Determinants Of Oral corticosteroid Responsiveness in Wheezing Asthmatic Youth (DOORWAY): protocol for a prospective multicentre cohort study of children with acute moderate-to-severe asthma exacerbations.

INTRODUCTION: Oral corticosteroids are the cornerstone of acute asthma management in the emergency department. Recent evidence has raised doubts about the efficacy of this treatment in preschool-aged children with viral-induced wheezing and in smoking adults. The aims of the study were to: (1) document the magnitude of response to oral corticosteroids in children presenting to the emergency department with moderate or severe asthma; (2) quantify potential determinants of response to corticosteroids and (3) explore the role of gene polymorphisms associated with the responsiveness to corticosteroids. METHODS AND ANALYSIS: The design is a prospective cohort study of 1008 children aged 1-17 years meeting a strict definition of asthma and presenting with a clinical score of ≥4 on the validated Pediatric Respiratory Assessment Measure. All children will receive standardised severity-specific treatment with prednisone/prednisolone and cointerventions (salbutamol with/without ipratropium bromide). Determinants, namely viral aetiology, environmental tobacco smoke and single nucleotide polymorphism, will be objectively documented. The primary efficacy endpoint is the failure of emergency department (ED) management within 72 h of the ED visit. Secondary endpoints include other measures of asthma severity and time to recovery within 7 days of the index visit. The study has 80% power for detecting a risk difference of 7.5% associated with each determinant from a baseline risk of 21%, at an α of 0.05. ETHICS AND DISSEMINATION: Ethical approval has been obtained from all participating institutions. An impaired response to systemic steroids in certain subgroups will challenge the current standard of practice and call for the immediate search for better approaches. A potential host-environment interaction will broaden our understanding of corticosteroid responsiveness in children. Documentation of similar effectiveness of corticosteroids across determinants will provide the needed reassurance regarding current treatment recommendations. RESULTS: Results will be disseminated at international conferences and manuscripts targeted at emergency physicians, paediatricians, geneticists and respirologists. TRIAL REGISTRATION NUMBER: This study is registered at Clinicaltrials.gov (NCT02013076).

Metastatic spread of gynaecological neoplasms to the adrenal gland: case reports with a review of the literature.

Metastatic involvement of the adrenal glands due to gynaecological neoplasms is a relatively rare condition. The aim of our study was to present four cases of metastases to the adrenal gland due to endometrial adenocarcinoma, ovarian and cervical cancer. These cases are correlated with a review of the literature. CT scan and MRI have been previously used in an attempt to define the nature of the adrenal mass but this approach is of limited value in diagnosis. Image-guided pathological confirmation of an adrenal lesion may significantly change the staging or management of the primary neoplasm. The authors suggest that isolated adrenal metastasis should be routinely considered for surgical management.

[Surgical and radiotherapeutic approaches according to postoperative margins analysis in breast cancer: survey realized in 20 French cancer centers]. / Attitudes chirurgicales et radiothérapiques en fonction de l'analyse des berges-marges dans les tumeurs mammaires: enquête réalisée auprès de 20 centres de lutte contre le cancer.

Margin status is regarded as a major prognostic factor for local recurrence after breast conservative treatment. Margin definition in the literature is not always clear and precise. The impact on the therapeutic management may be quite different. This paper presents the radiotherapeutic attitude according to a survey realized in the twenty French cancer centers. The surgical practice in terms of margins status is appraised. The radiotherapist attitude in terms of boost's modulation is specified.

Modulation of cytokine release from colonic explants by bacterial antigens in inflammatory bowel disease.

