Expression of surfactant associated protein-A and Clara cell 10 kilodalton mRNA in neoplastic and non-neoplastic human lung tissue as detected by in situ hybridization.

Two markers for the progenitor cells of peripheral airways and their tumors are the 10 kilodalton (kd) Clara cell protein and the major surfactant associated protein-A (SP-A). We used the RNA-RNA in situ hybridization technique to study expression of the genes encoding these proteins at the cellular level in 19 pairs of non-neoplastic and neoplastic tissues from resected human lungs. Our results show that in non-neoplastic lung tissue, the Clara 10 kd protein gene was expressed in nonciliated cells of both bronchial and bronchiolar epithelium, indicating that, in contrast to previous assumptions, cells with Clara cell-like differentiation in humans may not be restricted to bronchiolar cells. The incidence of Clara 10 kd protein gene expression, as detected in lung carcinomas (1 out of 19 cases positive) was less than expected based on previous ultrastructural reports. The SP-A gene was strongly expressed in normal alveolar type II cells in non-neoplastic lung and, at higher levels, in hyperplastic cells. In addition, SP-A mRNA expression was observed in scattered bronchial and bronchiolar epithelial cells in 40% of the airways examined. Five out of 17 lung tumors, all of which were adenocarcinomas, were positive for SP-A expression, albeit generally less intense than type II cells. This expression was seen in carcinomas with papillolepidic as well as solid and glandular growth patterns. Our findings provide new insights into the peripheral airway cell differentiation.     

The effect of RG 12525 on leukotriene D4-mediated pulmonary responses in guinea pigs

RG 12525 (5-(2-[4-quinolin-2-yl)methoxy] phenoxymethyl)benzyl tetrazole) is under investigation as a specific inhibitor of leukotriene D₄ (LTD₄). The present studies examine the effect of orally administered RG 12525 on LTD₄ mediated pulmonary responses in three separate guinea pig models. The compound inhibited antigen-induced mortality in the systemic anaphylaxis model with an ED₅₀ (95% confidence interval)=2.2 (0.8–6.4) mg/kg. In this model, the activity half-life of RG 12525 was shown to be 6.5 hours and the compound offered significant protection within 15 minutes of administration. RG 12525 also protected against LTD₄-induced bronchoconstriction in a model measuring changes in pulmonary function with an ED₅₀=0.6 (0.4–1.0) mg/kg. The same level of activity was observed in a similar model which monitored changes in pulmonary function in response to exogenous antigen in actively-sensitized guinea pigs. Together, these data indicate that RG 12525 is a potent, orally active LTD₄ antagonist which possesses the requisite profile for potential clinical development.     

Bileaflet Aortic Valve Prosthesis Pivot Geometry Influences Platelet Secretion and Anionic Phospholipid Exposure

The clinical histories of the Medtronic Parallel (MP) and St. Jude Medical (SJM) Standard valves suggest pivot geometry influences the thrombogenic characteristics of bileaflet prostheses. This work studied the effects of various pivot geometries on markers of platelet damage in a controlled, in vitro apparatus. The Medtronic Parallel valve, two St. Jude Medical valves, and two demonstration prostheses were used to study the effects of bileaflet pivot design, gap width, and size on platelet secretion and anionic phospholipid expression during leakage flow. A centrifugal pump was used to drive blood through a circuit containing a bileaflet prosthesis. Samples were taken at set time intervals after the start of the pump. These samples were analyzed by cell counting, flow cytometry, and enzyme-linked immunosorbant assay. No significant differences were observed in platelet secretion or anionic phospholipid expression between experiments with the SJM 27 Standard regular leaker, the SJM 20 regular leaker, and the MP 27 valves. Significant differences in platelet secretion and anionic phospholipid expression were observed between a SJM 27 Standard regular leaker and a SJM 27 high leaker valve. These studies suggest that leakage gap width within bileaflet valve pivots has a significant effect on platelet damage initiated by leakage flow. © 2001 Biomedical Engineering Society. PAC01: 8719Uv, 8719Tt, 8380Lz, 8768+z     

