A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight.

Schizophrenia is a chronic, severe and highly complex mental illness. Current treatments manage the positive symptoms, yet have minimal effects on the negative and cognitive symptoms, two prominent features of the disease with critical impact on the long-term morbidity. In addition, antipsychotic treatments trigger serious side effects that precipitate treatment discontinuation. Here, we show that activation of the trace amine-associated receptor 1 (TAAR1), a modulator of monoaminergic neurotransmission, represents a novel therapeutic option. In rodents, activation of TAAR1 by two novel and pharmacologically distinct compounds, the full agonist RO5256390 and the partial agonist RO5263397, blocks psychostimulant-induced hyperactivity and produces a brain activation pattern reminiscent of the antipsychotic drug olanzapine, suggesting antipsychotic-like properties. TAAR1 agonists do not induce catalepsy or weight gain; RO5263397 even reduced haloperidol-induced catalepsy and prevented olanzapine from increasing body weight and fat accumulation. Finally, TAAR1 activation promotes vigilance in rats and shows pro-cognitive and antidepressant-like properties in rodent and primate models. These data suggest that TAAR1 agonists may provide a novel and differentiated treatment of schizophrenia as compared with current medication standards: TAAR1 agonists may improve not only the positive symptoms but also the negative symptoms and cognitive deficits, without causing adverse effects such as motor impairments or weight gain.

Dimorphic effects of leptin on the circadian and hypocretinergic systems of mice.

The hormone leptin controls food intake and body weight through its receptor in the hypothalamus, and may modulate physiological functions such as reproduction, sleep or circadian timing. In the present study, the effects of leptin on the resetting of the circadian clock, the hypothalamic suprachiasmatic nucleus (SCN) and on the activity of the hypocretinergic system were examined in vivo, with comparative analysis between male and female mice. A single leptin injection (5 mg/kg) at both the onset and offset of the activity period did not alter locomotion of mice housed under a 12 : 12 h light/dark cycle and did not shift the circadian behavioral rhythm of mice housed in constant darkness. By contrast, leptin potentiated the phase-shifting effect of a 30-min light-pulse on behavioural rhythms during the late subjective night, although only in females. This was accompanied by a higher induction of the clock genes Per1 and Per2 in the SCN. A 2-week chronic exposure to a physiological dose of leptin (100 µg/kg per day) decreased locomotor activity, expression of hypocretin receptor 1 and 2, as well as the number of hypocretin-immunoreactive neurones only in female mice, whereas the number of c-fos-positive hypocretinergic neurones was reduced in both genders. These results highlight a dimorphic effect of leptin on the hypocretinergic system and on the response of the circadian clock to light. Leptin may thus modulate the sleep/wake cycle and circadian system beside its well-established action on food intake and regulation of body weight.

Suspected acute coronary syndrome in a theater of operations: first management, medical evacuation, and final diagnosis: experience of the French Medical Army.

OBJECTIVE: to evaluate the treatment of the acute coronary syndrome (ACS) among soldiers stationed on a theater of operations by structures usually conceived to treat combat-related trauma. METHODS: We performed a retrospective study involving the whole medical evacuations out of a theater of operations to the benefit of the French Armed forces, for a suspected diagnosis of ACS. RESULTS: 35 patients were included in this study with 20 for a diagnosis of persistent ST-Segment Elevation Myocardial Infarction (STEMI). Only an active smoking defined a population at risk in these high medical selective soldiers. The agreement between the initial and the final diagnosis was excellent for STEMI but remains perfectible for NSTEMI. CONCLUSION: the medical structures deployed in a theater of operations were able to provide first treatment in ACS. The use of powerful diagnosis test, like troponine assay, must allow a better selection of the patients justifying a medical evacuation.

[A myocardial infarction complicated with mitral anterior papillary muscle rupture during long-term corticotherapy]. / Un infarctus du myocarde compliqué d'une rupture du pilier antérieur de la valve mitrale au cours d'une corticothérapie prolongée.

The authors report anterolateral papillary muscle rupture, occurring in a 67-year-old patient admitted for acute coronary syndrome. Mitral regurgitation, a rare but dramatic complication of myocardial infarction, is most often a consequence of posterior papillary muscle rupture. The 'protection' of the anterior papillary muscle is associated with vascularization via a dual coronary artery supply. Possible myocardial weakening associated with long-term corticotherapy is otherwise discussed in this observation.

