Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models.

Although fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice its involvement in human cancer is not well characterized. Here we report that FGF19 and its cognate receptor FGF receptor 4 (FGFR4) are coexpressed in primary human liver, lung and colon tumors and in a subset of human colon cancer cell lines. To test the importance of FGF19 for tumor growth, we developed an anti-FGF19 monoclonal antibody that selectively blocks the interaction of FGF19 with FGFR4. This antibody abolished FGF19-mediated activity in vitro and inhibited growth of colon tumor xenografts in vivo and effectively prevented hepatocellular carcinomas in FGF19 transgenic mice. The efficacy of the antibody in these models was linked to inhibition of FGF19-dependent activation of FGFR4, FRS2, ERK and beta-catenin. These findings suggest that the inactivation of FGF19 could be beneficial for the treatment of colon cancer, liver cancer and other malignancies involving interaction of FGF19 and FGFR4.

Structural changes to airway smooth muscle in cystic fibrosis.

BACKGROUND: Chronic airway obstruction is characteristic of cystic fibrosis (CF) but there are few studies of airway smooth muscle remodelling in CF. METHODS: Airway smooth muscle content and mean airway smooth muscle cell size were measured by applying design-based stereology to bronchoscopic biopsy specimens obtained from seven subjects with CF and 15 healthy controls. RESULTS: The smooth muscle content increased by 63% in subjects with CF (mean (SD) 0.173 (0.08) v 0.106 (0.042) mm(3) smooth muscle/mm(3) submucosa, mean difference -0.067; 95% CI -0.12 to -0.013, p = 0.017) but there was no increase in mean cell size (2705 (351) v 2654 (757) microm(3), mean difference -51; 95% CI -687 to 585, p = 0.87). CONCLUSIONS: These findings indicate hyperplasia of airway smooth muscle cells without hypertrophy and suggest that accumulation of airway smooth muscle cells may contribute to airway narrowing and bronchial hyperresponsiveness in CF.

Multislice CT cholangiography without biliary contrast agent: technique and initial clinical results in the assessment of patients with biliary obstruction.

Our objective was to describe our technique for multislice CT cholangiography without cholangiographic contrast agent, and to present our preliminary clinical results. Thirty-seven patients with suspected biliary obstruction were studied. A multislice CT unit was used with the following technical parameters: 2.5-mm collimation; 7.5-mm/s table speed; pitch 6; 0.8-s rotation time; 300 mA; 120 kVp; 18- to 24-s scan time; scan volume ranging from the hepatic dome to below the pancreatic head; 70-s delay after injection of 150 ml of iodinated contrast agent at 4 ml/s. No biliary contrast material was given; oral iodinated contrast agent was administered to opacify bowel loops. Axial, multiplanar reformatted, and minimum intensity projection images were evaluated. The CT findings were compared with the gold standard techniques: endoscopic retrograde cholangiography (ERCP) in 30 patients, percutaneous transhepatic cholangiography in 5, and intraoperative cholangiography in 2. In 5 patients with ampullary lesions biopsy was made during ERCP, 9 underwent surgery, and 11 US-guided fine-needle aspiration. Bile ducts appeared hypodense within the surrounding enhanced structures. Regarding the site of obstruction, agreement between multislice CT and conventional cholangiography was observed in all cases. One patient presented negative findings on both CT and ERCP. In 31 of 36 (86%) patients, multislice CT cholangiography without cholangiographic contrast agent correctly assessed the cause of bile duct obstruction. Multislice CT cholangiography without cholangiographic contrast agent seems to be a promising diagnostic tool in the assessment of patients with bile duct obstruction.

Allergen challenge causes inflammation but not goblet cell degranulation in asthmatic subjects.

