The impact of estrogen and progesterone on asthma.

OBJECTIVE: This paper describes evidence of a positive effect of both endogenous and exogenous estrogen and progesterone on lung function across the life span in women. DATA SOURCES: Articles were identified using the keywords asthma, pulmonary function, menarche, menopause, estrogen, progesterone, hormone replacement therapy, oral contraceptives, and menstrual cycle from years 1966 to 2001 in MEDLINE. Additional studies were identified from article reference lists. STUDY SELECTION: Relevant, peer-reviewed original research articles in the English language were selected. RESULTS: Estrogen and/or progesterone may alter pulmonary function and asthma. Premenopausal women experience decreases in pulmonary function and increases in asthma exacerbations and hospitalizations during the premenstrual and menstrual phases. Oral contraceptives and hormone replacement therapy are associated with improved pulmonary function and decrease in asthma exacerbation. Some asthmatic patients experience improved pulmonary function and reduced asthma medication requirement during pregnancy. CONCLUSIONS: Estrogen and progesterone modify airway responsiveness. Further research is needed to elucidate the clinical relevance of estrogen and progesterone in the pathophysiology and therapy of asthma.     

Distinct microtubule and chromatin characteristics of human oocytes after failed in-vivo and in-vitro meiotic maturation

BACKGROUND: While a complete failure of meiotic maturation following hCG administration is rare during IVF cycles, cases arise in which patients repeatedly display a high incidence of failure to complete maturation to metaphase II (MII) in vivo. For the immature oocytes of such patients, our objectives were (i) to ask whether progression to MII could be supported in vitro, and (ii) to define their microtubule/chromatin properties following in-vitro maturation (IVM). Together, these studies were aimed at augmenting our understanding of factors underlying meiotic arrest in the human. METHODS: Cases are presented here for two patients (A and B) producing oocytes that recurrently showed the inability to mature to metaphase II in vivo. Following IVM attempts, chromatin and microtubule characteristics were identified in those oocytes that remained arrested during meiosis I. RESULTS: In patient A, meiotically arrested oocytes exhibited clear defects in spindle and chromatin arrangements. In contrast, the majority of oocytes from patient B displayed normal MI and MII spindles with aligned chromosomes, although some oocytes exhibited indications for possible defects in cell cycle control. CONCLUSIONS: Together, these analyses illustrate two cases with oocytes exhibiting a common gross defect, that is meiotic maturation arrest, but revealing different aetiologies or manifestations as evidenced by the presence or absence of abnormal spindle/chromatin organization. This work reinforces the existence of intrinsic defects in oocytes of some patients, the molecular and cellular bases of which merit further investigation.     

Collaboration--a new IT-service in the next generation of regional health care networks

During the past 10–15 years, Regional Health Care Networks (RHCN) have been established in many regions throughout the world. RHCN build on well-known techniques, methodologies and appropriate standards. Most of the European Countries today have set up IT strategic plans that focus on the establishment of RHCN. The benefits of having access to all relevant information are tremendous and contribute to cost-effective and coherent health services. By the rapid spread and use of Internet, technology has made it possible to interconnect all kinds of applications. In 2000, the most experienced regions in Europe joined PICNIC, a European project to develop the Next Generation Regional Health Care Networks and to support their new ways of providing health and social care. The previous generation of Regional Health Care Networks supported the interconnection of applications by transfer of messages. Messaging is an effective means of integration for isolated high-specialised systems that only need to exchange data. This service will continue to be one of the most important services in the future health care networks. However, tighter coupling may be desirable in some instances to avoid replicating the same functionality in several applications. In other words, certain services can be common and used by a number of applications instead of building that service inside each application. These common services are called middleware services. In PICNIC (http://www.medcom.dk/picnic), a new middleware Collaboration IT service has been identified and developed. This service allows the end users to perform real-time clinical collaboration, with exchange of text, structured data, voice and images across the limits of a single region. A clinical collaboration is associated with the shared clinical context to provide a record of relevant clinical information and facilitates synchronous as well as asynchronous collaboration. This new IT service builds on the increasing popularity of instance messaging and presence systems that facilitate smooth transition between synchronous and asynchronous interaction. The new Collaboration IT service is expected to have a strong impact on the practice of health care in the next generation of Regional Health Care Networks.     

Streptococcus pneumoniae Resistance to Complement-Mediated Immunity Is Dependent on the Capsular Serotype

