NOX enzymes: potential target for the treatment of acute lung injury

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), is characterized by acute inflammation, disruption of the alveolar-capillary barrier, and in the organizing stage by alveolar pneumocytes hyperplasia and extensive lung fibrosis. The cellular and molecular mechanisms leading to the development of ALI/ARDS are not completely understood, but there is evidence that reactive oxygen species (ROS) generated by inflammatory cells as well as epithelial and endothelial cells are responsible for inflammatory response, lung damage, and abnormal repair. Among all ROS-producing enzymes, the members of NADPH oxidases (NOXs), which are widely expressed in different lung cell types, have been shown to participate in cellular processes involved in the maintenance of lung integrity. It is not surprising that change in NOXs' expression and function is involved in the development of ALI/ARDS. In this context, the use of NOX inhibitors could be a possible therapeutic perspective in the management of this syndrome. In this article, we summarize the current knowledge concerning some cellular aspects of NOXs localization and function in the lungs, consider their contribution in the development of ALI/ARDS and discuss the place of NOX inhibitors as potential therapeutical targe

Metastasis of a pleural mesothelioma to a hyperplastic stomach polyp: an increase of vimentin expression is seen during a gain in deciduoid morphology

Deciduoid mesothelioma is a rare variant of the epithelioid histotype spectrum, resembling decidua of gravid uterus. It is found in the peritoneum of young women, but also in the pleura of elderly people. Histotype plasticity from epithelioid to sarcomatoid mesothelioma may be considered as epithelial-mesenchymal transition (EMT). A full autopsy was performed and mesothelioma infiltrates were analysed by immunohistochemistry. The metastasis of an epithelioid pleural mesothelioma to a hyperplastic polyp of the stomach is presented in this autopsy case. Deciduoid morphology increased during tumour progression and metastasis. The increase in eosinophilic cytoplasm correlated with the upregulation of the intermediate filament vimentin. High expression of vimentin was found in both central and superficial periglandular regions of the polyp. High vimentin expression also can occur in epithelioid rather than sarcomatoid differentiation. Thus, although vimentin is considered to be the major EMT marker, additional pathways must regulate its expression

sCR1sLeX reduces lung allograft ischemia-reperfusion injury but does not ameliorate acute rejection

Background: Combined inhibition of complement and leukocyte adhesion by sCR1sLeX reduces lung allograft dysfunction up to 24 h. In the present study its effect on graft function and acute rejection was evaluated up to 5 days after experimental transplantation. Methods: Orthotopic single left lung transplantation was performed in 35 male rats (Brown Norway to Fischer 344) after a total ischemic time of 20 h. Two groups were assessed after 1, 3, and 5 days post-transplant, respectively (n=5 per group and time point): controls vs. recipients which received 10 mg/kg sCR1sLeX 15 min prior to reperfusion. In addition, five animals received 10 mg/kg per day sCR1sLeX for 5 days. For blood gas analysis of the graft, the contralateral lung was occluded for 5 min to assess graft function. Lung grafts were flushed, and histological grading was performed in blinded fashion according to the International Society for Heart and Lung Transplantation criteria. Results: Graft PaO2 in recipients treated with sCR1sLeX was superior on day 1 (383±118 vs. 56±15 mmHg; P≪0.0001) and day 3 (446±48 vs. 231±108 mmHg; P≪0.0001). Five days after transplantation, no difference in PaO2 was found (61±28 vs. 83±31 mmHg; P=0.59). Repeated treatment with sCR1sLeX for 5 days did not improve PaO2 (64±5 mmHg; P=0.65 vs. control; P=0.93 vs. sCR1sLeX). At any time point, there was no difference in the degree of rejection between groups. Conclusions: In this model sCR1sLeX provided marked improvement of graft function up to 3 days, but inhibition of both complement system and selectin dependent leukocyte adhesion failed to protect against acute rejectio

Pulmonary blastoma: report of five cases and identification of clinical features suggestive of the disease

