Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors.

BACKGROUND AND PURPOSE: Marijuana smoking is widespread in many countries, and the use of smoked synthetic cannabinoids is increasing. Smoking a marijuana joint leads to bronchodilation in both healthy subjects and asthmatics. The effects of Δ(9) -tetrahydrocannabinol and synthetic cannabinoids on human bronchus reactivity have not previously been investigated. Here, we sought to assess the effects of natural and synthetic cannabinoids on cholinergic bronchial contraction. EXPERIMENTAL APPROACH: Human bronchi isolated from 88 patients were suspended in an organ bath and contracted by electrical field stimulation (EFS) in the presence of the phytocannabinoid Δ(9) -tetrahydrocannabinol, the endogenous 2-arachidonoylglycerol, the synthetic dual CB1 and CB2 receptor agonists WIN55,212-2 and CP55,940, the synthetic, CB2 -receptor-selective agonist JWH-133 or the selective GPR55 agonist O-1602. The receptors involved in the response were characterized by using selective CB1 and CB2 receptor antagonists (SR141716 and SR144528 respectively). KEY RESULTS: Δ(9) -tetrahydrocannabinol, WIN55,212-2 and CP55,940 induced concentration-dependent inhibition of cholinergic contractions, with maximum inhibitions of 39, 76 and 77% respectively. JWH-133 only had an effect at high concentrations. 2-Arachidonoylglycerol and O-1602 were devoid of any effect. Only CB1 receptors were involved in the response because the effects of cannabinoids were antagonized by SR141716, but not by SR144528. The cannabinoids did not alter basal tone or contractions induced by exogenous Ach. CONCLUSIONS AND IMPLICATIONS: Activation of prejunctional CB1 receptors mediates the inhibition of EFS-evoked cholinergic contraction in human bronchus. This mechanism may explain the acute bronchodilation produced by marijuana smoking.

[Endobronchial ultrasonography]. / Échoendoscopie bronchique.

Endobronchial ultrasonography is a minimally invasive examination that offers new opportunities for exploring the mediastinum. It reaches and characterizes previously inaccessible lesions. Its relevance is largely supported by abundant and compelling literature, which explains its increasing medical application and the growing number of places offering it. This issue offers us an opportunity to review the key points of this technique and to report on some of our findings.

Tiotropium reduction of lung inflammation in a model of chronic gastro-oesophageal reflux.

Gastro-oesophageal reflux is frequent in chronic airway diseases and is considered a trigger for symptoms. In animal models, bilateral vagotomy or muscarinic antagonists prevent the increase in airway resistance and the microvascular leakage induced by acute oesophageal acid instillation. The present study investigates lung inflammation and remodelling in an animal model of chronic gastro-oesophageal reflux disease (GORD), and the effectiveness of pretreatments with tiotropium, atropine and dexamethasone. Mice were exposed to twice-daily intra-oesophageal HCl instillations for 21 days. Exposure to HCl causes: marked infiltration by inflammatory cells of the airways and of peribronchial areas; an increase in epithelial thickness; histological features of interstitial pneumonitis; an increase in cell numbers and in the levels of interleukin-8; and soluble intercellular adhesion molecule in bronchoalveolar lavage fluids, as well as of in vitro tracheal contractility. The administration of nebulised tiotropium or intraperitoneal atropine prior to each instillation of HCl, considerably inhibited all these changes. These results indicate a major role of acetylcholine in airway inflammation and remodelling in a GORD model, and demonstrate that tiotropium and atropine can prevent lung inflammation with an effectiveness similar to intraperitoneal dexamethasone, providing additional evidence that anticholinergics might contribute to the control of inflammatory processes in airway diseases.

Combined heart and kidney transplantation in a patient with Fabry disease in the enzyme replacement therapy era.

Fabry disease (FD) is an X-linked genetic disease, resulting from the deficiency of alpha-galactosidase A, a lysosomal enzyme responsible for the cleavage of glycosphingolipids. In absence of enzyme replacement therapy (ERT), globotriaosylceramide (Gb3) accumulates in tissue, leading to progressive organ damage with severe renal, cardiac and central nervous system complications. We herein describe the first case of successful combined and simultaneous heart and kidney transplantation in a young male patient with FD complicated by end-stage renal disease and severe heart failure not responding to late-onset ERT. Combined heart and kidney transplantation can be recommended for Fabry patients with end-stage renal disease and overt hypertrophic cardiomyopathy, severe ischemic or valvular heart disease.