BACKGROUND: An allergen challenge to the airways of sensitized mice causes eosinophilic airway inflammation and degranulation of goblet cells, which lead to airway obstruction. However, whether allergen challenge causes a similar pattern of airway inflammation and goblet cell degranulation in human beings is unknown. OBJECTIVE: The purpose of this study was to determine whether allergen challenge increases airway inflammatory cells and causes goblet cell degranulation in human subjects with asthma. METHODS: In bronchial biopsy specimens taken from 8 asthmatic subjects at 1 and 24 hours after allergen challenge, we measured eosinophil and neutrophil numbers as indicators of inflammation. We also measured goblet cell mucin stores and the amounts of secreted mucin in bronchial lavage as indicators of goblet cell degranulation. RESULTS: Airway eosinophil numbers at both 1 and 24 hours after allergen challenge were twice as high as those after diluent challenge. Changes in neutrophil numbers were smaller and statistically insignificant. Goblet cell mucin stores measured in tissue stained with alcian blue/periodic acid-Schiff did not decrease significantly from baseline to 1 hour and actually tended to increase at 24 hours. This increase was significant in the subgroup of subjects with normal stored mucin levels at baseline. Mucin-like glycoprotein concentrations in bronchial lavage did not change significantly at either time point. CONCLUSION: Although allergen challenge in asthmatic subjects increases airway eosinophil numbers as early as 1 hour after challenge, this inflammatory response does not cause goblet cell degranulation. In fact, in subjects with normal baseline mucin stores, allergen challenge increases goblet cell mucin stores.

A novel method of gene transcript profiling in airway biopsy homogenates reveals increased expression of a Na+-K+-Cl- cotransporter (NKCC1) in asthmatic subjects.

Comprehensive and systematic analysis of airway gene expression represents a strategy for addressing the multiple, complex, and largely untested hypotheses that exist for disease mechanisms, including asthma. Here, we report a novel real-time PCR-based method specifically designed for quantification of multiple low-abundance transcripts using as little as 2.5 fg of total RNA per gene. This method of gene expression profiling has the same specificity and sensitivity as RT-PCR and a throughput level comparable to low-density DNA microarray hybridization. In this two-step method, multiplex RT-PCR is successfully combined with individual gene quantification via real-time PCR on generated cDNA product. Using this method, we measured the expression of 75 genes in bronchial biopsies from asthmatic versus healthy subjects and found expected increases in expression levels of Th2 cytokines and their receptors in asthma. Surprisingly, we also found increased gene expression of NKCC1--a Na+-K+-Cl- cotransporter. Using immunohistochemical method, we confirmed increased protein expression for NKCC1 in the asthmatic subject with restricted localization to goblet cells. These data validate the new transcriptional profiling method and implicate NKCC1 in the pathophysiology of mucus hypersecretion in asthma. Potential applications for this method include transcriptional profiling in limited numbers of laser captured cells and validation of DNA microarray data in clinical specimens.

Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression.

Excessive airway mucus is an important cause of morbidity and mortality in asthma, but the relationship between accumulation of mucus and goblet cell size, number, and function is incompletely understood. To address these questions, stored mucin in the epithelium and goblet cell size and number were measured morphometrically, and mucin gene expression was measured by polymerase chain reaction and immunohistochemistry in endobronchial biopsies from 13 subjects with mild and moderate asthma and from 12 healthy control subjects. Secreted mucin was measured in induced sputum. We found that stored mucin in the airway epithelium was three times higher than normal in the subjects with asthma (p < 0.005). Goblet cell size was similar in both groups, but goblet cell number was significantly higher in the subjects with asthma (93,043 +/- 15,824 versus 41,959 +/- 9,230/mm3, p < 0.05). In mild asthma (FEV1 > or = 80% pred, n = 7), the level of stored mucin was as high as in moderate asthma (FEV1 < 80% pred, n = 6), but the level of secreted mucin was significantly lower (28.4 +/- 6.3 versus 73.5 +/- 47.5 microg/ml, p < 0.05). Secreted mucin was inversely correlated with stored mucin for the whole asthma group (rs = -0.78, p = 0.007). MUC5AC was the predominant mucin gene expressed in healthy subjects and subjects with asthma, and MUC5AC protein was increased in the subjects with asthma. We conclude that even mild asthma is associated with goblet cell hyperplasia and increased stored mucin in the airway epithelium, whereas moderate asthma is associated with increased stored mucin and secreted mucin. These findings suggest that acute degranulation of hyperplastic goblet cells may represent a mechanism for asthma exacerbations in mild and moderate asthma and that chronic degranulation of goblet cells may contribute to chronic airway narrowing in moderate asthma.

