Insulin downregulates M(2)-muscarinic receptors in adult rat atrial cardiomyocytes: a link between obesity and cardiovascular complications.

OBJECTIVE: To determine whether decreased cardiac parasympathetic activity observed in obesity is due to insulin-induced alterations in cardiac M(2)-muscarinic receptors and/or adenylyl cyclase activity. DESIGN AND METHODS: After incubation with increasing concentrations of insulin, adult rat atrial cardiomyocytes were assayed for M(2)-muscarinic receptor binding density and affinity, and for M(2)R mRNA expression using RT-PCR analysis. Forskolin-stimulated adenylyl cyclase activity and its inhibition by carbachol were also assayed, as was endothelial nitric oxide synthase mRNA expression. The effects of insulin on M(2)-muscarinic receptor density and mRNA expression levels were analyzed using the insulin signaling inhibitors rapamycin, wortmanin and PD 098059. RESULTS: Insulin induces a concentration- and time-dependent decrease in expression of the M(2)R mRNA, and in [(3)H]N-methylscopolamine binding by the receptor. These effects on the M(2)R mRNA levels and on [(3)H]N-methylscopolamine binding were prevented by PD 98059, but not by wortmanin or rapamycin. Basal and forskolin-induced cAMP production did not differ, but the inhibition of forskolin-simulated enzyme activity by carbachol was blunted by insulin. No change in the mRNA levels for endothelial nitric oxide synthase was observed. CONCLUSION: In rat atrial cardiomyocytes, insulin markedly alters both the M(2)-muscarinic receptor density, and its mRNA expression through transcriptional regulation and adenylyl cyclase activity. These data suggest that the obesity-associated decrease in cardiac parasympathetic tone may be related to hyperinsulinemia, which could directly contribute to cardiovascular morbidity in obese patients.

[Ablation of ventricular extra-systole in the left Valsalva sinus. A case report]. / Ablation d'une extrasystolie ventriculaire dans le sinus de Valsalva gauche. A propos d'un cas.

We report the case of a patient presenting with unrelenting isolated or repetitive monomorphic ventricular extra-systoles, with left block and right axis deviation, which appeared to arise from the right ventricular chamber, but for which ablation was finally performed in the left Valsalva sinus. The ECG and endocavity electro-physiological features which led us to suspect this atypical, although not exceptional, situation are reported, as well as the techniques for ablation available in this case.

Electrical storm in Brugada syndrome successfully treated using isoprenaline.

A case of an electrical storm occurring in a patient implanted with a cardioverter-defibrillator for Brugada syndrome is reported. Recurrent ventricular fibrillation was initiated by short-coupled isolated monomorphic ventricular premature beats probably originating from the right ventricular outflow tract, associated with a manifest electrocardiographic pattern of Brugada syndrome. Infusion of atropine accelerated the heart rate but did not prevent ventricular fibrillation, however, low doses of isoprenaline quickly obviated any recurrence of ventricular fibrillation. This was associated with the disappearance of the short-coupled premature beats together with a normalization of the electrocardiographic pattern. Possible mechanisms are discussed according to the accepted pathophysiological hypothesis.

Technical and oncological feasibility of laparoscopic total mesorectal excision with pouch coloanal anastomosis for rectal cancer.

AIM: The aim of this study was to evaluate the technical and oncological feasibility of laparoscopic total mesorectal excision (TME) with coloanal anastomosis for mid and low rectal cancer. METHODS: During a 2-year period, 50 patients underwent laparoscopic TME with coloanal anastomosis for rectal carcinoma located at a median of 4.5 (range 2-11) cm from the anal verge. Pre-operative radiotherapy was used in 46 patients. Intersphincteric dissection was combined with the laparoscopic procedure to achieve sphincter preservation. RESULTS: Conversion to a laparotomy was necessary in six patients. Postoperative mortality and morbidity were 2% and 28%, respectively. Morbidity was lower in patients operated on during the second part of the study, who had extraction of the rectal specimen through a small laparotomy incision, than in those operated on during the first part of the study when removal of the specimen was by transanal extraction. Oncological quality of excision was safe in 44 patients with intact or almost intact rectal fascia in 88% and R0 resection in 90%. At a median follow-up of 18 months, there was no local or port-site recurrence. CONCLUSION: This study confirms our preliminary results of oncological feasibility of laparoscopic TME with sphincter preservation for mid and low rectal cancer, and showed that morbidity can be decreased by using a standardized surgical procedure.

Influence of postoperative morbidity on long-term survival following liver resection for colorectal metastases.

