Altered Gene Expression in Pulmonary Tissue of Tryptophan Hydroxylase-1 Knockout Mice: Implications for Pulmonary Arterial Hypertension

The use of fenfluramines can increase the risk of developing pulmonary arterial hypertension (PAH) in humans, but the mechanisms responsible are unresolved. A recent study reported that female mice lacking the gene for tryptophan hydroxylase-1 (Tph1(−/−) mice) were protected from PAH caused by chronic dexfenfluramine, suggesting a pivotal role for peripheral serotonin (5-HT) in the disease process. Here we tested two alternative hypotheses which might explain the lack of dexfenfluramine-induced PAH in Tph1(−/−) mice. We postulated that: 1) Tph1(−/−) mice express lower levels of pulmonary 5-HT transporter (SERT) when compared to wild-type controls, and 2) Tph1(−/−) mice display adaptive changes in the expression of non-serotonergic pulmonary genes which are implicated in PAH. SERT was measured using radioligand binding methods, whereas gene expression was measured using microarrays followed by quantitative real time PCR (qRT-PCR). Contrary to our first hypothesis, the number of pulmonary SERT sites was modestly up-regulated in female Tph1(−/−) mice. The expression of 51 distinct genes was significantly altered in the lungs of female Tph1(−/−) mice. Consistent with our second hypothesis, qRT-PCR confirmed that at least three genes implicated in the pathogenesis of PAH were markedly up-regulated: Has2, Hapln3 and Retlna. The finding that female Tph1(−/−) mice are protected from dexfenfluramine-induced PAH could be related to compensatory changes in pulmonary gene expression, in addition to reductions in peripheral 5-HT. These observations emphasize the intrinsic limitation of interpreting data from studies conducted in transgenic mice that are not fully characterized

Placental lactogens induce serotonin biosynthesis in a subset of mouse beta cells during pregnancy

AIMS/HYPOTHESIS: Upregulation of the functional beta cell mass is required to match the physiological demands of mother and fetus during pregnancy. This increase is dependent on placental lactogens (PLs) and prolactin receptors, but the mechanisms underlying these events are only partially understood. We studied the mRNA expression profile of mouse islets during pregnancy to gain a better insight into these changes. METHODS: RNA expression was measured ex vivo via microarrays and quantitative RT-PCR. In vivo observations were extended by in vitro models in which ovine PL was added to cultured mouse islets and MIN6 cells. RESULTS: mRNA encoding both isoforms of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase (TPH), i.e. Tph1 and Tph2, were strongly induced (fold change 25- to 200-fold) during pregnancy. This induction was mimicked by exposing islets or MIN6 cells to ovine PLs for 24 h and was dependent on janus kinase 2 and signal transducer and activator of transcription 5. Parallel to Tph1 mRNA and protein induction, islet serotonin content increased to a peak level that was 200-fold higher than basal. Interestingly, only a subpopulation of the beta cells was serotonin-positive in vitro and in vivo. The stored serotonin pool in pregnant islets and PL-treated MIN6 cells was rapidly released (turnover once every 2 h). CONCLUSIONS/INTERPRETATION: A very strong lactogen-dependent upregulation of serotonin biosynthesis occurs in a subpopulation of mouse islet beta cells during pregnancy. Since the newly formed serotonin is rapidly released, this lactogen-induced beta cell function may serve local or endocrine tasks, the nature of which remains to be identified

Effects of Music Intervention on Anxiety and Pain Reduction in Ambulatory Maxillofacial and Otorhinolaryngology Surgery: A Descriptive Survey of 27 Cases

PURPOSE: The aim of this study is to determine patients\u27 opinion regarding listening to music before an ambulatory maxillofacial surgery and effects on anxiety and pain reduction. METHODS: This study was conducted on outpatients having a maxillofacial surgery between December 2015 and April 2016 at Poissy/Saint-Germain-en-Laye hospital (France). Patients listened with headphones to an easy-listening music in the operation theater before the first ambulation. A questionnaire including a visual analog scale (VAS) for pain and anxiety was given to participants. The primary endpoint was to determine patients\u27 opinion regarding listening to music before surgery. Secondary endpoints were to determine VAS pain mean, VAS anxiety mean before surgery, VAS anxiety mean after surgery, and if patients wanted to listen to their own playlist. We decided to compare VAS anxiety and pain mean between patients who accepted to listen to music (ALM) and who refused to listen to music (RLM). RESULTS: Nineteen patients ALM and 8 patients RLM to music. 78.9% of patients considered that listening to music before surgery decreased their anxiety. In patients who ALM, the mean (standard deviation, SD) of VAS pain after surgery was 3.42 (1.95), the mean (SD) of VAS anxiety before surgery was 3.1 (2.3), and the mean (SD) of VAS anxiety was 1.21 (0.85). There was a statistically significantly difference of the VAS anxiety mean (SD) before surgery between patients who ALM 3.10 (2.30) and who RLM 6.12 (1.88) (p = 0.005). There was a statistically significantly difference of the VAS anxiety mean (SD) after surgery between patients who ALM 1.21 (0.85) and who RLM 2.62 (1.30) (p = 0.009). Fifty percent of the patients wanted to choose their own music. CONCLUSION: Music seems to reduce anxiety before maxillofacial surgery. An interventional randomized study is needed to demonstrate the positive impact of music on anxiety before maxillofacial surgery

Erratum: Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis (Nature Medicine (2011) 17 (1242-1250))

Erratum: Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephriti

Maternal serotonin is crucial for murine embryonic development

The early appearance of serotonin and its receptors during prenatal development, together with the many effects serotonin exerts during CNS morphogenesis, strongly suggest that serotonin influences the development and maturation of the mammalian brain before it becomes a neuromodulator/neurotransmitter. Sites of early serotonin biosynthesis, however, have not been detected in mouse embryos or extraembryonic structures, suggesting that the main source of serotonin could be of maternal origin. This hypothesis was tested by using knockout mice lacking the tph1 gene, which is responsible for the synthesis of peripheral serotonin. Genetic crosses were performed to compare the phenotype of pups born from homozygous and heterozygous mothers. Observations provide the first clear evidence that (i) maternal serotonin is involved in the control of morphogenesis during developmental stages that precede the appearance of serotonergic neurons and (ii) serotonin is critical for normal murine development. Most strikingly, the phenotype of tph1−/− embryos depends more on the maternal genotype than on that of the concepti. Consideration of the maternal genotype may thus help to clarify the influence of other genes in complex diseases, such as mental illness