[Cardiac toxicity of catecholamines. Report of two cases]. / Toxicité myocardique des catécholamines: à propos de deux observations.

INTRODUCTION: The role of catecholamines in the cardiac expression of pheochromocytoma is well-known. The physiopathology of the syndrome of Tako-tsubo remains more unclear. EXEGESIS: We describe 2 clinical cases of acute coronary syndrome with left ventricular dysfunction and no coronary artery stenosis. The first, a syndrome of Tako-tsubo, also known as transient left ventricular apical ballooning syndrome, is characterized by transient wall-motion in the absence of obstructive epicardial coronary disease. The second is a pheochromocytoma with myocardial suffering during hypertension crisis. Through the similarities of these 2 observations, we discuss the physiopathological assumptions to explain the syndrome of Tako-tsubo by underlining the essential place of the catecholamine hypersecretion. CONCLUSION: Syndrome of Tako-tsubo and pheochromocytoma are 2 distinct clinical entities. The link between these 2 affections is probably the pathogenic role in cardiac toxicity with the catecholamines.

[Increased secretion of Nt-proBNP immediately after percutaneous coronary intervention: about 90 cases]. / Elévation de la sécrétion du Nt-proBNP dans les 24 heures suivant une angioplastie coronaire: à propos de 90 cas.

Nt-proBNP have emerged as useful biomarker for the diagnosis and prognostic of heart failure but also recently in acute coronary syndrome. Myocardial ischemia is probably an important stimulus for Nt-proBNP release. Transient myocardial ischemia is inducing by balloon inflation during percutaneous coronary intervention (PCI). The authors propose to determine the Nt-proBNP secretion after uncomplicated coronary intervention in patients with preserved cardiac function. Ninety patients were enrolled in this study. Plasma Nt-proBNP was increased significantly from 135.5 to 157.8 pg/ml and 202.5 pg/ml at 8 and 24 hours following PCI, respectively. History of myocardial infarction and complex lesions were the most powerful predictors of higher Nt-proBNP peak concentration. Prognostic value must be evaluated in larger studies.

[Left auricle myxoma, a rare cause of myocardial infarction]. / Le myxome de l'oreillette gauche, une cause rare d'infarctus du myocarde.

INTRODUCTION: The association of left auricle myxoma and myocardial infarction is exceptional. Nevertheless, a causal relationship exists between the 2 affections. OBSERVATION: A 54 year-old woman was hospitalised in a rush for myocardial infarction. Sonography revealed a voluminous tumoral formation in the left auricle. The diagnosis of myxoma was confirmed by the anatomopathological examination. DISCUSSION: Although systemic embolism represents the most frequent causal link between left auricle myxoma and myocardial infarction, hypercoagulability is another possible cause. This can be explained by the secretion of interleukins 6 and 8 by the myxoma.

Analysis of adrenergic regulation of melatonin synthesis in Siberian hamster pineal emphasizes the role of HIOMT.

Seasonal variations of environmental factors are translated into annual fluctuations in synthesis and release of melatonin, which in turn acts as a neuroendocrine messenger for the synchronization of annual functions. So far, most studies performed to understand the regulation of melatonin synthesis have used the non seasonal laboratory rat. It was demonstrated that nocturnal melatonin synthesis depends on alpha- and beta-adrenergic activation of the enzyme arylalkylamine N-acetyltransferase (AA-NAT). In this study, we investigated the mechanisms of melatonin synthesis in the Siberian hamster, a seasonal species with marked photoperiodic variation in melatonin peak duration and amplitude. A beta-adrenergic receptor agonist alone markedly stimulated AA-NAT activity and melatonin synthesis and release. An alpha-adrenergic receptor agonist, while having no effect per se, potentiated the beta-adrenergic stimulation of AA-NAT activity both in vitro and in vivo. Strikingly, the potentiation of AA-NAT activity did not result in a potentiation of melatonin synthesis, suggesting that the rate of melatonin production is limited downstream in the metabolic pathway, most probably at the level of hydroxyindole-O-methyltransferase (HIOMT). HIOMT presented a constitutively high activity that was not acutely (within hours) stimulated by beta-adrenergic agonist, but was rather up-regulated by chronic application of the agonist. This long-term beta-adrenergic regulation may explain the reported large photoperiodic variation of HIOMT activity that drives the photoperiodic variation in melatonin peak.