The intestinal flora play an important role in experimental colitis and inflammatory bowel disease (IBD). Using colonic explant cultures from 132 IBD and control subjects, we examined tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 and interleukin-1 receptor antagonist (IL-1RA) production in vitro in response to bacterial activators. Unstimulated TNF-alpha release was increased significantly in rectal biopsies from involved IBD tissue, correlating with inflammation severity. Whereas lipopolysaccharide (LPS) only moderately stimulated TNF-alpha production from inflamed tissue, pokeweed mitogen (PWM) induced its release in all groups, with a stronger response in involved IBD tissue. Superantigen staphylococcal enterotoxin A (SEA) had a similar, but weaker effect. SEB was observed to be the strongest inducer of TNF-alpha for all groups, again with a more marked response in inflamed tissue. Stimulated release of IL-1 was considerably less than for TNF-alpha. The superantigens' superior potency over LPS was not as marked for IL-1 as it was for TNF-alpha. In addition to IL-1, IL-1RA release was also triggered by the bacterial products. The net effect of activation on the IL-1RA/IL-1 ratio was relatively modest. Release of the proinflammatory cytokines TNF-alpha and IL-1, as well as that of the anti-inflammatory cytokine IL-1RA was increased by incubation of colonic tissue with bacterial factors. TNF-alpha production and release was increased significantly in involved colonic explants from IBD. SEB was even capable of inducing TNF-alpha release from uninvolved colonic tissue.

Detection and localization of a peptidoglycan hydrolase in Lactobacillus delbrueckii subsp. bulgaricus.

Peptidoglycan hydrolase activities in Lactobacillus delbrueckii subsp. bulgaricus were detected by analysis of bacterial extracts on denaturing polyacrylamide gel electrophoresis containing lyophilized Micrococcus lysodeikticus cells as substrate. A hydrolase with an estimated molecular mass of 80 kDa was found to cross-react on Western blot with monoclonal antibodies raised against muramidase-2 of Enterococcus hirae. These antibodies were also used to demonstrate that the method of cell sample preparation affected protein detection. Slot and Western blots indicate that the peptidoglycan hydrolase from L. bulgaricus is bound to the cell wall. Immuno-labeling followed by optical and electron microscopic observations suggest that this hydrolase is intracellular and restricted mainly to the space between the membrane and the cell wall.

Follicle center lymphoma is associated with significantly elevated levels of BCL-6 expression among lymphoma subtypes, independent of chromosome 3q27 rearrangements.

The BCL-6 gene, located on chromosome 3q27, is implicated in the normal germinal center formation and is frequently rearranged in a wide spectrum of lymphomas. However the links between genetic alterations and expression of the gene are not clearly determined. We established a quantitative RT-PCR assay based on TaqMan technology to quantify BCL-6 mRNA expression in different subtypes of lymphomas and to compare the level of expression in lymphomas characterized by the presence or absence of BCL-6 translocation. Total RNA was extracted from 105 nodes biopsies (35 diffuse large B cell lymphomas (DLBCL); 26 follicle center lymphomas (FCL); 7 marginal zone lymphomas (MZL); 6 mantle cell lymphomas (MCL); 6 chronic lymphocytic leukemia (CLL); 5 T cell lymphomas (TCL); 7 classical Hodgkin diseases (HD); 6 nodal metastasis (NM); and 7 reactive hyperplasia (RH)). BCL-6 gene rearrangement was assessed by Southern blot analysis in 75% of 3q27(+) DLBCL (n = 20) cases and 67% of 3q27(+) cases (n = 10). The highest level of relative BCL-6 expression was observed in FCL (9.12 +/- 7.28) comparatively to the other lymphoma subtypes including DLBCL (2.53 +/- 1.82; P < 0.001), MCL (1.23 +/- 0.73), MZL (1.49 +/- 1.3), HD (1.60 +/- 1.00), TCL (1.75 +/- 1.64), but also RH (3.91 +/- 3.12) or NM (1.95 +/- 2.6). Among the 26 FCL cases, we observed a lower expression in grade 3 (n = 8) than in grade 1/2 (P < 0.001). Conversely, we failed to show any difference between 3q27(+) DLBCL and 3q27(-)DLBCL cases (P = 0.42). Paradoxically BCL-6 expression in 3q27(+) FCL (n = 10) was significantly lower than in 3q27(-) FCL cases (P = 0.035). Finally, this study showed that BCL-6 expression in lymphoma is largely independent of chromosome 3q27 rearrangement and is more related to the histological subtype. Clinical implication and alternative deregulation pathways of BCL-6 expression remain to be determined.

Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations.