Epithelial desquamation in asthma: artifact or pathology?

To determine whether the denudation of the bronchial epithelium observed in endobronchial biopsies from asthmatic subjects is a true pathologic feature or an artifact of tissue sampling, we analyzed epithelial integrity in bronchial biopsies from 14 subjects with mild and moderate asthma and 12 healthy subjects. In each subject, 4 to 8 bronchial biopsies were taken from large airways during bronchoscopy, fixed in 4% paraformaldehyde, embedded in glycomethacrylate, cut into 2-microM sections, and stained with toluidine blue. A x4 image of each biopsy was copied to a computer file using a video camera, and lines were drawn and measured along the basement membrane underlying areas completely denuded of overlying epithelium, areas covered by a single layer of basal cells, and areas of intact epithelium. We found that the percentage of basement membrane that was denuded of epithelium was similar in the healthy and asthmatic subjects (14.8 +/- 11.8 versus 11.4 +/- 9.8% respectively, p = 0.38); the percentage of basement membrane that was covered by a single layer of basal cells was also similar in the two groups (46.4 +/- 11.0 versus 54.5 +/- 9.8%, respectively, p = 0. 11). In the asthmatic subjects, we found no significant correlation between the percentage of basement membrane covered by denuded epithelium or by a single layer of basal cells and the FEV(1) percentage of predicted or the PC(20) methacholine. We conclude that denudation of bronchial epithelium in endobronchial biopsies from asthmatic subjects with stable mild and moderate disease is an artifact of tissue sampling and is not a true pathologic feature of the disease, and that the extent of airway epithelial denudation is not correlated with the severity of airway narrowing or the severity of bronchial hyperresponsiveness.

Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1.

Members of the integrin family of adhesion receptors mediate both cell-cell and cell-matrix interactions and have been shown to play vital roles in embryonic development, wound healing, metastasis, and other biological processes. The integrin alpha9beta1 is a receptor for the extracellular matrix proteins osteopontin and tenacsin C and the cell surface immunoglobulin vascular cell adhesion molecule-1. This receptor is widely expressed in smooth muscle, hepatocytes, and some epithelia. To examine the in vivo function of alpha9beta1, we have generated mice lacking expression of the alpha9 subunit. Mice homozygous for a null mutation in the alpha9 subunit gene appear normal at birth but develop respiratory failure and die between 6 and 12 days of age. The respiratory failure is caused by an accumulation of large volumes of pleural fluid which is rich in triglyceride, cholesterol, and lymphocytes. alpha9(-/-) mice also develop edema and lymphocytic infiltration in the chest wall that appears to originate around lymphatics. alpha9 protein is transiently expressed in the developing thoracic duct at embryonic day 14, but expression is rapidly lost during later stages of development. Our results suggest that the alpha9 integrin is required for the normal development of the lymphatic system, including the thoracic duct, and that alpha9 deficiency could be one cause of congenital chylothorax.

Effects of azithromycin on ozone-induced airway neutrophilia and cytokine release.

Exposure of humans to ozone causes increased neutrophils and inflammatory cytokines in airway lining fluid. Recent research shows that macrolide antibiotics may reduce interleukin (IL)-8 production by bronchial epithelial cells and inhibit neutrophil chemotaxis. A double-blind, cross-over study was performed in which 12 healthy subjects underwent two separate 4-h exposures to 0.2 parts per million ozone while exercising intermittently. In the 73.5 h before exposure, subjects were pretreated with either 1,250 mg azithromycin or placebo. Sputum induction conducted 74 h pre- and 18 h post-exposure was used to measure total cells, per cent neutrophils, IL-6, and IL-8. There were significant (p<0.05) pre- to post-exposure increases in total cells, neutrophils, IL-6 and IL-8 in both the azithromycin and placebo arms. However, no significant differences were found between azithromycin and placebo conditions in the post- minus pre-exposure value for these variables. The results suggest that in healthy subjects, in the design used, azithromycin, in usual clinical doses, does not have anti-inflammatory effects on human airways as indicated in the measured variables.

