Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet.

The hypothalamic melanocortin system, which controls appetite and energy expenditure, develops during the third trimester in primates. Thus, maternal nutrition and health may have a profound influence on the development of this system. To study the effects of chronic maternal high-fat diet (HFD) on the development of the melanocortin system in the fetal nonhuman primate, we placed adult female macaques on either a control (CTR) diet or a HFD for up to 4 yr. A subgroup of adult female HFD animals was also switched to CTR diet during the fifth year of the study (diet reversal). Third-trimester fetuses from mothers on HFD showed increases in proopiomelanocortin mRNA expression, whereas agouti-related protein mRNA and peptide levels were decreased in comparison with CTR fetuses. Proinflammatory cytokines, including IL-1beta and IL-1 type 1 receptor, and markers of activated microglia were elevated in the hypothalamus, suggesting an activation of the local inflammatory response. Fetuses of diet-reversal mothers had normal melanocortin levels. These results raise the concern that chronic consumption of a HFD during pregnancy, independent of maternal obesity and diabetes, can lead to widespread activation of proinflammatory cytokines that may alter the development of the melanocortin system. The abnormalities in the fetal POMC system, if maintained into the postnatal period, could impact several systems, including body weight homeostasis, stress responses, and cardiovascular function. Indeed, the HFD offspring develop early-onset excess weight gain. These abnormalities may be prevented by healthful nutrient consumption during pregnancy even in obese and severely insulin-resistant individuals.

Central role of the melanocortin-4 receptors in appetite regulation after endotoxin.

Melanocortin-4 receptors (MC4R) are key factors in the depression of appetite during disease. This study was designed to determine the role of agouti-related protein (AgRP) in the effect of endotoxin (lipopolysaccharide, LPS) on appetite. Sheep received an intracerebroventricular injection of either saline or AgRP (0.5 nmol/kg of BW) 1 h before intravenous injection of either saline or LPS (0.6 microg/kg of BW) at time 0 and again at 4 h. Agouti-related protein prevented the reduction in feed intake due to LPS (P < 0.05). In a second experiment, AgRP gene expression was unaffected at 3 h and increased (P < 0.01) at 6 h after LPS. Immunohistochemical evidence indicated that there was an increase in the percentage of AgRP neurons with c-Fos immunoreactive nuclei 6 h after sheep were injected with LPS (P < 0.04) and a corresponding decrease in a-melanocyte-stimulating hormone neurons coexpressing c-Fos (P < 0.001). In situ hybridization provided evidence for an increase in AgRP gene expression and a decrease in proopiomelanocortin gene expression 6 h after LPS (P < 0.05). In a final experiment, physiological elevation of orexigenic agents by short-term fasting kept feed intake at the same level as controls, in spite of the presence of LPS, similar to the effects of AgRP in Exp. 1. The AgRP inhibition of the MC4R prevents appetite inhibition in response to LPS and well after LPS inhibition of feed intake, both AgRP and a-melanocyte-stimulating hormone may change in a pattern that favors appetite increases. These studies support the notion of the MC4R as a critical component of the mechanism for appetite suppression due to endotoxin.

The effect of aminocandin (HMR 3270) on the in-vitro adherence of Candida albicans to polystyrene surfaces coated with extracellular matrix proteins or fibronectin.

Aminocandin is a new representative of the echinocandins that could potentially affect the cellular morphology and metabolic status of Candida albicans cells within biofilms. This study investigated the influence of a sub-inhibitory concentration (MIC/2) of aminocandin on in-vitro growth of C. albicans and subsequent fungal adherence to plastic surfaces coated with fibronectin or extracellular matrix (ECM) proteins. Eleven strains of C. albicans were studied, of which six were susceptible and five were resistant to fluconazole. All 11 strains were susceptible to aminocandin in vitro, regardless of the culture medium used for the microdilution method. Aminocandin induced a significant (p <0.005) decrease in adherence when polystyrene was coated with ECM gel (ten strains) or fibronectin (seven strains). Growth in medium containing aminocandin (MIC/2) decreased the adherence of five (ECM gel) or three (fibronectin) of the six strains susceptible to fluconazole, and inhibition was observed for all five (ECM gel) or four (fibronectin) of the five fluconazole-resistant strains. Overall, the study demonstrated the anti-adherent properties of aminocandin with fluconazole-susceptible strains, and suggested that this activity was at least equivalent with fluconazole-resistant strains. Thus, the ability of aminocandin to inhibit the first step in the development of C. albicans biofilms appeared to be independent of the in-vitro resistance of C. albicans to fluconazole.

