Role of toll-like receptor 7 (TLR7) in voluntary alcohol consumption.

Overactivation of neuroimmune signaling has been linked to excessive ethanol consumption. Toll-like receptors (TLRs) are a major component of innate immune signaling and initiate anti- and pro-inflammatory responses via intracellular signal transduction cascades. TLR7 is upregulated in post-mortem brain tissue from humans with alcohol use disorder (AUD) and animals with prior exposure to ethanol. Despite this evidence, the role of TLR7 in the regulation of voluntary ethanol consumption has not been studied. We test the hypothesis that TLR7 activation regulates voluntary ethanol drinking behavior by administering a TLR7 agonist (R848) during an intermittent access drinking procedure in mice. Acute activation of TLR7 reduced ethanol intake, preference, and total fluid intake due, at least in part, to an acute sickness response. However, chronic pre-treatment with R848 resulted in tolerance to the adverse effects of the drug and a subsequent increase in ethanol consumption. To determine the molecular machinery that mediates these behavioral changes, we evaluated gene expression after acute and chronic TLR7 activation. We found that acute TLR7 activation produces brain region specific changes in expression of immune pathway genes, whereas chronic TLR7 activation causes downregulation of TLRs and blunted cytokine induction, suggesting molecular tolerance. Our results demonstrate a novel role for TLR7 signaling in regulating voluntary ethanol consumption. Taken together, our findings suggest TLR7 may be a viable target for development of therapies to treat AUD.

Cortical astrocytes regulate ethanol consumption and intoxication in mice.

Astrocytes are fundamental building blocks of the central nervous system. Their dysfunction has been implicated in many psychiatric disorders, including alcohol use disorder, yet our understanding of their functional role in ethanol intoxication and consumption is very limited. Astrocytes regulate behavior through multiple intracellular signaling pathways, including G-protein coupled-receptor (GPCR)-mediated calcium signals. To test the hypothesis that GPCR-induced calcium signaling is also involved in the behavioral effects of ethanol, we expressed astrocyte-specific excitatory DREADDs in the prefrontal cortex (PFC) of mice. Activating Gq-GPCR signaling in PFC astrocytes increased drinking in ethanol-naïve mice, but not in mice with a history of ethanol drinking. In contrast, reducing calcium signaling with an astrocyte-specific calcium extruder reduced ethanol intake. Cortical astrocyte calcium signaling also altered the acute stimulatory and sedative-hypnotic effects of ethanol. Astrocyte-specific Gq-DREADD activation increased both the locomotor-activating effects of low dose ethanol and the sedative-hypnotic effects of a high dose, while reduced astrocyte calcium signaling diminished sensitivity to the hypnotic effects. In addition, we found that adenosine A1 receptors were required for astrocyte calcium activation to increase ethanol sedation. These results support integral roles for PFC astrocytes in the behavioral actions of ethanol that are due, at least in part, to adenosine receptor activation.

[Ventricular repolarisation disorders and long QT syndrome: clinical and genetic study in 10 paediatric cases]. / Troubles de la repolarisation ventriculaire et syndrome du QT long: étude clinique et génétique à propos de 10 cas pédiatriques.

We report 10 paediatric cases of ventricular repolarisation disorders and long QT syndrome, which differed in their mode of revelation, from asymptomatic forms to syncope events or heart arrest. Diagnosis is based on electrophysiological explorations and exhaustive genetic investigation. It allows a well-codified preventive and therapeutic action according to the genotype.

Management of shoulder instability in a military population.