BACKGROUND: Survival after resection of colorectal liver metastases may be influenced by the patient, the primary tumour and the liver metastases. Postoperative morbidity is associated with poor survival in several cancers. The aim of this retrospective study was to evaluate prognostic factors of survival after resection of colorectal liver metastases, including postoperative morbidity. METHODS: From 1985 to 2000, 311 consecutive patients with liver metastases from colorectal cancer underwent resection with curative intent. Univariate and multivariate analyses were performed to assess the influence of age, sex, site and stage of the colorectal tumour, disease-free interval, number, size and distribution of metastases, type of hepatectomy, pedicular clamping, resection margin, blood transfusion, postoperative morbidity and adjuvant chemotherapy on overall and disease-free survival. RESULTS: The postoperative mortality and morbidity rates were 3 and 30 per cent respectively. The 3- and 5-year overall survival rates were 53 and 36 per cent respectively. Both overall and disease-free survival rates were independently associated with nodal status of the colorectal tumour, number of metastases and postoperative morbidity. Patients with postoperative morbidity had an overall and disease-free 5-year survival rate half that of patients with no morbidity: 21 versus 42 per cent for overall survival (P < 0.001) and 12 versus 28 per cent for disease-free survival (P = 0.001) respectively. CONCLUSION: Long-term survival can be altered by postoperative morbidity after resection of colorectal liver metastases by increasing the risk of tumour recurrence. This justifies optimizing the surgical treatment of colorectal liver metastases to decrease postoperative morbidity and the use of efficient adjuvant treatments in patients with postoperative morbidity.

Laparoscopic intersphincteric resection with coloplasty and coloanal anastomosis for mid and low rectal cancer.

BACKGROUND: The feasibility of laparoscopic rectal resection in patients with mid or low rectal cancer was studied prospectively with regard to quality of mesorectal excision, autonomic pelvic nerve preservation and anal sphincter preservation. METHODS: Laparoscopic rectal excision was performed in 32 patients (21 men) with rectal carcinoma located 5 cm from the anal verge. Most patients had T3 disease and received preoperative radiotherapy. The surgical procedure was performed 6 weeks after radiotherapy and included total mesorectal excision, intersphincteric resection, transanal coloanal anastomosis with coloplasty and loop ileostomy. RESULTS: Three patients needed conversion to a laparotomy. Postoperative morbidity occurred in ten patients, related mainly to coloplasty. Macroscopic evaluation showed an intact mesorectal excision in 29 of 32 excised specimens; microscopically, 30 of the 32 resections were R0. Sphincter preservation was achieved in 31 patients. The hypogastric nerves and pelvic plexuses were identified and preserved in 24 of the 32 patients. Sexual function was preserved in ten of 18 evaluable men. CONCLUSION: A laparoscopic approach can be considered in most patients with mid or low rectal cancer.

[Study of ventricular repolarization in an experimental model of arterial hypertension associated with obesity]. / Etude de la repolarisation ventriculaire dans un modèle expérimental d'HTA associée à l'obésité.

UNLABELLED: High fat diet (HFD) in dogs is associated with obesity and hypertension (HTN) but also with a significant and early decrease in heart rate variability (HRV). Decreased HRV has been shown to be a good predictor of sudden cardiac death due mainly to arrhythmic event. The aim of this work was to investigate the changes in ventricular repolarization through 24 hours EKG recordings in dogs with hypertension and rendered obese by 20 weeks of HFD. This was achieved through 24 hour EKG recording analysis of QT parameters. The aims of this work was i) feasibility of this method in dogs and ii) identification of potential arrhythmic risk factors that could explain overmortality during obesity. METHOD: Six dogs received a high fat diet (HFD) ad libitum during 20 weeks. A 24 hour EKG recording was realized just before and after 20 weeks of HFD. The following parameters studying QT interval were collected: QT interval lasting from the beginning of the Q wave to the apex (QTa) and to the end of the T wave (QTe), QT intervals plotted against RR intervals and two regression lines were calculated characterized by their slope and intersection with the Y axis, QT dispersion (longest minus shortest QT interval for each RR value) as well as the difference of QT interval between night and day at a fixed RR value considered as a marker of the sympathovagal balance. Our results show that HFD significantly increased body weight, blood pressure, heart rate, left ventricular mass and insulinemia. QT dispersion was increased in a non-significant manner both during day (+35%) and night (16%) for QTa and only during day for QTe (+27%). This increased dispersion of QT was not associated to any increase of QT interval. There was no effect of HFD on QT dynamicity parameter nor on the night-day difference at any RR interval from 300 to 1,300 ms. CONCLUSION: HFD tend increase QT dispersion without any effect on QT interval. These results are compatible with a heterogeneous repolarization probably related to abnormal autonomic nervous system tone. This study could partly explain occurrence of lethal arrhythmias during obesity which might lead to overmortality of obese patients. These results are different for QTa and QTe, but these two parameters are characterizing different type of ventricular cells. This study confirms the feasibility of this method in an experimental model, but results need to be validated in larger groups and in human.