Expression of ciliary neurotrophic factor receptor in myasthenia gravis.

In myasthenia gravis, high anti-nicotinic receptor (AChR) antibody titers are not always associated with severity of the disease, suggesting the involvement of other pathological effectors. We showed that ciliary neurotrophic factor receptor (CNTFR) gene expression was higher in muscle biopsy tissue from severely affected MG patients regardless of anti-nAChR antibody titer. This increase was also triggered in vitro by a seric factor from MG patients. CNTFR protein expression was decreased in muscles from seropositive MG patients only.Altogether, our data indicate that the alteration of CNTFR expression in some MG patients could contribute to the severity of the disease in a subgroup of patients.

Surgical treatment of lung cancer invading the chest wall: results and prognostic factors.

BACKGROUND: The study was performed to assess prognostic factors in patients with lung cancer invading the chest wall treated by surgery. METHODS: We reviewed retrospectively clinical records of all patients operated on for lung cancer invading chest wall structures between 1984 and 1998. RESULTS: Two hundred one patients were operated on in this 14-year period. One hundred thirty-seven lobectomies, 55 pneumonectomies, and 9 wedge resections were performed. Extrapleural resection (when invasion was limited to the parietal pleura) and chest wall resection (in the case of invasion of deeper structures) were combined with pulmonary resection in 79 (39%) and 122 (61%) cases, respectively. Pathologic TNM stages were T3N0 in 116 (57.5%) cases, T3N1 in 52 (26%), T3N2 in 27 (13.5%), and T4N0-N1 in 6 (3%). A complete resection was achieved in 167 (83%) cases. Fourteen postoperative deaths (7%) occurred. One hundred thirty-nine patients (74%) underwent postoperative radiotherapy. Actuarial 5-year survival was 24% and 13% after complete and incomplete resection, respectively (p < 0.05). Actuarial 5-year survival after complete resection was 25% in T3N0 patients, 20% in T3N1, and 21% in T3N2. In completely resected patients, univariate and multivariate analyses identified three independent prognostic factors: nodal involvement, depth of parietal invasion, and age. Radiation therapy did not improve survival if a complete resection was possible. CONCLUSIONS: Completeness of resection, nodal involvement, depth of invasion, and age affect survival of patients with lung cancer invading the chest wall. N2 disease should not be considered a contraindication to surgery.

Management of empyema complicating lobectomy with superior vena cava replacement.

We present the case of a 49-year-old man with right upper lobe adenocarcinoma invading the right brachiocephalic vein and the origin of the superior vena cava. En bloc resection of right upper lobe with the involved venous segments was carried out through a median sternotomy. Venous pathway was reestablished with a Gore-Tex (W.L. Gore & Assoc, Flagstaff, AZ) prosthesis. Postoperative course was marked by right pneumonia complicated by empyema. The patient underwent thoracotomy with completion pneumonectomy and latissimus dorsi transposition to cover both the prosthesis and the bronchial stump, as well as to fill the cavity. A favorable outcome was observed and long-term survival achieved.

Open window thoracostomy followed by intrathoracic flap transposition in the treatment of empyema complicating pulmonary resection.