BACKGROUND: Cerebral cavernous malformation (CCM) is one of the most common vascular malformations of the CNS. Familial CCM are increasingly diagnosed, but little is known about their natural history, especially in asymptomatic patients. OBJECTIVE: To determine the degree of spontaneous evolution of familial CCM in a population of 33 symptom-free patients. METHODS: During a previous national survey, the authors analyzed the clinical and MRI features of 173 patients from 57 unrelated French families, including 73 asymptomatic subjects. Of these 73 subjects, 33 prospectively underwent two serial clinical and MRI examinations. Cerebral MRI systematically included spin echo and gradient echo sequences. Occurrence of clinical symptoms and MRI changes of CCM, namely, hemorrhage, change in signal intensity, change in size, and appearance of new lesions, were recorded by means of comparison of the first and last MRI examinations. RESULTS: The 33 patients (234 CCM, mean 7.1 lesions/subject, range 1 to 85 lesions/subject) were followed during a mean period of 2.1 years (range 0.5 to 4.5 years). Two patients became symptomatic: One presented with brainstem hemorrhage and one with partial seizure. Comparison of the two serial MR images found changes in 15 patients (46%): 1) Bleeding occurred in three type II lesions (1.3%) in three patients (9.1%); 2) 30 new lesions appeared in 10 patients (30.3%); 3) change in signal intensity was observed in one lesion (0.4%) in one patient (3%); and 4) increase in size was observed in four lesions (1.7%) in three patients (9.1%). CONCLUSIONS: This prospective study confirms the dynamic nature of CCM. The appearance of new lesions in 30% of patients has to be retained as a hallmark of the familial condition.

Critical residues for the specificity of cofactors and substrates in human estrogenic 17beta-hydroxysteroid dehydrogenase 1: variants designed from the three-dimensional structure of the enzyme.

Human estrogenic 17beta-hydroxysteroid dehydrogenase is an NADP(H)-preferring enzyme. It possesses 11- and 4-fold higher specificity toward NADP(H) over NAD(H) for oxidation and reduction, respectively, as demonstrated by kinetic studies. To elucidate the roles of the amino acids involved in cofactor specificity, we generated variants by site-directed mutagenesis. The results showed that introducing a positively charged residue, lysine, at the Ser12 position increased the enzyme's preference for NADP(H) more than 20-fold. Substitution of the negatively charged residue, aspartic acid, into the Leu36 position switched the enzyme's cofactor preference from NADPH to NAD with a 220-fold change in the ratio of the specificity toward the two cofactors in the case of oxidation. This variant dramatically abolished the enzyme's reductase function and stimulated its dehydrogenase activity, as shown by enzyme activity in intact cells. The substrate-binding pocket was also studied with four variants: Ser142Gly, Ser142Cys, His221Ala, and Glu282Ala. The Ser142Gly variant abolished most of the enzyme's oxidation and reduction activities. The residual reductase activity in vitro is less than 2% that of the wild-type enzyme. However, the Ser142Cys variant was fully inactive, both as a partially purified protein and in intact cells. This suggests that the bulky sulfhydryl group of cysteine entirely disrupted the catalytic triad and that the Ser142 side chain is important for maintaining the integrity of this triad. His221 variation weakened the apparent affinity for estrone, as demonstrated by a 30-fold increase in Michaelis-Menten constant, supporting its important role in substrate binding. This residue may play an important role in substrate inhibition via the formation of a dead-end complex. The formerly suggested importance of Glu282 could not be confirmed.

Increased expression of the chemoattractant cytokines eotaxin, monocyte chemotactic protein-4, and interleukin-16 in induced sputum in asthmatic patients.