OBJECTIVES: Recurrent instability is common after shoulder dislocation in the young, particularly those engaged in physical jobs or sport. The management of recurrent traumatic shoulder instability is predominantly operative. However, the best method of surgery i.e. open or arthroscopic is still a matter of debate. We have developed an algorithm to decide on the choice of surgery and the aim of this study is to report this and compare the two different groups of military patients. METHODS: A retrospective review of all shoulder stabilisations performed on military personnel, by a single surgeon, between August 2004 and August 2005 at a district general hospital serving both military and civilian population was undertaken. The presentation, clinical and operative findings were noted and compared in the groups treated by arthroscopic or open stabilisation. RESULTS: Using our protocol 39 shoulder stabilisations were performed in military personnel. Of the shoulders, 25 (64%) underwent arthroscopic and 14 (36%) underwent open stabilisation. The indication for surgery was more than 2 episodes of shoulder dislocation. Open surgery was found to be more common in those who had their first dislocation at a younger age. Bilateral shoulder laxity was the most common indication to choose the open method. Both open and arthroscopic stabilisation gave good results in the high demand military population. Only one patient had recurrent instability after arthroscopic procedure. However, this was not statistically significant when compared with open stabilisation.

Arrhythmic cardiac arrest due to isolated coronary artery spasm: long-term outcome of seven resuscitated patients.

OBJECTIVES: Our aim was to look at the clinical features and long-term follow-up of seven patients without coronary artery disease, who had a history of life-threatening ventricular arrhythmias due to coronary spasm. BACKGROUND: Arrhythmic cardiac arrest due to isolated coronary spasm is rare, and there is limited information on the patients affected by this entity alone. METHODS: The seven patients were recruited retrospectively from a cohort of survivors of cardiac arrest. None had a history of angina pectoris, structural heart disease or significantly narrowed coronary segments. All had a positive ergonovine provocation test result. RESULTS: The patients' mean age was 44 years; three were male and four female. All were habitual cigarette smokers. No arrhythmias were induced on programmed ventricular stimulation; corrected QT interval (QTc) and corrected JT interval (JTc) dispersion were within normal ranges. After the ergonovine provocation test, treatment with calcium channel blocking agents (diltiazem, verapamil, nifedipine or amlodipine) was initiated at a dose determined by titration until a negative test result was obtained. At a mean follow-up interval of 58 months for the total group, six patients remained free of symptoms, whereas the one patient who did not stop smoking had a new cardiac arrest despite treatment for coronary spasm. CONCLUSIONS: A favorable long-term outcome may be expected in survivors of cardiac arrest due to coronary spasm, in the absence of significant coronary artery disease. Calcium channel blockers are the most appropriate therapy in these patients. These observations provide further evidence for the role of silent ischemia in cardiovascular death.

Spontaneous metastasis, proliferation characteristics and radiation sensitivity of fractionated irradiation recurrent and unirradiated human xenografts.

PURPOSE: Do tumor cells which survive high dose fractionated irradiation exhibit modified metastasis activity, proliferation kinetics, and/or radiation sensitivity? To address this question experimentally, we have studied three recurrent human tumor xenograft systems. METHODS AND MATERIALS: Three models were derived from a soft tissue sarcoma (HSTS26T), a colon adenocarcinoma (HCT15), and a glioblastoma (HGL21) which had recurred after 90 Gy, 109 Gy, or 77.4 Gy administered in 30 equal doses, respectively. Their production of spontaneous metastasis and cell proliferation characteristics were studied in early generation xenografts in SCID mice, and were compared to those in their previously unirradiated counterparts. As a control, we have also studied each tumor as a post-surgical recurrence. Specimens from the irradiated recurrent and their unirradiated primary tumors were cultured in vitro and their radiation sensitivity determined by clonogenic assay. RESULTS: The three irradiated recurrent tumor systems retained the individual histological features of their unirradiated primary xenografts. A lower metastatic incidence was observed in two of the three irradiated recurrent tumor lines in comparison with their unirradiated control tumors and their surgical recurrent counterparts. No significant differences were found between the irradiated recurrent tumors and their unirradiated counterparts with respect to: volume doubling time, growth time, potential doubling time, mitotic index, PCNA index, and SF2 values. CONCLUSIONS: High dose irradiation given in 30 fractions did not increase the metastatic activity in the three human tumor xenograft systems. Furthermore, the fractionated irradiation did not significantly change their proliferation characteristics and cellular radiation sensitivity.