OBJECTIVE: Successful treatment of postoperative empyema remains a challenge for thoracic surgeons. We report herein our 12-year experience in the management of this condition by means of open window thoracostomy. METHODS: Open window thoracostomy was used in the treatment of 46 patients with empyema complicating pulmonary resection. A bronchopleural fistula was associated in 39 of 46 cases. Previous operations included pneumonectomy (n = 30), bilobectomy (n = 5), lobectomy (n = 9), and wedge resection (n = 2) performed for benign (n = 10) or malignant (n = 36) disease. In 10 patients open window thoracostomy was definitive because of patient death (n = 2), concomitant major illness (n = 2), tumor recurrence (n = 4), spontaneous closure (n = 1), or patient choice (n = 1). In 36 cases intrathoracic flap transposition was eventually performed. Muscular (n = 29), omental (n = 5), or combined muscular and omental (n = 2) flaps were used to obliterate the thoracostomy cavity and to close a possibly associated bronchopleural fistula. In 9 patients with postpneumonectomy cavities too wide to be filled by the available flaps, a limited thoracoplasty represented an intermediate step. RESULTS: Among patients treated with definitive open window thoracostomy, local control of the infection was achieved in all the survivors (8/8). After open window thoracostomy and subsequent flap transposition, success (definitive closure of the thoracostomy and, if present, of the bronchopleural fistula) was achieved in 27 (75. 0%) of 36 patients. Four initial failures could be salvaged by means of reoperation (initial reopening of thoracostomy and subsequent muscular or omental transposition). CONCLUSION: Open window thoracostomy followed by intrathoracic muscle or omental transposition represents a valid therapeutic option in patients with empyema complicating pulmonary resections.

Aspergilloma: a series of 89 surgical cases.

BACKGROUND: Surgery for pleuropulmonary aspergilloma is reputed to be risky. We reviewed our results, focusing attention on the postoperative complications. METHODS: During a 20-year period, 87 patients were operated on for pulmonary (86) or pleural (3) aspergillomas. Seventy-two percent of patients were complaining of hemoptysis. Eighty-nine resections were performed because there were two bilateral cases. Seventy percent of aspergillomas had developed in cavitation sequelaes from tuberculosis disease. Thirty-four patients had severe respiratory insufficiency that allowed us to perform only lobectomy (18), segmentectomy (2), or cavernostomy (14). RESULTS: Thirty-seven lobectomies (five with associated segmentectomies), two bilobectomies, 21 segmentectomies, 10 pneumonectomies, and 17 cavernostomies were performed. Total blood loss exceeded 1,500 mL in 14 cases, and 71% of patients required blood transfusion. There were five postoperative deaths (5.7%), related to respiratory failure (2), infectious complication (1), pulmonary embolus (1), and cardiorythmic disorder (1). Incomplete reexpansions were frequently seen in patients undergoing lobectomies or segmentectomies. No death or major complications occurred in asymptomatic patients. During follow-up, none of the patients had recurrent hemoptysis. CONCLUSIONS: Surgical resection of aspergilloma is effective in preventing recurrence of hemoptysis. It has low risk in asymptomatic patients and in the absence of underlying pulmonary disease. Incomplete reexpansion is frequent after lobectomy and segmentectomy, especially when there is underlying lung disease. Cavernostomy is an effective treatment in high-risk patients. Long-term prognosis is mainly dependent on the general condition of patients.

Extended resections for bronchogenic carcinoma invading the superior vena cava system.

BACKGROUND: Extended resection of non-small-cell lung cancer (NSCLC) involving the superior vena cava (SVC) system is infrequently performed and oncologic benefits are still uncertain. METHODS: From 1983 to 1996, 25 patients underwent resection of the SVC system for T4, NSCLC. RESULTS: A total of 12 pneumonectomies (48%), ten lobectomies (40%), and three wedge resections (12%) were performed. Seven patients had complete resection of the SVC with graft interposition, 12 patients underwent tangential resection of the SVC, and 1 patient had a pericardial patch; 5 patients underwent resection of right innominate and subclavian veins without vessel reconstruction. The lymph node status was N0 in 8 patients (32%), N1 in 3 (12%) and N2 in 14 patients (56%). Five patients (20%) underwent incomplete resection. Nine patients (36%) developed postoperative complications (36%) that were fatal in 3 patients (12%). At the completion of the study, 10 patients were still alive. The median survival was 11.5 months and the 5-year actuarial survival rate was 29%, with 4 patients alive at 5 years. CONCLUSIONS: The resection of the SVC system for direct involvement by T4, NSCLC can be performed in selected patients with an acceptable postoperative mortality. Even though no significant prognostic factors were observed, the patients who required a lobectomy with limited lymph node involvement seemed to benefit the most from surgery.