[Screening of the abdominal aortic aneurysms during an echocardiography]. / Dépistage d'un anévrisme de l'aorte abdominale sous-rénale lors d'une échocardiographie.

We examined the abdominal aorta by ultrasound in 1106 patients during transthoracic echocardiography, whatever the reason of the echocardiography, to track abdominal aortic aneurysms. The study group comprised 822 men and 284 women. We found 88 patients having an abdominal aorta with a diameter of more than 23 mm and 11 patients with a diameter of more than 35 mm. Ninety sixteen per cent of the patients having an aortic ecstasy are more than fifty years old. Ther are more smokers among the patients having an aortic ecstasy. In conclusion, the track of the ecstasies and the abdominal aortic aneurysms is easily realizable during an echocardiography and presents a good rentability.

[The heart and cocaine]. / Coeur et cocaïne.

Cocaine abuse should be considered in everyday cardiological practice for three reasons. The first one is epidemiological as there is an unprecedented increase in cocaine abuse in France and it may result in serious complications, mainly cardiovascular. The second reason concerns modality of consumption: it is usually associated with other toxic substances (including tobacco) and poly-intoxication is a more serious problem and the diagnostic difficulties are greater. Finally, chest pain is the first symptom of myocardial infarction in about 6% of cases. In cardiological practice, young adults with this symptom should be suspected of cocaine abuse and the diagnosis should be eventually confirmed by toxicological analysis.

[Malignant non-Hodgkin's lymphoma presenting with arrhythmia and conduction defects. Report of 2 cases]. / Troubles du rythme et de la conduction révélateurs d'une localisation cardiaque de lymphome malin non hodgkinien. A propos de 2 cas.

Primary cardiac lymphoma is very rare. Secondary localisations are more common, observed in 15 to 30% of autopsy series. Clinical symptoms of cardiac involvement are rare, explaining the usual post-mortem diagnosis. The presentation of cardiac involvement by arrhythmias and conduction defects is very uncommon. The authors report two cases, the first of a 35 year old man in whom primary cardiac lymphoma presented with ventricular tachycardia complicated secondarily by complete atrioventricular block (AVB) with pseudo-inferior wall infarction. The second case was a 37 year old man with a cutaneous T cell lymphoma in whom complete AVB was the first sign of a secondary cardiac localisation of his disease. The finding of cardiac lymphoma should lead to aggressive chemotherapy as soon as possible.

[Coronary vessel ectasia: coronary artery disease with a high thromboembolic risk]. / L'ectasie des vaisseaux coronaires. Une coronaropathie à haut risque thrombo-embolique.

Coronary dystrophy is characterized by the presence of successively stenotic and ectatic or even aneurysmal zones in the coronary network. The authors report a new case of coronary ectatic dystrophy presenting in with myocardial infarction. They review the literature and suggest the various aetiologies, the main one being atherosclerosis. The management of this particular form of atherosclerosis is dominated by the thromboembolic risk related to these aneurysmal zones responsible for myocardial infarction, justifying long-term anticoagulant therapy.

[Giant aneurysm of the interventricular septum. Value of imaging techniques]. / Anévrisme géant du septum interventriculaire. Apport des techniques d'imagerie.

A pseudosubaortic left ventricular aneurysm was discovered in a 32 year old African presenting with pyrexia after a long history of chest pains and dyspnea. Echographic and radiological techniques showed a large pulsatile mediastinal mass and the patient was referred for aneurysmorrhaphy. The actiology of this pseudo-aneurysm is discussed with reference to data in the literature. Infection is the first cause to be excluded in view of the pyrexia truncated by "blind" anti-inflammatory and antibiotic therapy. The hypothesis of an interventricular septal abscess secondary to septicaemia with secondary rupture into the pericardium is discussed. Precessive endocarditis with an aseptic abscess is unlikely because of the minimal aortic valve lesions, the absence of vegetations and the very long clinical evolution. Finally, idiopathic pseudo-aneurysms in sub-Saharian Africans, due to a congenital defect of the fibrous aortico-mitral and subannular zones must be considered. The risk of complications of these pseudo-aneurysms justifies surgical intervention on the accurate anatomical description of the lesions provide by transthoracic and transoesophageal echocardiography and magnetic resonance imaging.