Prevalence of factor V Leiden (APCR) and other inherited thrombophilias in young patients with myocardial infarction and normal coronary arteries.

OBJECTIVE: To investigate the role of activated protein C resistance (APCR, factor V Leiden) in coronary artery thrombosis. METHODS: The prevalence of APCR and of congenital deficiencies of antithrombin III, protein C, protein S, plasminogen, and factor XII was investigated in adult patients under 45 years of age with acute myocardial infarction. The results were compared with those of a group of 53 age and sex matched control subjects. RESULTS: Among 75 patients under the age of 45 years who were admitted from November 1994 to April 1996 for acute myocardial infarction, 22 (29.3%) had normal coronary arteriography (group I) and 53 (70.7%) had significant coronary artery disease (group II). Inherited thrombophilia was more often found in group I (4/22, 18.2%) than in group II (4/53, 7.5%) but the difference was not significant (F test: p = 0.22). The prevalence of APCR was 9.1% (2/22) in group I, 3.8% (2/53) in group 2 (p = 0.57), and 3.8% (2/53) in the normal control group (p = 0.57). CONCLUSIONS: The prevalence of congenital thrombophilias, including APCR, does not seem to be increased in young patients with myocardial infarction and normal coronary angiograms, compared with young patients with coronary atherosclerosis and with normal control subjects. However, the statistical power of the study is too low to detect a significant difference and these results are published to allow a meta-analysis of this problem in the future.

Safety and tolerability of intravenous cibenzoline for acute termination of spontaneous sustained ventricular tachycardia. Cibenzoline and spontaneous VT.

STUDY OBJECTIVES: To evaluate prospectively, the tolerability and safety of intravenous cibenzoline therapy, for the cardioversion of spontaneous monomorphic ventricular tachycardia (VT). SETTING AND PATIENTS: Between February 1990 and December 1996, fifty-eight patients aged 59+/-10 years old (fifty-three males, five females), with spontaneous VT not causing cardiac arrest, received intravenous cibenzoline. Their underlying heart conditions were: ischemic heart disease [35], dilated cardiomyopathy [14], right ventricular dysplasia [3], hypertrophic cardiomyopathy [1], valvulopathy [2], Fallot's Tetralogy [1] and primary arrhythmogenic disease [2]. The left ventricular ejection fraction was 42+/-13% (range 20%-76%). RESULTS: The mean dose of cibenzoline was 70+/-12 mg. The tachycardia stopped within 6+/-3 min in 47 (81%) patients. Side effects from cibenzoline occurred in two patients. The hemodynamic complications were limited to hypotension, that required vasopressor therapy in one patient. The only apparent proarrhythmic effect consisted of an isolated change in the morphology of the VT, that resolved spontaneously on withdrawal of the drug. No mortality occurred at the hospital. CONCLUSION: With appropriate rules for its administration, intravenous cibenzoline has the potential to become one of the first-line antiarrhythmic drugs, to be used for cardioversion of patients with spontaneous VT.

[Paradoxical embolism of the aortic arch diagnosed by transesophageal echocardiography. Surgical treatment]. / Embolie paradoxale de la crosse aortique diagnostiquée par échocardiographie transoesophagienne. Traitement chirurgical.

The authors report the case of a woman who presented with a pulmonary embolism followed by systemic embolism. Transoesophageal echocardiography showed a persistent foramen ovale compatible with a possible paradoxical embolism. In addition, a mobile embolism in the aortic arch was demonstrated. This embolism was extracted under cardiopulmonary bypass to avoid a recurrence of embolism. Transoesophageal echocardiography is the only reliable, non-invasive method allowing simultaneous diagnosis of a right to left shunt and visualisation of the thoracic aorta.