BACKGROUND: Induced sputum from asthmatic patients has been recently used to assess inflammatory cells. We have previously reported an increased expression of Th-2-type cytokines in induced sputum of asthmatic patients. C-C chemokines, particularly eotaxin and monocyte chemotactic protein (MCP)-4, are associated with eosinophilic infiltration. Interleukin (IL)-16 is associated with chemotactic activity for CD4+ cells. Chemokine expression in BAL and bronchial biopsy specimens has been demonstrated in asthmatic airways, but not in induced sputum. METHODS: We examined whether eotaxin, MCP-4, and IL-16 expression could be detected in induced sputum of asthmatic patients (n = 10), and whether the expression was increased compared to normal control subjects (n = 9). Eotaxin, MCP-4, and IL-16 immunoreactivity were determined by immunocytochemistry. In addition, inflammatory cells were investigated using markers for T cells (CD3), eosinophils (major basic protein [MBP]), macrophages (CD68), neutrophils (elastase), and epithelial cells (cytokeratin). RESULTS: Our results showed that there was a significant difference in the percentages of MBP-positive and epithelial cells between asthmatic patients and normal control subjects (p < 0.05). However, there was no difference between these two groups in the percentage of CD3-, elastase-, and CD68-positive cells. Immunoreactivity for eotaxin, MCP-4, and IL-16 was expressed in the induced sputum of all asthmatic patients, and expression of these chemotactic cytokines was significantly greater than in control subjects (p < 0.001, p < 0.005, and p < 0.001, respectively). CONCLUSIONS: This study showed that induced sputum could be used to detect chemokines in patients with bronchial asthma, and that the upregulation of chemotactic cytokines in the airways can be seen using noninvasive techniques.

Unusual methyl-branched alpha,beta-unsaturated acyl chain substitutions in the Nod Factors of an arctic rhizobium, Mesorhizobium sp. strain N33 (Oxytropis arctobia).

Mesorhizobium sp. strain N33 (Oxytropis arctobia), a rhizobial strain isolated in arctic Canada, is able to fix nitrogen at very low temperatures in association with a few arctic legume species belonging to the genera Astragalus, Onobrychis, and Oxytropis. Using mass spectrometry and nuclear magnetic resonance spectroscopy, we have determined the structure of N33 Nod factors, which are major determinants of nodulation. They are pentameric lipochito-oligosaccharides 6-O sulfated at the reducing end and exhibit other original substitutions: 6-O acetylation of the glucosamine residue next to the nonreducing terminal glucosamine and N acylation of the nonreducing terminal glucosamine by methyl-branched acyl chains of the iso series, some of which are alpha,beta unsaturated. These unusual substitutions may contribute to the peculiar host range of N33. Analysis of N33 whole-cell fatty acids indicated that synthesis of the methyl-branched fatty acids depended on the induction of bacteria by plant flavonoids, suggesting a specific role for these fatty acids in the signaling process between the plant and the bacteria. Synthesis of the methyl-branched alpha,beta-unsaturated fatty acids required a functional nodE gene.

IL-16 inhibits IL-5 production by antigen-stimulated T cells in atopic subjects.

BACKGROUND: We have previously shown increased expression of the CD4+ cell chemoattractant IL-16 at sites of airway allergic inflammation. Little is known about the significance of IL-16 in allergic inflammation and its role in allergen-driven T-cell cytokine responses. Because IL-16 interacts specifically with CD4+ T cells, we hypothesized that IL-16 released at sites of inflammation may modulate the pattern of cytokines produced by CD4+ T cells. OBJECTIVE: We investigated the effects of exogenous rhIL-16 on cytokine production of PBMCs from atopic and nonatopic subjects in response to antigen and PHA. METHODS: Primary cultures of freshly isolated PBMCs from ragweed-sensitive atopic subjects and nonatopic subjects were stimulated with ragweed or PHA in the presence or absence of rhIL-16. Supernatant levels of IL-4, IL-5, and IFN-gamma were determined by means of ELISA at different time points between 2 and 6 days. Effects of IL-16 on antigen-induced cellular proliferative responses were determined. RESULTS: No IL-4 protein was detected after antigen stimulation of PBMCs from atopic subjects, whereas significant levels of IL-5 were measured on day 6 (median, 534.9 pg/mL). IL-5 secretion was abolished in PBMC cultures depleted of CD4+ cells. The addition of rhIL-16 in antigen-stimulated PBMC cultures significantly reduced the amount of IL-5 released (median, 99.8 pg/mL; P <.001). Detectable levels of IFN-gamma (median, 53.3 pg/mL) were identified after antigen stimulation. The addition of rhIL-16 in antigen-stimulated PBMC cultures significantly increased IFN-gamma levels (median, 255.6 pg/mL; P <.05). Effects of rhIL-16 appear to be specific for antigen-stimulated PBMCs in atopic subjects because rhIL-16 did not alter IL-5 or IFN-gamma production in response to PHA nor did rhIL-16 alter cytokine production in nonatopic normal subjects. CONCLUSION: These studies suggest that IL-16 can play a role in regulating the production of cytokines seen in allergic states in response to antigen.

