Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle-specific laminopathies, to create a faithful mouse model of this type of laminopathy. The mutant mice exhibit overtly normal embryonic development and sexual maturity. At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age. As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects. These abnormal skeletal and cardiac features were also observed in the female homozygous mice but with a later-onset than in males. Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles. These results demonstrate that LmnaH222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases.

The MECC system is suitable to maintain total extracorporeal circulation and demonstrates a lower inflammatory reaction when compared to standard CPB.

Serotonin (5-HT) controls a wide range of biological functions. In the brain, its implication as a neurotransmitter and in the control of behavioral traits has been largely documented. At the periphery, its modulatory role in physiological processes, such as the cardiovascular function, is still poorly understood. The rate-limiting enzyme of 5-HT synthesis, tryptophan hydroxylase (TPH), is encoded by two genes, the well characterized tph1 gene and a recently identified tph2 gene. In this article, based on the study of a mutant mouse in which the tph1 gene has been inactivated by replacement with the ␤-galactosidase gene, we establish that the neuronal tph2 is expressed in neurons of the raphe nuclei and of the myenteric plexus, whereas the nonneuronal tph1, as detected by ␤-galactosidase expression, is in the pineal gland and the enterochromaffin cells. Anatomic examination of the mutant mice revealed larger heart sizes than in wild-type mice. Histological investigation indicates that the primary structure of the heart muscle is not affected. Hemodynamic analyses demonstrate abnormal cardiac activity, which ultimately leads to heart failure of the mutant animals. This report links loss of tph1 gene expression, and thus of peripheral 5-HT, to a cardiac dysfunction phenotype. The tph1 ؊/؊ mutant may be valuable for investigating cardiovascular dysfunction observed in heart failure in humans. S erotonin (5-hydroxytryptamine, 5-HT) was discovered in blood as a vasoconstrictor of large vessels (1). Subsequently, it has been found in the gastrointestinal tract as a contractile substance identical with enteramine (2), in the CNS as a neurotransmitter (3), and in the pineal gland as an intermediate in the synthesis of melatonin, the neurohormone implicated in the circadian rhythmicity of physiological functions (4). 5-HT is detected early during brain development, suggesting its involvement in neuronal proliferation, migration, and differentiation (5). 5-HT modulates a variety of behavioral functions, including regulation of sleep͞wakefulness, appetite, nociception, mood, stress, and maternal or sexual behavior (6). Altered regulation of 5-HT in human affects behavioral traits and personality disorders, such as impulsive aggression, manic depressive illness, anxiety and alcoholism, and neurological conditions, such as migraine (7-10).About 95% of the 5-HT in the periphery is in the gastrointestinal tract (11), where it initiates responses as diverse as nausea, intestinal secretion, and peristaltis and has been implicated in gastroenteric diseases, such as irritable bowel syndrome (12). The 5-HT originating from the gastrointestinal tract is stored in blood platelets and participates in blood coagulation and pressure and in homeostasis. In the heart, an increased 5-HT availability has been shown to produce arrhythmia, leading to heart block or to valvular fibroplasia (13). 5-HT has also been suggested to regulate cardiovascular development (14). Recently, disruption of 5HT-2B receptor revealed a role for 5-HT by means of...