[Pulmonary lymphangioleiomyomatosis in a menopaused woman]. / Lymphangioléiomyomatose pulmonaire chez une femme ménopausée.

We report an unusual case of pulmonary lymphangioleiomyomatosis in a menopaused woman who had been taking estrogen hormone replacement therapy for several years. The characteristic feature of this uncommon disease is a proliferation of non-tumoral abnormal smooth muscle cells within the alveolar walls, and around the bronchi, lymph nodes and blood vessels. About twenty cases of pulmonary lymphangioleiomyomatosis have been described in menopaused women, who generally were taking estrogen hormone replacement therapy. This subpopulation does not appear to present any particular clinical, functional or radiographic features.

Defective priming of the phagocyte oxidative burst in a child with recurrent intracellular infections.

Human phagocytes (polymorphonuclear neutrophils and monocytes) play a critical role in host defense against invading microorganisms. Recent studies reported that circulating phagocytes undergo a final maturation process, in particular in terms of oxidative burst, during extravasation and migration to local sites of inflammation. This process is known as priming. We report here on a nine-year-old boy with successive disseminated infections due to intracellular microorganisms (Mycobacterium bovis, BCG, and Salmonella typhimurium). No T- or B-cell quantitative or qualitative defects were found. Polymorphonuclear neutrophil (PMN) migration and NADPH oxidase in PMNs and monocytes stimulated with various agents at optimal concentrations were normal, ruling out a leukocyte adhesion deficiency syndrome, a Chediak Higashi syndrome, and a chronic granulomatous disease. Nevertheless, the patient's PMNs and monocytes showed defective priming capacity, as measured by H(2)O(2) production after pretreatment with LPS (5 microg/mL for 30 min), TNFalpha (100 units/mL for 30 min), or IL-8 (50 ng/mL for 30 min) in response to bacterial N-formyl peptides (fMLP 10(-6) M for 5 min). In these conditions, H(2)O(2) production of PMNs and monocytes from the patient did not exceed that of the samples treated with fMLP or LPS alone, while the controls strongly produced H(2)O(2). Moreover, monocytes from the patient showed an impaired capacity to kill S. typhimurium in vitro. Such an impairment could be related at least in part to the priming deficiency of phagocyte oxidative burst. This case suggests, for the first time, that in vivo priming processes are critical in host defence against intracellular pathogens.

Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease targeting the skeletal muscle acetylcholine receptor. We have previously demonstrated a selection bias of CD4+ T cells expressing the Vbeta5.1 T-cell receptor gene in the thymus of HLA-DR3 patients with MG. To evaluate the pathogenicity of these cells, severe combined immunodeficiency mice engrafted with MG thymic lymphocytes were treated with anti-Vbeta5.1 antibody. Signs of pathogenicity (eg, acetylcholine receptor loss and complement deposits at the muscle end plates of chimeric mice) were prevented in anti-Vbeta5.1-treated severe combined immunodeficiency chimeras. Pathogenicity was mediated by autoantibodies against acetylcholine receptor. Thymic cells depleted of Vbeta5.1-positive cells in vitro before cell transfer were nonpathogenic, indicating that Vbeta5.1-positive cells are involved in the production of pathogenic autoantibodies. Acetylcholine receptor loss was prevented by Vbeta5.1 targeting in HLA-DR3 patients only, demonstrating specificity for HLA-DR3-peptide complexes. The action of the anti-Vbeta5.1 antibody involved both the in vivo depletion of Vbeta5.1-expressing cells and an increase in the interferon-gamma/interleukin-4 ratio, pointing to an immune deviation-based mechanism. This demonstration that a selective and specific T-helper cell population is involved in controlling pathogenic autoantibodies in MG holds promise for the treatment of MG.

Thrombosis of an idiopathic saccular azygos aneurysm.

We report a case of a large saccular idiopathic aneurysm of the azygos vein which was discovered totally thrombosed at operation. To our knowledge, such a case of thrombosis occurring in this exceptional aneurysm location has never been previously reported.

Prognostic factors and results after surgical treatment of primary sarcomas of the lung.