Objective: Identification of clinical features suggestive of pulmonary blastoma (PB) through a retrospective comparison with cases of non-small cell lung cancer (NSCLC) operated during the same period. Methods: Between 1977 and 1999, five patients were operated for PB at Geneva University Hospital (four women and one man, aged 32-46 years - mean 36.8) versus 1913 consecutive patients (1558 men and 355 women, mean age 61.2) for primary NSCLC. In the PB subgroup (0.3%), the pulmonary tumor was single, located in an upper lobe in all but one instance, and measured between 5 and 13 cm (mean 9.6), whereas in the total NSCLC group, 27% of patients had tumors <3 cm (T1), evenly distributed in both lungs. All but one PB patients were symptomatic, compared to 45% in the NSCLC group. Results: The five patients with PB underwent curative pulmonary excisions (lobectomy in three and pneumonectomy in two) with mediastinal lymph node sampling. Pathological examination revealed extensive tumor necrosis in four, and N2 lymph node metastases in four (in the total NSCLC group, N2 disease was diagnosed in 21%). Postoperatively, three PB patients received radio- and/or chemotherapy. Four patients died between six and 30 months after the operation (mean 15), whereas 5-year survival in the NSCLC group was 32%, with a median survival of 3.7 years; the fifth patient is alive 28 months later, without any sign of recurrence. Conclusions: Compared to operated NSCLC, PB are rare, large, and symptomatic tumors; they affect younger patients and carry a worse prognosi

Delayed but Complete Response following Oral Temozolomide Treatment in Melanoma Leptomeningeal Carcinomatosis

Isolated leptomeningeal recurrence of melanoma is rare, occurring in 2% of patients with central nervous system involvement secondary to melanoma. The optimal treatment of leptomeningeal carcinomatosis (LMC) in melanoma has not yet been determined and remains a major challenge. We report a melanoma patient who presented with isolated LMC in the form of a new-onset weakness of the lower limbs, paresthesia of the left hand and foot, lumbago and headache. A lumbar puncture and spinal MRI confirmed LMC. The patient was treated with temozolomide 75 mg/m2/day on a 4 weeks on/2 weeks off schedule. After an initial transient clinical deterioration, the patient showed a complete radiological response as well as a dramatic improvement in quality of life. The encouraging clinical response reported here suggests that dose-intensified temozolomide might have significant activity in the treatment of leptomeningeal dissemination of melanoma and may be a valid treatment option for patients who have not been previously exposed to this agent. Moreover, this treatment regimen is extremely well tolerated and obviates the need for repeated intrathecal administrations of chemotherapeutic agents, which are often not well tolerated by patients who have significant co-morbidities due to their disease. As illustrated in this case, response to temozolomide may occur in a delayed manner, highlighting the importance of following temozolomide treatment long enough before determining that it is inefficient in a given patient

Primary Hyperparathyroidism: Can Parathyroid Carcinoma Be Anticipated on Clinical and Biochemical Grounds? Report of Nine Cases and Review of the Literature

Background: Parathyroid carcinoma (PC) mimics benign primary hyperparathyroidism (PHP), but the diagnosis of PC is seldom available at the time of the first operation. Because PC is plagued by recurrences usually beyond cure, one may wonder whether some of these could be prevented by more extensive resections initially, i.e., if the diagnosis of PC were available at that time. Methods: Over a 25-year period, 311 consecutive patients with PHP underwent operation in our department: 302 had benign disease (adenomas or hyperplasias), and 9 had PC. Several clinical parameters, serum calcium and parathyroid hormone (PTH) levels, and the weight of the parathyroid tumor removed were compared in both groups. Receiver operating characteristic curves and logistical regression analyses were used to distinguish PC from benign PHP. Results: Eight of 9 patients with PC had symptoms, versus 238 (79%) of 302 with benign PHP (not significant). In the PC subgroup, serum calcium and PTH levels and the tumor weights of the parathyroid glands removed were significantly higher than in the benign PHP cohort, even if these three parameters were regularly flawed by low positive predictive values (14%, 20%, and 15%, respectively). Conclusions: Serum calcium, PTH levels, and tumor weights were significantly greater in the PC subgroup, even if not invariably in a discriminatory way. However, when PTH is <4 times the upper limit of normal and tumor weight is <1.9 g, the probability of PC is ni

Diagnostic changes as a reason for the increase in papillary thyroid cancer incidence in Geneva, Switzerland

Objective: Several studies have reported upward incidence trends of papillary thyroid cancer. It is unclear whether these trends reflect a real risk increase, by some attributed to iodine supplementation, or an artificial one, due to increased diagnostic activity or changed histological criteria. This study examines if these artificial factors explain the increased papillary thyroid cancer incidence in the Swiss canton of Geneva. Methods: All thyroid carcinomas (n = 436) recorded between 1970 and 1998 at the Geneva Cancer Registry were considered. European age-adjusted incidence trends were estimated using linear regression analysis. For papillary cancers we evaluated diagnostic modalities and way of presentation (in particular microcarcinoma < 1 cm or silent carcinoma). In addition, we reviewed the histological slides of follicular carcinomas. Results: Papillary thyroid cancer incidence increased significantly from 0.7 to 1.8/100,000 for men and from 3.1 to 4.3/100,000 for women between 1970-74 and 1995-98. The proportion of microcarcinomas and silent carcinomas increased from 17% to 24% between 1970-79 and 1990-98. At histological review, follicular cancers were more often reclassified as papillary cancer for cases diagnosed between 1970 and 1979 than for cases diagnosed between 1990 and 1998 (45% vs 25%, p = n.s.). Conclusions: The increasing papillary thyroid cancer incidence seems mainly due to changes in histological diagnostic criteria and, to a lesser extent, to increased diagnostic activity. If confirmed, the results of this study indicate that fears of increasing incidence rates of papillary thyroid cancer should not prevent implementation of adequate programs of iodine supplementation in the many areas where iodine deficiency still prevail