[Keratitis caused by Acanthamoeba in patients with contact lenses]. / Queratitis producida por Acanthamoeba en pacientes portadores de lentes de contacto.

BACKGROUND: Keratitis by Acanthamoeba is a severe infectious complication which may be derived from the use and bad preservation of contact lens. This disease la increasingly more frequent and rapid diagnosis and treatment condition the posterior evolution of the disease. PATIENTS AND METHODS: The cases of 2 contact lens waters who developed keratitis by Acanthamoeba are presented. The diagnostic methods and treatment are commented upon. RESULTS: Keratitis by Acanthamoeba was diagnosed in 2 patients following analysis of corneal scrapings and of the saline solution used for lens maintenance. Trophozoites and cystes of this parasite were observed in all the samples processed. The evolution was good in the patient treated at 15 days after initiation of the symptoms. However, the evolution was very bad in the patient who delayed in initiating the amebicide treatment. Penetrating keratoplasty was performed in both patients. CONCLUSIONS: Specific treatment with derivates of propamidine implemented early may avoid severe ocular complications. As prophylaxis for contact lens users, it is recommended that the contact lens be maintained clean and correctly care for, and the use of home-made saline solutions which are easily contaminated by Acanthamoeba, should be avoided.

[Defecography by spiral computed tomography]. / La defecografia con Tomografia Computerizzata spirale.

PURPOSE: We investigated the possible role of helical CT defecography in pelvic floor disorders by comparing our results with those of conventional defecography. MATERIAL AND METHODS: Our series consisted of 90 patients, namely 62 women and 28 men, ranging in age 24-82 years. They were all submitted to conventional defecography, and 18 questionable cases were also studied with helical CT defecography. The conventional examination was performed during the 4 standard phases of resting, squeezing, Valsalva and straining; we used a remote-control unit. The parameters for helical CT defecography were: 5 mm beam collimation, pitch 2, 120 KV, 250 mAs and 18-20 degrees gantry inclination to acquire coronal images of the pelvic floor. The rectal ampulla was distended with a bolus of 300 mL nonionic iodinated contrast agent (dilution: 3 g/cc). The patient wore a napkin and was seated on the table, except for those who could not hold the position and were thus examined supine. Twenty-second helical scans were performed at rest and during evacuation; multiplanar reconstructions were obtained especially on the sagittal plane for comparison with conventional defecographic images. RESULTS: An unquestionable diagnosis could be made in all the 18 patients submitted to helical CT defecography. The diagnosis was in agreement with proctology results and added new information in all cases. Sixteen patients had constipation and 2 fecal incontinence--one from rectal prolapse and the other from a rectovaginal fistula. In this latter case helical CT defecography permitted to confirm the fistula and suggest its course. One patient had a previously undetected ovarian cancer metastatic to the anterior rectal wall. DISCUSSION AND CONCLUSIONS: Coronal helical CT defecography images permitted to map the perineal floor muscles, while sagittal reconstructions provided information on the ampulla and the levator ani. To conclude, helical CT defecography performed well in the study of pelvic floor disorders and can follow conventional defecography especially in questionable cases.

Ozone-induced inflammation is attenuated with multiday exposure.

