive a mismatch between auditory and visual cues: they looked longer at the mouth in the mismatched, non-fusible visual/ba/- audio/ga/display compared with the congruent visual/ga/- audio/ga/display, demonstrating that they perceive an uncommon, and therefore interesting, speech-like percept when looking at the incongruent mouth (repeated ANOVA: displays x fusion/mismatch conditions interaction: F(1,16) = 17.153, p = 0.001). The looking behaviour of high-risk infants did not differ according to the type of display, suggesting difficulties in matching auditory and visual information (repeated ANOVA, displays x conditions interaction: F(1,25) = 0.09, p = 0.767), in contrast to low-risk infants (repeated ANOVA: displays x conditions x low/high-risk groups interaction: F(1,41) = 4.466, p = 0.041). In some cases this reduced ability might lead to the poor communication skills characteristic of autism.

Differential habituation to repeated sounds in infants at high risk for autism.

It has been suggested that poor habituation to stimuli might explain atypical sensory behaviours in autism. We investigated habituation to repeated sounds using an oddball paradigm in 9-month-old infants with an older sibling with autism and hence at high risk for developing autism. Auditory-evoked responses to repeated sounds in control infants (at low risk of developing autism) decreased over time, demonstrating habituation, and their responses to deviant sounds were larger than responses to standard sounds, indicating discrimination. In contrast, neural responses in infants at high risk showed less habituation and a reduced sensitivity to changes in frequency. Reduced sensory habituation may be present at a younger age than the emergence of autistic behaviour in some individuals, and we propose that this could play a role in the over responsiveness to some stimuli and undersensitivity to others observed in autism.