Abstract-Cytoplasmic overexpression of Akt in the heart results in a myopathy characterized by organ and myocyte hypertrophy. Conversely, nuclear-targeted Akt does not lead to cardiac hypertrophy, but the cellular basis of this distinct heart phenotype remains to be determined. Similarly, whether nuclear-targeted Akt affects ventricular performance and mechanics, calcium metabolism, and electrical properties of myocytes is unknown. Moreover, whether the expression and state of phosphorylation of regulatory proteins implicated in calcium cycling and myocyte contractility are altered in nuclear-targeted Akt has not been established. We report that nuclear overexpression of Akt does not modify cardiac size and shape but results in an increased number of cardiomyocytes, which are smaller in volume. Additionally, the heart possesses enhanced systolic and diastolic function, which is paralleled by increased myocyte performance. Myocyte shortening and velocity of shortening and relengthening are increased in transgenic mice and are coupled with a more efficient reuptake of calcium by the sarcoplasmic reticulum (SR). This process increases calcium loading of the SR during relengthening. The enhanced SR function appears to be mediated by an increase in SR Ca 2ϩ -ATPase2a activity sustained by a higher degree of phosphorylation of phospholamban. This posttranslational modification was associated with an increase in phospho-protein kinase A and a decrease in protein phosphatase-1. Together, these observations provide a plausible biochemical mechanism for the potentiation of myocyte and ventricular function in Akt transgenic mice. Therefore, nuclear-targeted Akt in myocytes may have important implications for the diseased heart. Key Words: Akt Ⅲ myocyte mechanics Ⅲ myocyte size and number P rotein kinase B, also referred to as Akt, phosphorylates multiple cytoplasmic and nuclear substrates implicated in cell survival and growth of several organs including the heart. 1 Although myocyte survival and cellular hypertrophy may be viewed as important adaptations of the overloaded heart against the onset of ventricular decompensation, 2 the targeted expression of constitutively activated Akt to the myocardium has resulted in cardiac hypertrophy [3][4][5][6][7] and ventricular dysfunction. 6 In these cases, however, transgene activity was widespread throughout cardiomyocytes at nonphysiological levels, raising the possibility that the nuclear accumulation of Akt may retain the antiapoptotic effects of this serine-threonine kinase, without promoting organ hypertrophy and alterations in cardiac performance. In this regard, hearts of mice expressing nuclear-targeted Akt show no evidence of myopathy 8 in contrast to other cardiac-specific Akt transgenics created with constitutively activated kinase. Targeting of Akt to myocyte nuclei preserves cell viability through the phosphorylation of survival factors within the nucleus that interfere with apoptotic death signaling. 1,8 -11 Thus, whether Akt is expressed in the cytoplasm or in t...

Objective To evaluate the efficacy and safety of topical anaesthesia in reducing pain and incidence of vasovagal reactions during diagnostic hysteroscopy with endometrial biopsy in postmenopausal women.Design Randomised placebo-controlled double-blind study. Setting University hospital.Participants Eighty postmenopausal women undergoing diagnostic hysteroscopy and endometrial biopsy.Interventions Two millilitres of 2% mepivacaine or saline solution were injected transcervically into the uterine cavity before performing the procedures.Main outcome measures Evaluation of pain reduction on a visual analogue scale and continuous monitoring of heart rate and blood pressure. ResultsThe use of the anaesthetic significantly reduced the pain experienced at hysteroscopy and endometrial biopsy. The occurrence of vasovagal reactions was significantly lower in the anaesthetised group.Conclusions Topical anaesthesia attenuated pain and effectively prevented the occurrence of vasovagal reactions during hysteroscopy and endometrial biopsy in postmenopausal women.

Our results suggest that a significant proportion of patients with migraine may have CD, and that a gluten free diet may lead to a improvement in the migraine in these patients.