It is well known that ozone (O3) causes acute lung inflammation. What is not known is whether there is progression of the inflammatory response in humans with repeated short-term exposures. Our study was designed to test the hypothesis that repeated exposures to a high-ambient concentration of O3 (0.2 ppm) over several days would cause more inflammation than a single exposure. Fifteen healthy volunteers were exposed in random fashion to 0.2 ppm ozone for 4 h on a single day and to 0.2 ppm O3 for 4 h on 4 consecutive days while exercising moderately for 30 min of each hour. Pulmonary function tests were obtained immediately before and after each 4-h exposure. Bronchoscopy was performed 20 h after the completion of each exposure arm to obtain bronchoalveolar lavage (BAL) for measurement of markers of inflammation. Our results show initial progression followed by attenuation of the acute physiologic response to O3 with repeated daily exposures. We found a significant difference in percent change in FEV1, FVC, and specific airway resistance (SRaw) across the single-day exposure when compared with the change across Day 4 of the 4-d exposure. Bronchial fraction (the first 15 ml of BAL return) and BAL were analyzed for the following end points: total and differential cell counts, total protein, lactate dehydrogenase (LDH), fibronectin, interleukin-6 (IL-6), interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the bronchial fraction the number of polymorphonuclear cells (PMN)s and fibronectin concentration were significantly decreased after 4-d exposure compared with single-day exposure. In BAL, significant decreases in the number of PMNs, fibronectin, and IL-6 were found after 4-d exposure versus single-day exposure. These results suggest that there is attenuation of the O3-induced inflammatory response in both proximal airways and distal lung with repeated daily exposures.

Presentation of integrins on leukocyte microvilli: a role for the extracellular domain in determining membrane localization.

Adhesion of blood leukocytes to the endothelium involves multiple steps including initial attachment (tethering), rolling, and firm arrest. Presentation of adhesion molecules on leukocyte microvilli can substantially enhance tethering. Localization of L-selectin to microvilli and of CD44 to the planar cell body have been shown to depend upon their transmembrane and cytoplasmic domains. We investigated the role of leukocyte integrin transmembrane and cytoplasmic domains in initiating adhesion under flow and in microvillous localization. Integrins alpha4beta7, alphaLbeta2, and alphaMbeta2 were heterologously expressed in K562 cells. alpha4beta7 initiated adhesion under flow and localized to microvilli, whereas beta2 integrins did not initiate adhesion and localized to the cell body. Chimeric integrins were produced by replacing the alpha4beta7 cytoplasmic and/or transmembrane domains with the homologous domains of alphaLbeta2 or alphaMbeta2. Unexpectedly, these chimeras efficiently mediated adhesion to the alpha4beta7 ligand mucosal addressin cell adhesion molecule-1 under flow and localized to microvilli. Therefore, differences between the transmembrane and cytoplasmic domains of alpha4 and beta2 integrins do not account for differences in ability to support attachment under flow or in membrane localization. Integrins alpha4beta1, alpha5beta1, alpha6Abeta1, alphavbeta3, and alphaEbeta7 also localized to microvilli. Transmembrane proteins known or suspected to associate with extracellular domains of microvillous integrins, including tetraspans and CD47, were concentrated on microvilli as well. These findings suggest that interactions between the extracellular domains of integrins and associated proteins could direct the assembly of multimolecular complexes on leukocyte microvilli.

Effects of ozone on normal and potentially sensitive human subjects. Part I: Airway inflammation and responsiveness to ozone in normal and asthmatic subjects.

We report here the results of a multiphase project to assess the significance of airway responsiveness and airway injury in ozone (O3)* sensitivity. In Phase I, we measured the preexposure methacholine responsiveness of 66 normal subjects and then exposed these subjects to 0.2 ppm O3 for 4 hours with moderate exercise. Preexposure methacholine responsiveness was weakly correlated with O3-induced increases in specific airway resistance (sRaw) but not O3-induced declines in forced expiratory volume in one second (FEV1) or forced vital capacity (FVC). In addition, O3-induced lower respiratory symptoms were not well correlated with O3-induced changes in lung function. In Phase II, we exposed 23 normal subjects to O3, following an identical protocol to that of Phase I, and then performed bronchoscopy with proximal airway lavage (PAL), bronchoalveolar lavage (BAL), and bronchial biopsy at 18 hours after exposure. Ozone-induced increases in percentage of neutrophils and total protein concentration were observed in both bronchial fraction and BAL fluids; increased percentage of neutrophils also was observed in PAL fluid. These increases were correlated with O3-induced increases in sRaw, but not with O3-induced declines in FEV1 or FVC. Ozone also appeared to increase expression of intercellular adhesion molecule-1, an important mediator of neutrophil recruitment, in bronchial mucosa. In Phase III, we exposed a group of 19 asthmatic subjects to O3, following a protocol identical to that of Phase II. We then compared the lower respiratory symptom and lung function responses of the asthmatic subjects to those of the 81 normal subjects who participated in Phase I, Phase II, or both. The changes in the PAL and BAL fluids of the asthmatic subjects were compared with those of the normal subjects who participated in Phase II. Although both the asthmatic and nonasthmatic subjects showed significant O3-induced changes in lower respiratory symptoms, FEV1, FVC, and sRaw, no significant differences were found between the groups. For sRaw, however, a nonsignificant trend toward a greater O3-induced increase was noted for the asthmatic subjects. In contrast, the O3-induced increases in percentage of neutrophils and total protein concentration in BAL fluid were significantly greater for the asthmatic subjects than for the nonasthmatic subjects. These data suggest that although the lower respiratory symptom and lung function responses to O3 are not markedly greater in asthmatic subjects than in healthy subjects, the inflammatory response of the asthmatic lung may be more intense.