The clinical significance of stool isolates of aeromonas

The purpose of this study was to determine the clinical significance of different Aeromonas species isolated from stool. During a 17-month period, 29 strains of Aeromonas were isolated and identified to species with the following results: 22, A. caviae, 5, A. hydrophila, and 2, A. sobria. Clinical significance was determined independently of knowledge of speciation result. Nineteen isolates represented colonization, implying that Aeromonas can be recovered from the gastrointestinal tract without causing primary disease. The remaining 10 isolates were of indeterminate significance and may have played a role in infection, but pertinent tests to rule out other enteric pathogens had not been done. A correlation between species and clinical significance could not be established. Antimicrobial susceptibility testing was performed on the 29 isolates. A. caviae showed an unexpected resistance to cefazolin and cefoxitin, whereas representatives of all three species displayed resistance to trimethoprim/sulfamethoxazole.     

The histopathologic spectrum in Mycobacterium marinum infection

Review of nine culture-positive cases of Mycobacterium marinum infection revealed a broad range in the histopathologic features of lesions produced by this organism. Four synovial lesions and five cutaneous infections were observed. A range of inflammatory changes were seen in both synovial and skin lesions, varying from mostly acute inflammation with suppuration to a more chronic process with numerous, well-formed granulomas. Organisms were observed in the biopsy sections of only one of the nine cases. Therefore, culture of the biopsy tissue at 30 degrees C is crucial in establishing the diagnosis. These cases emphasize the importance of considering mycobacterial infection and performing cultures even when granulomatous changes in the synovium or skin are subtle.     

Pulmonary atypical carcinoid: predictors of survival in 106 cases

Pulmonary neuroendocrine tumors (NE) include a spectrum of tumors from typical carcinoid (TC) to atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). Little is known about prognostic predictors for AC because of its rarity. Survival analysis was performed on 106 ACs with clinical follow-up from the AFIP and the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). The tumors fulfilled the 1999 WHO/IASLC criteria for AC of a NE tumor with a mitotic rate of 2 to 10 per 2 mm(2) of viable tumor or coagulative necrosis. Multiple clinical and histologic features were analyzed by Kaplan-Meier and Cox regression analysis. Of the clinical features, higher stage (P = .003) and a tumor size of 3.5 cm or greater (P = .003) were associated with a worse prognosis. Features that were histologically unfavorable by univariate analysis were mitotic rate (P =.002), pleomorphism (P = .018), and aerogenous spread (P =.007). Histologically favorable features by univariate analysis were the presence of palisading (P = .008), papillary (P = .039), pseudoglandular (P =.026), and rosette (P = .022) patterns. Female gender showed a trend toward a poorer prognosis (P =.085) and was included in the multivariate model. Multivariate analysis stratified for stage showed mitoses (P<.001), a tumor size of 3.5 cm or greater (P =.017), and female gender (P =.012) to be the only negative independent predictors of prognosis and the presence of rosettes (P = .016) to be the only independent positive predictor. We further divided the AC into subgroups of low (2 to 5 mitoses/2 mm(2)) and high (6 to 10 mitoses/2 mm(2)) mitotic rate and compared the survival with TC and with LCNEC. Within the category of AC, the patients with a higher mitotic rate had a significantly worse survival than those with a lower mitotic rate (P<.001) stratified for stage. Five- and 10-year survival rates for AC (61% and 35%, respectively) stratified for stage were significantly worse than for TC and better than that for LCNEC and SCLC. Chemotherapy or radiation therapy was given in 12 of 52 and 14 of 52 cases, respectively, but the data were insufficient to evaluate tumor response. We conclude that AC is an aggressive neuroendocrine neoplasm with survival intermediate between TC and LCNEC and SCLC. Higher mitotic rate, tumor size of 3.5 cm or greater, female gender, and presence of rosettes are the only independent predictors of survival. Surgical resection remains the treatment of choice, and the role of chemotherapy and radiation therapy remains to be proven.     