BACKGROUND: Primary sarcoma of the lung is a rare tumor. Our purpose was to study survival after resection and prognostic factors, which have been rarely reported. METHODS: In a 24-year period, we performed 20 complete resections and three exploratory thoracotomies only for primary lung sarcomas. One patient declined operation. Mean diameter of resected tumors was 9 cm (range, 4 to 18 cm). There were eight stage IB, eight stage IIB, one stage IIIA, and three stage IIIB. Sixty percent of patients with resected tumors received adjuvant therapy. Age, sex, resectability, tumor size, histologic cell type, stage, and adjuvant therapy were analyzed as predictors of survival. RESULTS: No postoperative deaths occurred. All 4 patients who had no resection died within 15 months. The 5- and 10-year actuarial survival after complete resection was 48%. The 5- and 10-year actuarial survival in stage IB was 83%, whereas the 4-year actuarial survival in stage IIB was 30% (p < 0.05). Complete resection and stage of disease were the sole significant prognostic factors. CONCLUSIONS: Complete resection of primary sarcoma of the lung, when feasible, can achieve prolonged survival, although almost half of the patients died of metastasis within 2 years of operation. Adjuvant therapy needs to be investigated.

[A retrospective study of 53 cases of resectable primary bronchopulmonary cancers associated with Pierre Marie syndrome]. / Etude rétrospective de 53 cancers broncho-pulmonaires primitifs résécables associés à un syndrome de Pierre Marie.

The prognosis of primary lung cancer associated with hypertrophic osteopulmonary arthropathy is not well known. Between July 1973 adn August 1995, we cared for 53 consecutive patients with resectable non-small-cell lung cancer associated with osteoplumonary arthropathy. There were 51 men and 2 women, mean age 56 years. In 83% of the cases the lung cancer was revealed by hypertrophic osteopulmonary arthropathy. The tumor generally involved the right lung (n = 38) and the upper lobe (n = 35). There was no peripheral or central predominance. Complete tumoral resection was performed in 47 patients, incomplete resection in 4 and exploratory thoracotomy in 2. The main histologies were adenocarcinoma (50%) and squamous cell carcinoma (40%). Among the 51 resected tumors, 27 were grade I, 5 grade II, 17 grade III and 2 grave IV. Overall 5-year survival was 39%, reaching 51% for grade I, 40% for grade II, 27% for grade III and 0% for grade IV. The pulmonary manifestations of hypertrophic osteopulmonary arthropathy regressed within the first postoperative hours in all the patients whose tumor was resected and in 1 of the 2 patients who underwent exploratory thoracotomy. AT follow-up, the hypertropic pulmonary arthropathy had disappeared in all resected patients except 1 with a grade I tumor. Tumor recurrence was proven in 18 resected patients, 5 of whom also had recurrent osteopulmonary arthropathy. Our results suggest that primary lung cancer associated with hypertrophic pulmonary arthropathy has characteristic features and that prognosis is comparable with primary lung cancer alone.

Survival and prognostic factors in patients undergoing parenchymal saving bronchoplastic operation for primary lung cancer: a series of 110 consecutive cases.

OBJECTIVE: The purpose of this study was to report our experience concerning bronchial sleeve lobectomy for treating bronchogenic cancer. METHOD: From 1980 to 1994, 110 patients underwent bronchial sleeve lobectomy for bronchogenic cancer. In 45 patients, preoperative investigations contraindicated pneumonectomy, whereas in 65 other patients, sleeve resection was performed without functional necessity. The most common procedures were sleeve lobectomy of the right upper lobe (64%), and of the left upper lobe (21%). Sixteen patients (15%) underwent additional arterial vascular resection. Seven patients had microscopic invasion of the bronchial margin without the possibility of further resection in six with regard to their limited respiratory function. Tumors were staged as follow: 32 stage IB (all T2 N0), 57 stage IIB (57T2 N1), and 17 stage IIIA (eight, T3N1; nine, T2N2), whereas four patients had an in situ cancer (four stage 0). RESULTS: Operative mortality was 2.75%. The 5- and 10-year actuarial survival rates were, respectively, 39 and 22% for the entire group. The 5-year actuarial survival rates were, 60% in stage IB, 30% in stage IIB, and 27% in stage IIIA. Four factors significantly influenced survival (P<0.05): nodal stage, arterial resection, invasion of the bronchial stump and poor functional respiratory status contraindicating pneumonectomy. CONCLUSIONS: In our experience, sleeve resection for stage I provides comparable survival to that of standard resection at equal stage. However, in patients with pathologically N1 disease, who can tolerate a pneumonectomy, a randomized study is mandatory to confirm that sleeve lobectomy can be performed without the risk of decreasing long-term survival. In our study, patients who required an associated vascular resection demonstrated a poor survival.