Differential regulation of airway epithelial integrins by growth factors.

The pattern of integrin expression on human airway epithelium changes significantly in injury or inflammation. In particular, two integrins, the fibronectin receptor, alpha 5 beta 1 and the fibronectin/tenascin receptor alpha v beta 6, are expressed at low or undetectable levels in normal airways in vivo but are induced in response to airway epithelial injury. We investigated the effects of various growth factors known to be present in the airways on the expression of constitutively expressed and inducible airway epithelial integrins using flow cytometry. In primary cultures of human airway epithelial cells, transforming growth factor-beta 1 (TGF beta 1) dramatically increased expression of alpha v beta 6 and essentially did not affect the expression of any other integrin, including alpha 5 beta 1. In contrast, epidermal growth factor (EGF) upregulated surface levels of both alpha v beta 6 and alpha 5 beta 1. Together, TGF beta 1 and EGF had an additive effect on alpha v beta 6 and alpha 5 beta 1 expression while increasing levels of alpha 2 beta 1 and decreasing expression of alpha 3 beta 1- and alpha 6-containing integrins. In contrast, the transformed airway epithelial cell line, BEAS-2B, expressed a markedly different repertoire of integrins. Integrin expression on BEAS-2B cells was not affected by any of the growth factors tested in this study. These results demonstrate that, in primary cultures of human airway epithelial cells, the pattern of integrin expression can be dramatically altered by growth factors. The inducible integrins, alpha v beta 6, and alpha 5 beta 1 are most subject to regulation by growth factors and expression of each of these can be differentially regulated. The differential regulation of the two principal fibronectin receptors on airway epithelial cells suggests that they may mediate different cellular responses to fibronectin.

Greater ozone-induced inflammatory responses in subjects with asthma.

In order to test the hypothesis that ozone (O3)-induced changes in lung function and respiratory tract injury/inflammation are greater in subjects with asthma than in normal subjects, we exposed 18 asthmatic subjects, on separate days, to O3 (0.2 ppm) and filtered air for 4 h during exercise. Symptom questionnaires were administered before and after exposure, and pulmonary function tests (FEV1, FVC, and specific airway resistance [SRaw]) were performed before, during, and immediately after each exposure. Fiberoptic bronchoscopy, with proximal airway lavage (PAL) of the isolated left main bronchus and bronchoalveolar lavage (BAL; bronchial fraction, the first 10 ml of fluid recovered) of the right middle lobe, was performed 18 h after each exposure. The PAL, bronchial fraction, and BAL fluids were analyzed for the following endpoints: total and differential cell counts; total protein, lactate dehydrogenase (LDH), fibronectin, interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), myeloperoxidase (MPO), and transforming growth factor-beta (TGF beta 2) concentrations. We found a significant O3 effect on FEV1, FVC, SRaw (p < 0.04) and lower respiratory symptoms (p < 0.001) for the asthmatic subjects. Ozone exposure also significantly increased the percent neutrophils in PAL (p < 0.01); percent neutrophils, total protein, and IL-8 in the bronchial fraction (p < 0.001, p < 0.05, and p < 0.01, respectively); and the percent neutrophils, total protein, LDH, fibronectin, IL-8, GM-CSF, and MPO in BAL (p < 0.001, p < 0.01, p < 0.01, p < 0.001, p < 0.05, p < 0.01, and p < 0.001, respectively) for the asthmatic subjects. There were no significant differences in the lung function responses of the asthmatic subjects in comparison with a group of normal subjects (n = 81) previously studied using an identical protocol, although there was a trend toward a greater O3-induced increase in SRaw in the asthmatic subjects (p < 0.13). In contrast, the asthmatic subjects showed significantly greater (p < 0.05) O3-induced increases in several inflammatory endpoints (percent neutrophils and total protein concentration) in BAL as compared with normal subjects who underwent bronchoscopy (n = 20). Our results indicate that asthmatic persons may be at risk of developing more severe O3-induced respiratory tract injury/inflammation than normal persons, and may help explain the increased asthma morbidity associated with O3 pollution episodes observed in epidemiologic studies.

