Downregulation of cyclin-dependent kinase inhibitors p21 and p27 in pressure-overload hypertrophy

We postulated that the cyclin-dependent kinase inhibitors p21 and p27 could regulate the alterations in growth potential of cardiomyocytes during left ventricular hypertrophy (LVH). LVH was induced in adult rat hearts by aortic constriction (AC) and was monitored at days 0, 1, 3, 7, 14, 21, and 42 postoperation. Relative to sham-operated controls (SH), left ventricle (LV) weight-to-body weight ratio in AC increased progressively with time without significant differences in body weight or right ventricle weight-to-body weight ratio. Atrial natriuretic factor mRNA increased significantly in AC to 287% at day 42 compared with SH (P < 0.05), whereas p21 and p27 mRNA expression in AC rats decreased significantly by 58% (P < 0.03) and 40% (P < 0.05) at day 7, respectively. p21 and p27 protein expression decreased significantly from days 3 to 21 in AC versus SH, concomitant with LV adaptive growth. Immunocytochemistry showed p21 and p27 expression in cardiomyocyte nuclei. Thus downregulation of p21 and p27 may modulate the adaptive growth of cardiomyocytes during pressure overload-induced LVH.

Differential protein expression and subcellular distribution of TGFβ1, β2 and β3 in cardiomyocytes during pressure overload-induced hypertrophy

The transforming growth factorβ(TGFβ) superfamily plays an important role in the myocardial response to hypertrophy. We have investigated the protein expression of TGFβ1,β2andβ3in left ventricular tissue, and determined their subcellular distribution in myocytes by immunoblotting and immunocytochemistry during the development of left ventricular hypertrophy (LVH), using isoform specific antibodies to TGFβ1,β2andβ3. LVH was produced in rats by aortic constriction (AC) and LV tissue was obtained at days (d)0, 1, 3, 7, 14, 21 and 42 following operation. Compared with age matched sham-operated controls (SH), TGFβ1levels in LV tissue of AC rats increased significantly from d1–d14 (P<0.03) concomitant with the adaptive growth of LV tissue. In contrast, TGFβ3levels decreased in LV tissue of AC rats from d3 post-operation (significant from d14–d42,P<0.03). No significant difference in TGFβ2levels were observed from SH and AC rats after operation. Antibodies to TGFβ1stained intercalated disks, sarcolemmal membranes and cytoplasm, but not nuclei, of cardiomyocytes on LV sections from untreated and SH rats. However, a trans-localisation of TGFβ1to the nuclei of cardiomyocytes was observed in AC hearts. Antibodies to TGFβ3stained T tubules, cytoplasm and the nuclei of cardiomyocytes from untreated and SH rats. However, by d7 post-AC operation, TGFβ3expression was lost rapidly from nuclei of cardiomyocytes followed by a reduction in total TGFβ3immunofluorescence in myocytes. Antibodies to TGFβ2stained sarcolemmal membranes of cardiomyocytes from both SH and AC rats without significant difference between groups. Thus, the differential pattern of protein expression and subcellular distribution of TGFβ1,β2andβ3in myocytes during the development of LVH suggests that these molecules play different roles in the response of cardiomyocytes to LVH.

Non-word repetition in adolescents with Specific Language Impairment and Autism plus Language Impairments: a qualitative analysis

Non-word repetition (NWR) was investigated in adolescents with typical development, Specific Language Impairment (SLI) and Autism Plus language Impairment (ALI) (n = 17, 13, 16, and mean age 14;4, 15;4, 14;8 respectively). The study evaluated the hypothesis that poor NWR performance in both groups indicates an overlapping language phenotype (Kjelgaard & Tager-Flusberg, 2001). Performance was investigated both quantitatively, e.g. overall error rates, and qualitatively, e.g. effect of length on repetition, proportion of errors affecting phonological structure, and proportion of consonant substitutions involving manner changes. Findings were consistent with previous research (Whitehouse, Barry, & Bishop, 2008) demonstrating a greater effect of length in the SLI group than the ALI group, which may be due to greater short-term memory limitations. In addition, an automated count of phoneme errors identified poorer performance in the SLI group than the ALI group. These findings indicate differences in the language profiles of individuals with SLI and ALI, but do not rule out a partial overlap. Errors affecting phonological structure were relatively frequent, accounting for around 40% of phonemic errors, but less frequent than straight Consonant-for-Consonant or vowel-for-vowel substitutions. It is proposed that these two different types of errors may reflect separate contributory mechanisms. Around 50% of consonant substitutions in the clinical groups involved manner changes, suggesting poor auditory-perceptual encoding. From a clinical perspective algorithms which automatically count phoneme errors may enhance sensitivity of NWR as a diagnostic marker of language impairment. Learning outcomes: Readers will be able to (1) describe and evaluate the hypothesis that there is a phenotypic overlap between SLI and Autism Spectrum Disorders (2) describe differences in the NWR performance of adolescents with SLI and ALI, and discuss whether these differences support or refute the phenotypic overlap hypothesis, and (3) understand how computational algorithms such as the Levenshtein Distance may be used to analyse NWR data.