[Early atrial gene regulation of obesity-related arterial hypertension]. / Modifications précoces du transcriptome auriculaire dans l'hypertension artérielle associée à l'obésité chez le chien.

High fat diet (HFD) induces both arterial hypertension and tachycardia in dogs. Changes in heart rate occur early and are in part due to a decrease in the parasympathetic drive to the heart secondary to down-regulation of atrial muscarinic M2 receptors (Pelat et al. Hypertension 1999; 340: 1066-72). These data suggest that HFD is able to modify genic expression at atrial level. Thus, the aim of this work was to perform a systematic study of the genic expression profile in dogs made obese and hypertensive by 9 weeks of HFD. Blood pressure and heart rate were measured by telemetry implanted 15 days before starting regimen in 6 HFD and in 6 control dogs. HFD was the normal canine diet administered to controls but mixed with 300 g of beef fat. At the end of the experience, animals were sacrified and right atria were collected. Gene regulation was assessed in pooled tissue samples from both groups using suppressive substractive hybridization and microarray analysis. Genes with induction or repression rates of at least 20% when compared to controls were sequenced. As previously reported HFD induced a significant increase in body weight, blood pressure and heart rate when compared to controls. The results of SSH experiments led to the identification of 32 genes which are differentially regulated in atria from HFD dogs. Most are genes encoding proteins which have been previously shown to be regulated during various cardiopathies (MMP9, Na/K-ATPase 3...). These changes indicate the existence of early remodeling processes of atrial myocardium secondary to HFD. Other group of genes encodes proteins with no role identified in heart up today (lec-3, ERK-3, TRIP1, nucleophosmin...) or which function remains totally unknown. This work confirms that HFD is associated with early changes in gene expression in atrium. These changes are unlikely to be related to ventricular hypertrophy which is observed only during long-term HFD. Further studies are necessary to demonstrate the role of these modifications in the pathophysiological mechanisms leading to the increase in heart rate in this model of obesity-related arterial hypertension.

Thymolipoma in association with myasthenia gravis.

A 52-year-old male presented with an anterior mediastinal tumor associated with a 2-year history of myasthenia gravis. The patient underwent thymectomy and a 185-g, 10 X 8 X 3.5 cm, well-delineated tumor was resected. On histologic examination the tumor proved to be a thymolipoma composed of mature adipose elements containing cords and nests of thymic tissue. The latter consisted mainly of cortical areas, the thymocytes of which displayed an immunohistochemical profile of cortical cells, i.e., CD 1+, CD 4+, CD 8+, and frequently Ki 67+. Ultrastructural study confirmed the predominant cortical differentiation of the thymic component. No germinal centers, dendritic reticulum cells, or myoid cells were detected by histologic, immunohistochemical, and ultrastructural studies. The association of thymolipoma with myasthenia gravis is rare; this case is the 10th reported. Our findings lead us to believe that (a) the cortical differentiation of the thymic component and the active thymocyte proliferation could represent a factor leading to myasthenia gravis; and (b) thymolipoma could be a peculiar form of thymoma rather than a mixed tumor of mesenchymal and entodermal origin, a lipoma, or a hamartoma of the thymic gland. The reported association of thymolipomas with other immune disturbances or with neoplastic conditions usually associated with true thymomas support these findings.

Prognostic value of the epithelial membrane antigen (EMA) in the case of Hodgkin's disease.

The study deals with the results obtained from 155 lymph node biopsies of patients suffering from Hodgkin's disease (HD) who were treated by MOPP and radiotherapy in the same establishment. The specimens in paraffin have been examined for the presence of antigens using several monoclonal antibodies, particularly epithelial membrane antigen (EMA). There exists no correlation between the immunophenotypes towards EMA and histological types. Thirty-three patients whose responses were EMA (+) have the assurance survival more than 10 years on the level 32.4% while those 122 patients with EMA(-) had the same survival on 90% level (p less than 0.001). Thus a new prognostic tool has been found which enables to detect the likely therapeutic failures in the case of Hodgkin's disease.

Translocation t(3;22)(q23;q11) in three patients with diffuse large B cell lymphoma.