Inserción del DIU posparto en el Perú: Experiencia en nueve hospitales / Pospartum IUD insertion. Experience at nine peruvian hospitals

Este trabajo presenta una revisión de las diferentes estrategias de entrega de servicios de planificación familiar y describe en mayor amplitud la anticoncepción posparto, con énfasis en el dispositivo intrauterino (DIU)). Muestra la experiencia mundial y nacional y, dentro de ella, los resultados de la primera investigación operativa realizadas en el país en nueve hospitales del sector público (5 del Instituto Peruano de Seguridad Social - IPSS- y 4 del Ministerio de Salud- MINSA-) comparando los resultados obtenidos a través de encuestas en el prenatal posparto y seguimiento de una muestra aleatoria de pacientes y usuarias. Se demuestra que la estrategia es aceptable, segura y costo efectiva , y que es una forma de aumentar la prevalencia con métodos de larga duración y de alta seguridad anticonceptiva. Sin embargo, pese a la alta demanda insatisfecha para limitar o espaciar los nacimientos, hay aspectos de mitos y temores por parte de las usuarias con respecto a los diferentes métodos anticonceptivos que deberán ser atendidos con una mejor información y consejería en planificación familiar. Palabras clave: Anticoncepción posparto, DIU posparto, consejería anticonceptiva, costo efectiva, prevalencia.

Distribution of integrins alpha v beta 6 and alpha 9 beta 1 and their known ligands, fibronectin and tenascin, in human airways.

We have previously identified two integrins, alpha 9 beta 1 and alpha v beta 6, from guinea pig airway epithelium. The extracellular matrix protein tenascin is a ligand for both of these receptors, and fibronectin is also a ligand for alpha v beta 6. In the present study, we used immunohistochemistry to examine the expression and spatial distribution of the alpha 9 subunit, alpha v beta 6, tenascin, and fibronectin in the proximal airways of 10 normal nonsmoking subjects and eight patients undergoing lung resection for cancer. We also performed the same analyses on sections of peripheral lung obtained from an additional seven subjects undergoing lung resection. alpha 9 was highly expressed throughout the airway epithelium (but not on alveolar epithelium) irrespective of clinical status. In contrast, alpha v beta 6 was expressed on proximal airway epithelial cells in four of eight smokers undergoing lung resection, but in none of the normal subjects and none of the distal airways examined. On bronchial epithelial cells cultured from resected airways, alpha v beta 6 was highly expressed on cells grown from patients who did not appear to express the receptor in vivo, as well as from subjects who did, suggesting that some component of the in vitro environment can induce expression. Although both tenascin and fibronectin were present below the proximal airway epithelium of both normal nonsmoking subjects and smokers, the spatial patterns of integrin and ligand expression were not congruent, because the integrins were present diffusely on the cell surface and on some cells that were not in contact with the basement membrane, whereas the ligands were present principally in the subepithelial layer. These findings are compatible with the existence of as-yet unidentified ligands for each of these integrins--for example, ligands involved in homotypic cell-cell interactions within the epithelium.