PCR-generated cDNA libraries from reduced numbers of mouse oocytes.

We describe a rapid and reproducible method for cloning cDNA amplified from 10 mouse oocytes. The procedure consists in priming cDNA synthesis from a crude cellular extract using an oligo d(T) containing primer and submitting the size-limited cDNA first strand to poly(dG) tailing. The whole cDNA population is then polymerase chain reaction (PCR) amplified using two primers complementary to oligo d(A) and oligo d(G) ends of the cDNA. In this procedure no purification steps are required. We obtained about 5 x 10(6) clones from 10 oocytes. Screening of the library showed that the relative abundance of the transcripts was preserved during amplification and cloning and that the procedure allows cloning of low-abundance sequences at least as rare as 0.008% of the mRNA. The repeatable generation of representative cDNA libraries from reduced numbers of oocytes or embryos should open new opportunities for obtaining genetic information from mammalian preimplantation embryos.

Low developmental capacity of in vitro matured and fertilized oocytes from calves compared with that of cows.

The developmental competence of oocytes from 3-month-old calves was studied through in vitro maturation, fertilization and culture up to the blastocyst stage and by embryo transfer into a foster mother. Oocytes were recovered from antral follicles of calves after or without ovarian stimulation with exogenous FSH and their developmental potential was compared with that of oocytes recovered from cow ovaries. Fertilization and cleavage rates from calf oocytes did not differ significantly from those of cow oocytes. However, after 7 days of culture, the blastocyst formation rate was significantly lower for calves (9% and 11% for nontreated and treated animals, respectively) than for cows (over 20%). Transfer of blastocysts obtained from calf oocytes resulted in a lower pregnancy rate (1 of 23 recipients; 4%) than that achieved with cow oocytes (10 of 26; 38%). The recipient cow that was pregnant from calf embryos delivered a full-term live calf. These data show that some key regulative event that determines the ability to form blastocysts in cattle has not been fully achieved in oocytes from 3-month-old calves.

[Course of the left ventricular mass in a population of 893 hypertensive patients. Effects of treatment with perindopril]. / Evolution de la masse ventriculaire gauche dans une population de 893 hypertendus. Effets d'une intervention thérapeutique par le perindopril.

Left ventricular hypertrophy is now recognized to be a major and independent risk factor of mortality and morbidity. Although all classes of antihypertensives are able to reduce left ventricular mass, two recent metaanalyses have shown that ACE inhibitors are the most effective. The antihypertensive efficacy of perindopril in man is accompanied with a significant improvement in the functional properties of large arteries and with a reduction of LVH. This study was designed to assess the course of left ventricular mass by echocardiography in a population of 893 hypertensive patients with moderate left ventricular hypertrophy, treated with perindopril for 3 months. A significant fall in blood pressure was observed by the 6th week. The morphological and functional echocardiographic parameters on a large population provided more valid statistical results than in a small series. The left ventricular cavity was found to undergo symmetrical remodelling, adapted to the new haemodynamic status. The reduction of the thickness of the wall was in line with the reduction of the size of the ventricular chamber, and left ventricular mass was reduced by 8% (p < 0.001). Systolic function was preserved and diastolic function was improved. In particular, the E/A ratio was increased by 8% (p < 0.001) and the duration of isometric relaxation was decreased by 11 ms (p < 0.02). This improvement of filling was confirmed by the reduction of the diameter of the left atrium by 0.2 mm (p < 0.001). This open study in 893 patients therefore confirmed that perindopril corrects LVH in hypertensive patients.

[Late abdominal metastases of primary meningeal melanoma. Contribution of MRI]. / Métastases abdominales tardives d'un mélanome méningé primitif. Apport de l'IRM.

A case of abdominal metastasis from primary meningeal melanoma is reported. MR imaging demonstrated hyperintensity on T1-weighted images in all the lesions and suggested their melanotic nature.