In our series of 134 patients with a diagnosis of non-Hodgkin's lymphoma (NHL) and clonal chromosomal abnormalities, three were found to show an identical t(3;22)(q28;q11) translocation. All were old patients with isolated lymphadenomegaly and diffuse large noncleaved cell lymphoma. All expressed a B cell immunophenotype, and all entered a complete remission when treated with aggressive chemotherapy. This translocation could, therefore, delineate a particular subtype of diffuse large cell NHL.

Production of granulopoiesis-stimulating and -inhibiting activities by T cells associated with malignant cells in lymphomas.

The possible role of T lymphocytes in the formation of granulomatous reactions seen in certain malignant lymphoid tumours was investigated by measuring the granulopoietic colony-stimulating activity (CSA) and granulopoietic-inhibiting activity (IA) produced by stimulated T-lymphocytes isolated from peripheral blood, spleen and lymph nodes of patients and normal subjects. Lymph-node T-cells from patients with benign lymphoid hyperplasia, B-cell non-Hodgkin's lymphoma (B-NHL), and non-granulomatous Hodgkin's disease (HD) showed no CSA, but the cells produced IA of 40 +/- 23%, 40 +/- 24% and 50.5 +/- 22.5% respectively. The corresponding cells from patients with HD accompanied by granulomatous reactions produced CSA of 6.85 +/- 6.5 u/microliters and IA of 23.5 +/- 21%. The presence of a granulomatous reaction in malignant lymphoma was correlated with the stimulation of granulopoiesis in vitro by T lymphocytes associated with malignant cells. A correlation was demonstrated between neutrophilic and eosinophilic colonies obtained in vitro under the influence of CSA-producing T cells isolated from malignant lymphomas and the neutrophils and eosinophils present in the granuloma. These results showed that tumour-infiltrating T cells play a role in the presence of granulomatous reactions seen in lymphomas. Peripheral-blood T cells from healthy subjects, and from patients with B-NHL, or with HD unaccompanied by granulocytic reactions produced CSAs of, respectively, 5 +/- 0.5 u/microliter, 4.8 +/- 2.2 u/microliters and 5.3 +/- 0.4 u/microliters, and IAs of 45 +/- 18%. 50 +/- 5.5% and 50.5 +/- 7% respectively. The corresponding values for HD patients with granulocytic reactions were CSA. 17 +/- 15.5 u/microliters, and IA, 9.5 +/- 9%. No correlation was demonstrated between neutrophilic colonies obtained in vitro under the influence of HD blood T cells and neutrophils present in blood. Only one correlation was found: between the percentage of eosinophilic colonies and the number of blood eosinophils. HD blood T cells did not seem to explain completely granulocytic reactions seen in blood.

T lymphocytes from invaded lymph nodes in patients with B-cell-derived non-Hodgkin's lymphoma: reactivity toward the malignant clone.

Tumor-infiltrating T lymphocytes (TIL-T) are always present in B-cell-derived non-Hodgkin's lymphoma (NHL). In this investigation, we explored the possibility that collaboration might exist between these cells. TIL-T were isolated from 39 lymph nodes of patients with NHL. In most of the cases, few of them (less than 10%) possessed surface activation receptors CD25 or OKT9. In 80% of the cases, they proliferated in response to recombinant interleukin-2 (rIL-2), but the degree of proliferation was often low as compared with control populations. The influence of irradiated autologous malignant cells on the TIL-T proliferation in response to rIL-2 (40 U/mL) was also investigated: in 38% of the cases, this proliferation was not modified (group O), and in 41% it was higher (group +) and in 21% it was lower (group -). The mechanism of this immune response (specific or not) is not elucidated at present. The definition of these groups was statistically correlated with different parameters of the disease: (1) percentage of TIL-T was higher in group + (44% +/- 17%) than in group O (31% +/- 18%) and group - (24% +/- 15%); (2) B-cell proliferation in centrofollicular lymphomas was more frequently nodular or nodular and diffuse in group + (83%) and O (55%) than in group - (0%); (3) low-grade malignancies in the Working Formulation were more frequent in group + (75%) than in group O (60%) or group - (12%); (4) favorable prognosis evaluated with the Grenoble cytologic classification was more frequent in group + and O (87%) than in group - (12%); (5) actuarial survival curves showed a significantly better prognosis for patients in group +.

Translocation t(13;17)(q12-14;p12-13) in two patients with lymphocytic lymphoma.