Appearance of new lesions in two nonfamilial cerebral cavernoma patients.

Cavernomas are vascular malformations mostly observed in the central nervous system. They occur in sporadic and familial forms. Familial forms are characterized by the presence of multiple lesions, an autosomal dominant pattern of inheritance and possible de novo lesions. We report two sporadic cases whose follow-up showed the appearance of new lesions.

The effect of inflammation severity and of treatment on the production and release of TNFalpha by colonic explants in inflammatory bowel disease.

BACKGROUND: Despite its pivotal role in mucosal inflammation, data on TNFalpha levels in inflammatory bowel diseases have been contradictory. AIM: To examine TNFalpha production in relation to the type and severity of inflammation and therapy, using colonic explant cultures. MATERIALS AND METHODS: Rectal mucosal biopsies from 271 paediatric patients (178 inflammatory bowel disease, 27 inflammatory controls, 66 normal) were cultured for 4 or 18 h. Basal TNFalpha tissue content and release into the medium were measured by ELISA and compared to histological severity and clinical parameters. RESULTS: TNFalpha release as well as tissue-associated TNFalpha levels were significantly increased in rectal biopsies from involved inflammatory bowel disease tissue. The amount of TNFalpha correlated with inflammation severity scores. TNFalpha levels were higher at 18 compared to 4 h in all groups, whether inflamed or not. TNFalpha released from rectal biopsies was lower among treated patients at 18 h. The presence of proximal colonic involvement was associated with higher TNFalpha release by uninvolved Crohn's disease rectal biopsies compared to patients with ileitis alone. CONCLUSIONS: TNFalpha production and release is increased in involved rectal explants from inflammatory bowel disease. Anti-inflammatory treatment diminishes this response.

The dnaJ (hsp40) locus in Rhizobium leguminosarum bv. phaseoli is required for the establishment of an effective symbiosis with Phaseolus vulgaris.

P121R25 is a Tn5-induced mutant of the effective Rhizobium leguminosarum bv. phaseoli strain P121R that is unable to use glutamate as the sole carbon and nitrogen source and is defective in symbiotic nitrogen fixation. Enzymatic analysis showed that three enzymes implicated in glutamate metabolism (glutamate dehydrogenase, 2-oxoglutarate dehydrogenase, and glutamate synthase) were affected by this mutation. Sequencing of the chromosomal locus bordering the Tn5 in P121R25 indicated the presence of the dnaK and dnaJ genes in an arrangement similar to that described in R. leguminosarum bv. viciae (GenBank accession number Y14649). The mutation was located in the dnaJ (hsp40) gene.

Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma.