[Myocardial infarction following rapid perfusion of corticoids]. / Infarctus du myocarde au décours d'une perfusion rapide de corticoïdes.

The authors report the case of myocardial infarction occurring immediately after rapid intravenous infusion of a high dose of corticosteroids prescribed for a relapse of multiple sclerosis. Ventriculography confirmed the myocardial damage but the coronary arteries were normal. An aetiological investigation was negative. The authors review the cardiac secondary effects which may be very serious and even fatal. Coronary insufficiency is rare (only 3 previously published cases); it is therefore difficult to determine the prognosis. The possible mechanisms of infarction are discussed. Finally, the authors underline the importance of recording an ECG before treatment, of ECG monitoring during the infusion, and the need for repeating the recordings and of prolonging hospital admission when necessary.

[Severe coronary events and corticoids bolus. An update apropos of 3 new cases]. / Accidents coronaires graves et bolus de corticoïdes. Mise au point à propos de trois nouvelles observations.

The authors report two new cases of angina and/or myocardial infarction and one sudden death after an infusion of a bolus of high dose steroids. Coronary spasm, demonstrated in one of the cases and highly probable in the other two, is proposed as the mechanism of ischaemia. The authors underline the importance of the underlying pathology, previous coronary history, and the modes of administration. This type of treatment is often essential in clinical medicine and therefore the potentially severe secondary effects must be understood. Therefore, a previous history of myocardial infarction constitutes a definitive contra-indication and the duration of injection must be over one hour for doses greater than 250 mg. In all cases, a detailed medical history and an ECG are essential before starting treatment.

[Traumatic rupture of the aorta diagnosed by transesophageal echocardiography. Apropos of a case and review of the literature]. / Rupture traumatique de l'isthme aortique diagnostiquée par l'échographie transoesophagienne. A propos d'une observation et revue de la littérature.

The authors report the case of subadventitial rupture of the isthmus of the aorta due to trauma, diagnosed by transoesophageal echocardiography. The role of transoesophageal echocardiography compared with conventional diagnostic techniques is discussed. This method of investigation is a very good diagnostic tool in cases of closed trauma of the thorax.

[Left main coronary artery disease]. / La pathologie du tronc coronaire gauche.

There are many causes of left main coronary artery disease, the first of which is atherosclerosis. Other rarer causes may be observed, such as acute and chronic occlusions, spasm and primary and secondary dissection. The prevalence of stenosis of the left main coronary artery at coronary angiography is about 5%. The risk factors are the same as for coronary artery disease. The symptoms are angina, especially unstable angina. The diagnosis is suspected on the finding of an extremely positive exercise stress test, confirmed by coronary angiography. The results of the prospective large scale Veterans Administration trial showed surgery to be the treatment of choice with a 30 months survival of 80% in the surgical group compared with 64% in the medical group. The operative morbidity and mortality is less than 10% at present. Recent studies have reported a medium-term mortality of 4.3 to 10.25% with follow-up periods of 24 and 43 months respectively. The long-term survival and functional improvement are excellent, with values of nearly 80%. Chronic occlusion of the left main stem is rare, 0.01 to 0.7% in coronary angiographic studies. There is no difference in presentation, electrocardiographic or stress test features compared with other severe coronary artery disease. The diagnosis is angiographic and the treatment surgical because of the mediocre natural history with risks of sudden death and severe infarction. Acute occlusion of the left main coronary is rare for generally fatal. The mechanism is acute thrombosis and the clinical presentation is that of extensive infarction usually with cardiogenic shock.(ABSTRACT TRUNCATED AT 250 WORDS)

[Hemomediastinum caused by spontaneous rupture of the thoracic aorta]. / Hémomédiastin par rupture spontanée de l'isthme aortique.