Cytogenetic studies were performed at the time of diagnosis on two patients with diffuse small cell lymphocytic lymphoma. Both patients had a similar simple karyotype with a t(13;17)(q12-14;p12-13). These observations confirm the nonrandom involvement of band 13q13 in chronic lymphoproliferative diseases.

[Mixed cryoglobulinemia with necrotizing angiitis. Apropos of 2 cases]. / Cryoglobulinémies mixtes avec angéites nécrosantes. A propos de deux observations.

Out of a series of 26 personal cases, 2 cases of mixed IgM-IgG cryoglobulinemia, one type II the other type III, are reported because they were associated with histologically proven necrotizing vasculitis. In both cases the numerous symptoms were due to renal damage (the vasculitis was discovered in the kidney) and to peripheral neuropathy. One of the patients died; the other had severely deteriorated general condition and required substitution hemodialysis. Cases of vasculitis associated with mixed cryoglobulinemia have often been published, but there are few reports mentioning necrotizing vasculitis; a search in the literature yielded only 9 cases. This small number does not mean that mixed cryoglobulinemia should not be listed among the causes of necrotizing vasculitis, but it makes it difficult to extract those specific features that would enable to predict which case of mixed cryoglobulinemia is associated or not with necrotizing vasculitis.

[Association of thymus carcinoma, Hashimoto's thyroiditis and polymyositis. Anatomoclinical case with autopsy findings]. / Association d'un carcinome thymique, d'une thyroïdite de Hashimoto et d'une polymyosite. Une observation anatomoclinique avec données autopsiques.

A 67-year-old woman presenting with a 9-month history of polymyositis, suddenly worsened her clinical state and died. An autopsy was performed, finding a tumor measuring 8 x 6 x 1 cm, located in the left pulmonary hilum. The thyroid gland, of normal volume, was firm. The histological analysis of the tumor, the thyroid gland and several skeletal muscles led to the following diagnoses: thymic carcinoma, Hashimoto's thyroiditis and polymyositis. The aim of the discussion is this thymic carcinoma, the originality of which are firstly its ectopic location, secondly its association with immune diseases usually described during the course of thymomas rather than thymic carcinomas.

Papillary meningioma. Clinicopathologic study of seven cases and review of the literature.

Seven cases of papillary meningioma are reported. The patients, 3 females and 4 males, were aged between 21 and 69 years. Five tumors were supratentorial, 1 was located in the left temporal bone, and 1 in the thoracic spinal canal. Five patients had local recurrences and died within 1.4 to 9 years of the original operation. In Case 2, one small pulmonary metastatic nodule was found at autopsy. Microscopically, these meningiomas showed foci of necrosis, numerous mitotic figures and local invasiveness. Psammoma bodies were occasional or absent. Forty-six papillary meningiomas have been identified in the literature. Certain histologic features (necrosis, high mitotic index, rich peripapillary reticulin network) and evolutive events (high rate of local recurrence, development of distant metastases) suggest that this aggressive variant of meningioma could form a histologic link between syncytial, fibroblastic, and hemangiopericytic meningiomas.

[Primary microvascular lesions of the kidney or pre-hypertensive nephroangiosclerosis. 25 cases]. / Lésions microvasculaires primitives du rein ou néphroangiosclérose pré-hypertensive. 25 observations.

Isolated non inflammatory lesions of renal microarteries (eventually with mild thickening of tubular basement membranes, but with negative immunofluorescent glomerular studies) were observed in 25 patients (22 males) in whom renal biopsy have been performed for proteinuria (P). Selection criteria were: pathological lesions by definition; absence of hypertension (HT) in clinical and at the time of biopsy; minimum follow up of 4 years after the first statement of the proteinuria (4 to 29 years; mean 14 years). Three groups have been isolated: 1. 3 patients have had an acute glomerulonephritis followed by disappearance of proteinuria. It reappears 1 to 5 years later. HT was discovered 2, 8 and 11 years after the proteinuria. Renal failure occurred 1 and 3 years after HT. 2. 14 patients had hereditary or acquired vascular risk factors (obesity, smoking, ethylism). In 7, HT occurred 3 to 15 years after P. In 2, renal failure occurred 4 to 8 years later. 3. 8 patients had no vascular risk factor; in 3 of them Ht developed 7, 13 and 20 years after the first statement. A positive immunofluorescence with IgM or C3 on renal arterioles had been found in only 3 of the 10 patients who in group 2 and 3 became hypertensive. A proteinuria may precede the occurrence of HT without being induced by glomerulonephritis. Group 2 and 3 suggest that these renal lesions of arterial sclerosis precede and may be a factor of HT. Indeed, this entity may be considered as a prehypertensive condition.