BACKGROUND: We have recently demonstrated an increased number of glucocorticoid receptor-beta (GRbeta)-positive cells in steroid-insensitive subjects with severe asthma. Insensitivity to steroids may be a major contributing factor in fatal asthma; however, no such direct evidence has been report previously. OBJECTIVE: Our aims were to investigate the expression of GRbeta immunoreactivity, an endogenous inhibitor of steroid action previously associated with steroid insensitivity, within the airways of patients who died of slow-onset fatal asthma and to compare its expression in patients with emphysema and in nonasthmatic subjects who died of unrelated causes. Sections from airways, both large and small, were obtained from 7 patients who died of asthma, 6 who died from emphysema, and 8 who died from nonpulmonary diseases. Sections from lungs of 6 patients with mild asthma whose lungs were resected for carcinoma were also included as controls. METHODS: Tissue samples were processed for immunocytochemistry with a polyclonal antibody to GRbeta with use of the avidin-biotin technique and with monoclonal CD3, major basic protein, CD68, and elastase antibodies with the alkaline phosphatase-anti-alkaline phosphatase technique. Sequential immunocytochemistry was performed to phenotype the GRbeta immunoreactive cells. Tissue sections from both large (>2 mm) and small (<2 mm) airways were examined. RESULTS: There was a significantly greater number of GRbeta immunoreactive cells in fatal asthma compared with emphysema and controls (P <.001 and P <.05, respectively). There was no difference in the expression of GRbeta in emphysema compared with controls. GRbeta immunoreactivity was also significantly higher in fatal asthma compared with mild asthma. The expression of GRbeta in the small airways of patients with severe asthma did not differ significantly from that in the large airways. The majority of GRbeta-positive cells were T cells and to a lesser extent eosinophils, macrophages, and neutrophils. CONCLUSION: The results of this study support the association of GRbeta expression with fatal asthma and suggest that alternative anti-inflammatory agents need to be considered in the acute setting for patients who are not responding to steroid therapy.

Increased expression of IL-16 immunoreactivity in bronchial mucosa after segmental allergen challenge in patients with asthma.

BACKGROUND: We have previously shown increased expression of the CD4(+) cell chemoattractant IL-16 in bronchial mucosa of patients with asthma. We investigated the effects of allergen challenge on airway IL-16 expression. METHODS: We investigated the expression of IL-16 immunoreactivity in bronchial biopsy samples obtained from atopic asthmatic subjects (n = 19) and normal subjects (n = 6) 24 hours after segmental allergen challenge. Control biopsy samples were obtained either at baseline or after diluent challenge. IL-16 expression was correlated to numbers of CD4(+) cells, CD25(+) cells, and activated eosinophils. IL-16 bioactivity was assessed in bronchoalveolar fluid obtained from patients with asthma. RESULTS: IL-16 expression was higher in control biopsy specimens obtained from subjects with asthma compared with normal subjects (P<.05). In patients with asthma, numbers of IL-16 immunoreactive cells were significantly higher in biopsy specimens obtained after allergen challenge compared with control biopsy specimens (P<.001). Allergen provocation was associated with release of IL-16 in bronchoalveolar fluid in patients with asthma. In normal subjects, there was no difference in the number of IL-16-immunoreactive cells in biopsy specimens obtained after allergen challenge compared with biopsy specimens obtained after diluent challenge. Allergen challenge was associated with an increase in the numbers of EG2(+) eosinophils in patients with asthma but not in normal subjects. IL-16 expression correlated with the numbers of CD4(+) cells and CD25(+) cells after allergen challenge in asthmatic subjects with a provocative concentration required to decrease the FEV(1) by 20% of its baseline value (PC(20)FEV(1)) < 4 mg/mL. IL-16-immunoreactive cells were identified mainly as T cells and eosinophils in asthmatic subjects after allergen challenge. CONCLUSION: Endobronchial allergen provocation in atopic asthmatic patients resulted in increased airway expression of IL-16 and release of bioactive IL-16 in airways. IL-16 may contribute to the immunoregulation of the inflammatory infiltrate in the airways in response to antigen.

The natural history of familial cerebral cavernomas: a retrospective MRI study of 40 patients.

Our objective was to determine the natural history and prognostic factors of familial forms of cerebral cavernous malformations (CCM). Cavernomas are one of the most common central nervous system vascular malformations. Familial CCM is increasingly diagnosed, but little is known about its natural history. In a national survey, we analysed clinical and MRI features of 173 patients from 57 unrelated French families. Of these 40 had undergone at least two clinical and MRI examinations. Occurrence of haemorrhage, new lesions, change in signal intensity and size of lesions have been studied by comparison between first and last MRI studies. The CCM were classified according to Zabramski et al. Mean follow-up was 3.2 years (range 0.5-6.5 years). We followed 232 cavernomas (mean 5.9 per patient, range 1-17). Serial MRI demonstrated changes in 28 patients (70%). Bleeding occurred in 21 lesions (9.1%) in 14 patients (35%). The haemorrhagic risk was 2.5% per lesion-year, higher in type I and brain-stem CCM. We saw 23 new lesions appear in 11 patients (27.5%), with an incidence of 0.2 lesions per patient year. Signal change was observed in 11 patients (27.5%), in 14 lesions (6%), while 9 lesions (3.9%) in 9 patients (22.5%) changed significantly in size.