Enhanced Pseudomonas aeruginosa biofilm development mediated by human neutrophils

Cystic fibrosis (CF) lung disease features persistent neutrophil accumulation to the airways from the time of infancy. CF children are frequently exposed to Pseudomonas aeruginosa, and by adulthood, 80% of CF patients are chronically infected. The formation of biofilms is a particularly important phenotypic characteristic of P. aeruginosa that allows for bacterial survival despite aggressive antibiotic therapy and an exuberant immune response. Here, we show that the presence of neutrophils enhances initial P. aeruginosa biofilm development over a period of 72 h through the formation of polymers comprised of actin and DNA. F-actin was found to be a site of attachment for P. aeruginosa. These actin and DNA polymers are present in CF sputum, and disruption of the polymers dispersed the associated P. aeruginosa cells and reduced biofilm development. These findings demonstrate a potential maladaptation of the primary innate response. When the host fails to eradicate the infection, cellular components from necrotic neutrophils can serve as a biological matrix to facilitate P. aeruginosa biofilm formation.     

Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage

CONTEXT: The histologic patterns of diffuse alveolar damage (DAD), bronchiolitis obliterans with organizing pneumonia (BOOP), and eosinophilic pneumonia (EP) are well-recognized histologic patterns of lung injury associated with an acute or subacute clinical presentation. We have recognized acute fibrinous and organizing pneumonia (AFOP) as a histologic pattern, which also occurs in this clinical setting but does not meet the classic histologic criteria for DAD, BOOP, or EP and may represent an underreported variant. OBJECTIVE: To investigate the clinical significance of the AFOP histologic pattern and to explore its possible relationship to other disorders, including DAD and BOOP. DESIGN: Open lung biopsy specimens and autopsy specimens were selected from the consultation files of the Armed Forces Institute of Pathology, which showed a dominant histologic pattern of intra-alveolar fibrin and organizing pneumonia. Varying amounts of organizing pneumonia, type 2 pneumocyte hyperplasia, edema, acute and chronic inflammation, and interstitial widening were seen. Cases with histologic patterns of classic DAD, BOOP, abscess formation, or eosinophilic pneumonia were excluded. To determine the clinical behavior of patients with this histologic finding, clinical and radiographic information and follow-up information were obtained. Statistical analysis was performed using Kaplan-Meier and chi(2) analysis. RESULTS: Seventeen patients (10 men, 7 women) with a mean age of 62 years (range, 33-78 years) had acute-onset symptoms of dyspnea (11), fever (6), cough (3), and hemoptysis (2). Associations believed to be clinically related to the lung disease included definitive or probable collagen vascular disease (3), amiodarone (1), sputum culture positive for Haemophilus influenza (1), lung culture positive for Acinetobacter sp. (1), lymphoma (1), hairspray (1), construction work (1), coal mining (1), and zoological work (1). Six patients had no identifiable origin or association. Follow-up revealed 2 clinical patterns of disease progression: a fulminate illness with rapid progression to death (n = 9; mean survival, 0.1 year) and a more subacute illness, with recovery (n = 8). Histologic analysis and initial symptoms did not correlate with eventual outcome, but 5 of the 5 patients who required mechanical ventilation died (P =.007). CONCLUSIONS: Acute fibrinous and organizing pneumonia is a histologic pattern associated with a clinical picture of acute lung injury that differs from the classic histologic patterns of DAD, BOOP, or EP. Similar to these patterns of acute lung injury, the AFOP pattern can occur in an idiopathic setting or with a spectrum of clinical associations. The overall mortality rate is similar to DAD and therefore may represent a histologic variant; however, AFOP appears to have 2 distinct patterns of disease progression and outcome. The need for mechanical ventilation was the only parameter that correlated with prognosis. None of the patients with a subacute clinical course required mechanical ventilation.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.