The authors report the rare case of spontaneous rupture of the aortic isthmus in the absence of preexisting aortic aneurysm or dissection in a hypertensive woman presenting with chest pain and haemomediastinum. The history of trauma 30 years previously, could have been a predisposing factor. The diagnosis of this condition remains difficult and is often missed. The physiopathological, aetiological, clinical and diagnostic features are reviewed. Transoesophageal echocardiography showing an intraparietal haematoma confirmed the aortic origin of the haemomediastinum. Conventional angiography was of no value in the reported case because of the absence of rupture of continuity or of an intimal tear.

[A rare cause of loss of consciousness: mastocytosis. Apropos of 3 cases]. / Une cause rare de pertes de connaissance: la mastocytose. A propos de 3 cas.

The authors report three cases of syncope due to systemic mastocytosis. This is a rare cause of syncope but should be recalled in certain circumstances. In the light of these cases, the authors review the literature with respect to this unusual presentation. Syncope may occur at any age. Loss of consciousness may be more or less complete, brief or prolonged, isolated or recurrent and usually accompanied by prodromal symptoms. The least controversial physiopathogenic mechanism of these syncopes is intense vasoplegia induced by the release of vasoactive mediators, especially histamine. When there is a clinical suspicion of mastocytosis, even in the absence of skin changes, the diagnosis is confirmed by biopsy which shows abnormally high numbers of mastocytes irrespective of the organ biopsied. The treatment of acute forms with collapse is based on intravenous infusion of macromolecular fluids and injections of epinephrine. Prevention is by drugs which inhibit the synthesis of histamine, the degranulation of mastocytes and the production of prostaglandin D2.

[Painless infarction in antiphospholipid syndrome]. / Infarctus indolore au cours du syndrome des antiphospholipides.

The authors report a rare case of myocardial infarction secondary to coronary thromboses caused by the antiphospholipid syndrome. The relations between the cardiac pathology, especially the coronary disease, and antiphospholipid antibodies are recalled. The importance and methods of monitoring the anticoagulant therapy are emphasised.

[Inflammatory pseudotumor of the intestine caused by necrotizing vasculitis in the course of Horton disease]. / Pseudo-tumeur inflammatoire de l'intestin par vascularite nécrosante au cours d'une maladie de Horton.

The authors report a case of giant-cell arteritis involving the digestive tract, revealed by a subocclusive syndrome. It appeared to be an unusual pattern according to the location, the tumour aspect and the histologic appearance of a periarteritis nodosa type. The digestive involvement and the histologic appearance are discussed in a review of the literature, as well as the link with the periarteritis nodosa.

[Periaortic fibrosis with pericardial and perirenal involvement: apropos of a case]. / Fibrose périaortique avec envahissement péricardique et périrénal: à propos d'un cas.

The authors report a case of right ventricular insufficiency by constrictive pericarditis revealing aortic and retroperitoneal fibrosis. Only one similar case has been published. We discuss the etiology of this affection, the possible analogies with idiopathic systemic fibrosis and Takayasu's disease and the possible participation of thyroiditis disease and therapy (particularly propranolol).

[Left bundle-branch block and chest pain of simultaneous occurrence during exercise]. / Bloc de branche gauche et douleur thoracique d'apparition simultanée à l'effort.

The authors report a new case of left bundle branch block with pain during exercise, with arteriographically normal coronary arteries. Clinical findings and the course of the condition are reviewed. Pathophysiological mechanisms are discussed, with attribution of first place to an ischemic theory.

[Localized type 2 dissection unrecognized by transesophageal echography. Apropos of a case]. / Dissections type 2 localisées méconnues par l'échographie transoesophagienne. A propos d'une observation.

The authors report a case of type 2 dissection, strictly confined to the terminal portion of the ascending aorta, not seen by transesophageal echocardiography because of the existence of a blind spot and responsible for a false negative. The role of TEE in the diagnostic approach to dissections is reviewed, as are its limitations, of which it is important to be aware because of the poor prognosis of pathology of this type.