De novo lesions in familial form of cerebral cavernous malformations: clinical and MR features in 29 non-Hispanic families.

BACKGROUND: To evaluate clinical and MR features of de novo lesions (DNL) in the familial form of cerebral cavernous malformation (CCM) in 40 patients belonging to 29 unrelated non-Hispanic families. METHODS: Forty patients followed up by serial cerebral MR examinations were included in this retrospective study. First and last available MR examinations were retrospectively analyzed and compared for each patient to diagnose DNL. Gradient-echo (GRE) sequences were performed in only 11 of the 40 patients and were not considered for this study. Incidence of DNL was evaluated in terms of lesions/patient-year. All DNL were characterized by their clinical and MR features (location, size, type). Type of CCM was determined according to the classification of Zabramski (1994). Patient groups with and without DNL were compared for sex, age, number of pre-existing CCMs, and follow-up. RESULTS: Twenty-three DNL were recorded in 11 patients (27.5%) and the incidence was 0.2 lesions/patient-year (mean follow-up = 3.2 years). All but one DNL were asymptomatic. Twenty DNL were supratentorial and three were infratentorial. Mean diameter was 8 mm (2-35 mm). Six DNL were classified as type 1 (subacute hemorrhage), six as type 2 (hemorrhages and thromboses of varying ages) and 11 as type 3 (chronic hemorrhage with hemosiderin staining). No statistical difference between groups was found in terms of sex, age, or number of pre-existing CCMs. On the other hand, duration of follow-up was significantly longer in the group with DNL. CONCLUSION: The occurrence of DNL seems to be a hallmark of the familial form of CCM in non-Hispanic families as well as in Hispanic families. Such DNL are usually asymptomatic and are mainly classified as type 3 (chronic hemorrhage with hemosiderin staining). Within the limits of the retrospective study design and potential selection bias introduced by the varying indications for MR scanning, it does seem that DNL may occur at any time in the lifespan of CCM patients, and occurrence does not seem to depend on age, sex, or the total number of pre-existing lesions.

Antigen-induced airway inflammation and hyper-responsiveness does not enhance airway responses to a subsequent antigen challenge in rats.

Brown-Norway (BN) rats develop airway hyper-responsiveness and lung eosinophilia 18-24 h after ovalbumin (OA) challenge. We hypothesized therefore that allergen-induced airway inflammation would further enhance airway responses to a subsequent antigen challenge. Animals were sensitized to both OA and bovine serum albumin (BSA) and, 14 days later, challenged by aerosols with both antigens 24 h apart. Measurements of pulmonary resistance (RL) were made for 8 h after the second antigen challenge and bronchoalveolar lavage (BAL) was performed. Animals were divided into three groups and received two challenges as follows: saline-BSA (n=9), OA-saline (n=8) and OA-BSA (n=10). Sensitization was confirmed by measurements of specific OA-IgE and BSA-IgE. Early responses [determined as the highest value of RL within the first 30 min after the challenge] were absent in all study groups. The late responses [determined from the area under the RL versus time curve from 120 to 480 min after the challenge] were significantly greater in animals challenged with BSA (15.16+/-3.86) compared to saline (3.76+/-4.09; P<0.05). However previous exposure to OA did not further increase the late response in animals subsequently challenged with BSA (20.11+/-3.67) despite enhanced airway responsiveness to LTD4 at this time point. BAL eosinophils and lymphocytes were significantly increased following BSA challenge in previously OA-challenged animals, compared to numbers retrieved from animals previously exposed to saline (P<0.05). These data indicate that previous exposure to OA did not further increase the LR to a second antigen challenge despite substantial increases in airway inflammatory cells and airway hyper-responsiveness to LTD4.