Bird breeder's disease: a rare diagnosis in young children

Bird breeder's lung disease is the most common form of hypersensitivity pneumonitis and is a rare entity in young children. We report three cases of children under 7 years of age in whom this diagnosis was confirmed early in the course of the disease. Three children aged 4.4 to 6.5 years presented with dry cough lasting for more than 1 month, dyspnoea, variable loss of appetite, weight loss, fatigue, fever and mild signs of respiratory distress. Chest X-ray films and CT scans showed a bilateral micronodular infiltrate. All three patients had strongly suggestive bronchoalveolar lavage fluid findings with lymphocytosis; two had elevated cell counts and decreased CD4/CD8 ratios. Lung biopsy confirmed the diagnosis in all children. Contact with allergens was identified in all children: two had spent holidays close to a farm in the previous month and one was living next to a pigeon house. In all children, avian precipitins were positive. The symptoms rapidly resolved after allergen avoidance and treatment with oral prednisone. Corticoid treatment was given between 11 and 15 weeks. One child relapsed and required long-term low-dose corticotherapy for 1 year. Lung function tests were normal in all three patients, 3.9 to 5.7 years after diagnosis. Conclusion:Bird breeder's lung disease is a rare entity but should be considered in young children presenting long lasting cough. While rapid allergen exclusion and start of treatment can avoid the evolution into irreversible lung fibrosis, clinical and biological evolution should be monitored carefully even after stopping corticoid treatment because of the possibility of relaps

Establishment of permanent cell lines purified from human mesothelioma: morphological aspects, new marker expression and karyotypic analysis

This study reports the establishment of three major subtypes of human mesothelioma cells in tissue culture, i.e. the epithelioid, sarcomatoid and biphasic forms, and compares their phenotypic and biological characteristics. Primary cells isolated from biopsies or pleural exudates were subcultured for over 50passages. We evaluated immunoreactivity using various mesothelial markers related to histological patterns of these cell lines. For epithelioid cells, calretinin and cytokeratin were found to be useful and easily interpretable markers as for control mesothelial cells. The biphasic form was only partially positive and the sarcomatoid type negative. Vimentin was expressed by all cell lines. BerEP4, a specific marker for adenocarcinoma, was negative. Interestingly, while the macrophage marker CD14 was negative, immunoreactivity for a mature macrophage marker (CD68) was expressed by all cell types, suggesting that this marker might constitute an additional tool useful in the differential diagnosis of mesothelioma. At the ultrastructural level, a cell surface rich in microvilli confirmed their mesothelial origin. PCR analysis revealed that none of the cell lines contained SV40 DNA. Karyotypic analyses showed more complex abnormalities in the epithelioid subtype than in the sarcomatoid form. These cell lines may be useful in the study of cellular, molecular and genetic aspects of the diseas

Cytopathological Aspects of Breast Discharge in Women without Palpable Breast Mass in Yaounde, Cameroon

Objective: Describe cytopathological characteristics of nipple discharge.Methods: Four years retrospective cross- sectional study in Yaounde, Cameroon. We included all complete files of adult women with cytopathological analyses of breast discharge without palpable mass. Exclusion Criteria: Pregnant or breastfeeding women, puerperium and first 4 weeks post- abortum. Cytological modifications were classified as benign or malignant. Results: We retained 153 cases. Mean age was 41.2+/-14.4 years. Cytological modifications were malignant in 27 (17.65%) and benign in 126 (82.35%) cases. Of the 27 malignant cases, 18 (11.77%) were carcinomas and 9 (5.88%) were lymphomas. Upon histological analyses, all suspected lymphomas were confirmed while only 1 case of suspected carcinoma turned to be an atypical ductal hyperplasia. Of the 126 cases with benign modifications, 54 (35.29%) had inflammatory lesions, 48 (31.38%) had non inflammatory lesions and 24 (15.69%) had papillomas. Conclusion: Cytology of breast discharge can enhance early detection of breast cancers