Completion pneumonectomy: experience in eighty patients.

OBJECTIVE: Because completion pneumonectomy is a procedure reputed to place patients at risk, we reviewed our results with the objective of identifying factors that influence complications and survival. METHODS: In a 25-year period, 80 completion pneumonectomies were performed after first operations for 17 cases of benign disease and 63 cases of lung cancer (89% stages I and II), with 7 of the latter patients receiving postoperative radiotherapy. Completion pneumonectomy was performed in 18 cases of benign disease and 62 cases of lung cancer: 28 second primary cancers, 26 recurrent cancers, 3 metastases, and 5 primary cancers in patients previously operated on for benign disease. RESULTS: No intraoperative deaths occurred. Postoperative mortality rates were 5% for the entire series, 6.4% for patients operated on for cancer, and 0% for patients operated on for benign diseases. Patients previously irradiated and those operated on for infectious disease were at risk for postoperative empyema and fistula formation. In the cancer treatment group the actuarial 5-year survival was 36%, without significant difference between patients with recurrent and second primary lung cancers. The actuarial 5-year survivals were 51% for patients with stage I disease, 42% for patients with stage II disease, and 18% for patients with stage IIIA disease (P <.05). CONCLUSIONS: Completion pneumonectomy can be performed with an acceptable operative mortality rate and offers a second chance for cure to patients with cancer. Patients previously irradiated and those requiring completion pneumonectomy for infectious benign disease are at risk for postoperative complications.

[Current indications and results of pulmonary decortication for nontuberculous chronic empyema]. / Indications actuelles et résultats des décortications pulmonaires pour pleurésies purulentes non tuberculeuses.

UNLABELLED: Pulmonary decortication for nontuberculous chronic empyema has become a rare operation, whose indications and results are now rarely analysed and discussed. The authors report a series of 40 consecutive decortications performed over a period of 15 years. PATIENTS: 40 patients treated by pulmonary decortication over 15 years for nontuberculous chronic empyema secondary to pneumonia (27 cases; 2/3 of cases), post-traumatic haemothorax (5 cases), iatrogenic infection after pleural tap (5 cases) and septicaemia (3 cases). Chronic empyema had been present for an average of 6 months (1 to 60 months). Decortication was performed for drainage of persistent pleural suppuration in 22 cases and to release the encysted lung in 18 cases. Decortication, always comprising parietal pleural stripping and visceral decortication, lasted an average of 3 hours (2 to 8 hours), and was accompanied by mean bleeding of 1 litre (of 200 ml to 3.41). RESULTS: 27 patients (67%) had an uneventful postoperative course, with drainage for 6 days and a mean hospital stay of 13 days. 13 patients (33%) developed various complications, mainly re-expansion defects (10 cases), responsible for pyothorax in 4 cases, 3 of which required secondary drainage. One patient died from intestinal obstruction in a context of peritoneal carcinomatosis (operative mortality: 2.5%). 25 patients were reviewed with a mean follow-up of 54 months, with complete pulmonary re-expansion in 23 cases (92%) and a residual pouch in 2 cases. Vital capacity (VC) was evaluated in 8 patients, with a mean improvement of 40% (15 to 66%) in 6 patients, stable VC in one patient, and a 25% reduction in the last patient, a smoker and with chronic bronchitis. CONCLUSION: Pulmonary decortication is an effective, but relatively major operation to treat chronic encysted empyema. Encystment must be prevented by effective drainage of empyema, now facilitated by the possibility of early videothoracoscopic pleural debridement.