Serotonin synthesis in mammals is initiated by 2 distinct tryptophan hydroxylases (TPH), TPH1 and TPH2. By genetically ablating TPH2, we created mice (Tph2 ؊/؊ ) that lack serotonin in the central nervous system. Surprisingly, these mice can be born and survive until adulthood. However, depletion of serotonin signaling in the brain leads to growth retardation and 50% lethality in the first 4 weeks of postnatal life. Telemetric monitoring revealed more extended daytime sleep, suppressed respiration, altered body temperature control, and decreased blood pressure (BP) and heart rate (HR) during nighttime in Tph2 ؊/؊ mice. Moreover, Tph2 ؊/؊ females, despite being fertile and producing milk, exhibit impaired maternal care leading to poor survival of their pups. These data confirm that the majority of central serotonin is generated by TPH2. TPH2-derived serotonin is involved in the regulation of behavior and autonomic pathways but is not essential for adult life.growth retardation ͉ maternal care ͉ respiration ͉ serotonin ͉ sleep S erotonin (5-hydroxytryptamine, 5-HT) is an extracellular signaling molecule with a multitude of functions in the central nervous system (CNS) and in the periphery. 5-HT effects are conveyed by at least 13 receptors classified in 7 families, 5-HT1 to 5-HT7. Serotonin synthesis from tryptophan is initiated by the enzyme tryptophan hydroxylase (TPH) generating 5-hydroxytryptophan followed by aromatic amino acid decarboxylase (AADC), which produces 5-HT. We have recently discovered that 2 TPH isoenzymes exist in all vertebrates, TPH1 and TPH2, encoded by 2 distinct genes (1, 2). Tph1 is mainly expressed in the gut, generating serotonin that is distributed into the whole body by thrombocytes, and in the pineal gland, where the resulting 5-HT is metabolized to melatonin. The Tph1-deficient mice generated by us (2) and others (3, 4) revealed that 95% of peripheral 5-HT is produced by TPH1. They also revealed that 5-HT in platelets and other peripheral cells is involved in such diverse processes as thrombosis (5), liver regeneration (6), hepatitis (7), colon cancer (8), mammary gland plasticity (9), pulmonary hypertension (10), and bone formation (11). TPH2, on the other hand, is responsible for the synthesis of serotonin in the raphé nuclei of the brainstem, from where all central serotonergic projections originate (12). Accordingly, polymorphisms and functional mutations in the human and mouse genes for this enzyme have been linked to neurological and behavioral abnormalities (13)(14)(15)(16).In this study, we generated mice lacking TPH2 by gene targeting and analyzed the physiological consequences resulting from a lack of brain serotonin. Results and DiscussionGeneration and Basic Characteristics of Tph2-Deficient Mice. Tph2-deficient (Tph2 Ϫ/Ϫ ) mice were generated by deleting the coding sequence in exons 1 and 2 (supporting information (SI) Fig. S1 A and B). In the resulting Tph2 Ϫ/Ϫ mice, no Tph2 mRNA could be found by RT-PCR (Fig. S1C) and in situ hybridization in the brain (Fig. 1A). Immu...

A combined CMR approach using T2-weighted imaging, early and late gadolinium enhancement, provides a high diagnostic accuracy and is a useful tool in the diagnosis and assessment of patients with suspected acute myocarditis.

Fibrosis as detected by CMR is a frequent feature of LVH, regardless of its cause, and depends on the severity of LV remodeling. As LGE emerges as a useful tool for risk stratification also in nonischemic heart diseases, our findings have the potential to individualize treatment strategies.

Background-Left ventricular noncompaction of the myocardium (LVNC) has been recognized as a cardiomyopathy with a genetic etiology. Mutations in genes encoding sarcomere proteins were shown to be associated with LVNC. We evaluated the potential clinical impact of genetic analysis of sarcomere genes in patients with LVNC. Methods and Results-We identified 5 mutations in cardiac myosin-binding protein C (MYBPC3) and 2 mutations in ␣-tropomyosin (TPM1) in a cohort of unrelated adult probands with isolated LVNC. The mutations in MYBPC3 and TPM1 and in 6 other previously reported sarcomere genes in this cohort resulted in a total of 18 (29%) heterozygous mutations in 63 probands. ␤-myosin heavy chain (MYH7) was the most prevalent disease gene and accounts for 13% of cases, followed by MYBPC3 (8%). Comparing sarcomere mutation-positive and mutation-negative LVNC probands showed no significant differences in terms of average age, myocardial function, and presence of heart failure or tachyarrhythmias at initial presentation or at follow-up. Familial disease was found in 16 probands of whom 8 were sarcomere mutation positive. Nonpenetrance was detected in 2 of 8 mutation-positive families with LVNC. Conclusions-Mutations