[Angiosarcoma of the breast. Apropos of 8 cases and review of the literature]. / Les angiosarcomes du sein. Etude de 8 cas et revue de la littérature.

The 8 cases of primary breast angiosarcoma which were diagnosed, treated and had their follow-up at the Gustave-Roussy Institute between 1954 and 1995 are reported. The age at presentation ranged from 32 to 68 years. In 4 patients the vascular nature of their mammary lesion was conspicuous by a violaceous discolorations of the overlying skin. No patient had enlarged ipsilateral axillary lymph nodes. One patient had metastases. In 2 out of 5 patients who had a partial surgical or fine-needle biopsy before treatment, the diagnosis was missed, and adequate treatment was unduly delayed. The tumor most often presents as an ill defined area made of dense endothelium-lined papillae. A remarkable picture of "soap bubbles" has been identified in 4 cases. The "meshes" of fatty areas appear to be reinforced as they are infiltrated by tumor cells. This appearance may be specific of mammary angiosarcoma. By the French Cancer Centers' grading system for soft tissue sarcomas in general, grade is III in 3 tumors, II in 2 tumors, I in 3 tumors. Five tumors were treated by total mastectomy only. In 3 cases a total mastectomy was followed by radiation therapy to the chest wall. At diagnosis a chemotherapy was administered only to the patient who had metastases. Median disease-free survival was 9 months. Median overall survival was 13 months. From a review of the literature a simple mastectomy appears to be necessary as well as enough for local treatment. Patients with a grade III angiosarcoma of the breast should be included into a therapeutical trial of adjuvant chemotherapy for soft tissue sarcomas in general.

[Anatomopathological problems of mastopathies at risk]. / Problèmes anatomopathologiques des mastopathies à risque.

As breast cancer screening programmes gain momentum, there is a parallel increase in histological problems mainly related to the identification of an increasing number of "borderline" breast lesions. The results of recent studies are often inconsistent, and bear witness to the lack of a consensus regarding the interpretation of both ductal and lobular epithelial hyperplasia. The authors insist on the need for an adequate number of samples and an irreproachable histologic technique which is indispensible if the morphologic subtleties, currently the only valid factors permitting the diagnosis, are to be appraised. The role of the pathologist is therefore crucial in the management of specimens which are entrusted to him and in helping the clinician to tailor treatment to fit each individual patient.

[The role of the pathologist in the treatment of osteogenic sarcoma]. / Place de l'anatomopathologiste dans le traitement des sarcomes ostéogènes.

The pathologist today has an important role in the treatment of osteosarcoma. He contributes during the operation by advising about the extent of the tumour and after the operation by studying the operative specimen to assess the extent of the tumour, and, when primary chemotherapy has been used, to estimate the effectiveness of the treatment by counting the percentage of viable tumour cells so that the type of chemotherapy used subsequently can be adapted to the situation. Only trained teams can make the best use of these studies.

[Granular myoblastoma of the breast. Apropos of 7 cases]. / Myoblastomes granuleux du sein. A propos de sept observations.

7 cases of mammary granular cell tumor have been studied, and some pitfalls on frozen section diagnosis are described. Erroneous diagnosis of mammary infiltrating carcinoma leads sometimes to an useless mutilation. Over-diagnosis is possible because of: --gross features like induration and ill-defined circumscription of the tumor, --histological features and especially infiltration of the lobules and fat by granular tumor cells.

Chondrosarcoma in children subsequent to other malignant tumours in different locations.

During recent years the combination of surgery, radiotherapy, and multiple chemotherapy in the treatment of patients with cancer has resulted in increased survival periods and, in some cases, complete cures. In children, however, the subsequent development of other and apparently unrelated malignancies has been observed 20 times more commonly than in a control group. This paper reports the occurrence of chondrosarcoma of the femur in two children who had been treated successfully for malignant tumours of soft tissue. One of these tumours was a malignant fibrous histiocytoma in the muscles of the forearm; the other was a rhabdomyosarcoma of the cheek. The intervals between termination of treatment of these lesions and recognition of the chondrosarcoma were five years and 10 years, respectively. In addition to surgical and radiotherapeutic measures, both children had received high doses of chemotherapy.