Streptococcus pneumoniae strains vary considerably in the ability to cause invasive disease in humans, and this is partially associated with the capsular serotype. The S. pneumoniae capsule inhibits complement- and phagocyte-mediated immunity, and differences between serotypes in these effects on host immunity may cause some of the variation in virulence between strains. However, the considerable genetic differences between S. pneumoniae strains independent of the capsular serotype prevent an unambiguous assessment of the effects of the capsular serotype on immunity using clinical isolates. We have therefore used capsular serotype-switched TIGR4 mutant strains to investigate the effects of the capsular serotype on S. pneumoniae interactions with complement. Flow cytometry assays demonstrated large differences in C3b/iC3b deposition on opaque-phase variants of TIGR4(−)+4, +6A, +7F, and +23F strains even though the thicknesses of the capsule layers were similar. There was increased C3b/iC3b deposition on TIGR4(−)+6A and +23F strains compared to +7F and +4 strains, and these differences persisted even in serum depleted of immunoglobulin G. Neutrophil phagocytosis of the TIGR4(−)+6A and +23F strains was also increased, but only in the presence of complement, showing that the effects of the capsular serotype on C3b/iC3b deposition are functionally significant. In addition, the virulence of the TIGR4(−)+6A and +23F strains was reduced in a mouse model of sepsis. These data demonstrate that resistance to complement-mediated immunity can vary with the capsular serotype independently of antibody and of other genetic differences between strains. This might be one mechanism by which the capsular serotype can affect the relative invasiveness of different S. pneumoniae strains.The important Gram-positive pathogen Streptococcus pneumoniae has an extracellular polysaccharide capsule that inhibits complement activity, neutrophil phagocytosis, and bacterial killing by neutrophil extracellular traps (19, 23, 25, 26, 29, 31), as well as having major effects on bacterial interactions with the epithelium (8, 25, 26, 29, 31, 37). As a consequence, the capsule is essential for virulence (6, 38). Different strains of S. pneumoniae can express capsules with different structures, depending on the type of monosaccharide units and their bonds within the polysaccharide chain, the enzymes for the synthesis of which are encoded by genes within a specific locus in the genome (5, 27, 30). The different types of capsules are divided into 91 capsular serotypes. Although most S. pneumoniae strains can cause disease in humans, the ability to cause invasive infections (septicemia and meningitis) varies up to 60-fold between strains and is closely associated with the capsular serotype (4, 12). Some serotypes (e.g., 1, 4, 5, 7, and 14) are overrepresented among invasive disease isolates compared to the frequency of their isolation as nasopharyngeal commensals, while other capsular serotypes only rarely cause invasive disease despite being common nasopharyngeal commensals (4, 12, 15).The mechanisms causing capsular serotype-dependent variation in virulence are largely unknown but could reflect differences between the abilities of strains of different serotypes to inhibit host immune responses. Potentially, strains expressing capsular serotypes that strongly inhibit immunity could be more likely to establish invasive infection than strains with capsular serotypes that weakly inhibit host immunity, and this hypothesis is partially supported by existing experimental data. The virulence of different capsular serotypes varies markedly in mouse models of infection, but as there is only a weak relationship between virulence in mice and invasive potential in humans, the clinical relevance of these findings is unclear (1, 7, 9, 33). Because of the central role of complement and phagocytosis for systemic immunity to S. pneumoniae (11, 20, 45, 46), differences in the effects of different capsular serotypes on complement activity or phagocytosis are strong candidates for explaining why the serotype can affect virulence. Indeed, existing data show that resistance to complement activity and phagocytosis varies between strains with different capsular serotypes (18, 28, 46). However, in general, these studies have not controlled for strain phase variation or for noncapsular genetic variation between strains. S. pneumoniae has two main phase variants, opaque with an increased capsule thickness and transparent with a thinner capsule but increased expression of some surface proteins, such as PspC, that can affect complement activity (24, 31). Differences in phase variation between strains could therefore affect complement susceptibility. Furthermore, there is considerable genetic variation between S. pneumoniae strains independent of the capsular serotype. Only 60% of gene clusters are common to all S. pneumoniae strains, and the genome content differs by 8 to 10%, on average, between any two strains (10, 13, 16, 17). This genetic variation is partially linked to the capsular serotype (http://www.mlst.net/), and hence, the relationship between the capsular serotype and invasiveness could be due to noncapsular genetic variation rather than direct effects of the capsule.To overcome strain genetic variation confounding the assessment of capsular serotype interactions with the immune system, the capsular loci of one strain can be replaced with the capsular loci from another, creating otherwise isogenic strains expressing different capsular serotypes (29, 35, 43). Data obtained using capsular serotype-switched strains have shown that expression of capsular serotype 3 reduced complement deposition on a previously serotype 2 strain (2), increased the virulence in mice of an originally serotype 6B strain, and conversely decreased the virulence of a serotype 5 strain (22). Furthermore, a recent study demonstrated variations in resistance to neutrophil killing of unopsonized bacteria between capsular serotype-switched strains expressing different capsular serotypes and correlated reduced sensitivity to neutrophil killing with increased prevalence of that capsular serotype as a nasopharyngeal commensal (39). These studies have established the principle that the capsular serotype can affect the complement sensitivity, neutrophil killing, and virulence of S. pneumoniae independently of the strain background. However, as yet, there are only limited data on the effects of different capsular serotypes on complement-dependent immunity to S. pneumoniae and a more detailed assessment is required to help understand why a strain''s capsular serotype is linked to its invasive potential.We have used opaque- and transparent-phase variants of TIGR4 S. pneumoniae strains modified to express different capsular serotypes, two representative of relatively invasive capsular serotypes (4 and 7F) and two representative of less invasive serotypes (6A and 23F), to assess capsular serotype-dependent effects on immunity. We have investigated the effects of the capsular serotype on opsonization of S. pneumoniae with the complement-derived opsonins C3b and iC3b, as well as on neutrophil phagocytosis and virulence in a mouse model of septicemia.     

Recombinant Allergens Combined with Biological Markers in the Diagnosis of Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis Patients

Allergic bronchopulmonary aspergillosis (ABPA) is a frequent complication in cystic fibrosis patients. The diagnosis remains difficult and requires a combination of clinical, radiological, biological, and mycological criteria. The aim of this study was to analyze the added value of two recombinant antigens, rAspf4 and rAspf6, associated with the detection of specific IgG; precipitins; total IgE; and Aspergillus fumigatus in sputum for the diagnosis of ABPA. In a retrospective study, we determined the specific IgE responses to these recombinants in 133 sera of 65 cystic fibrosis patients. We selected an average of five serum samples from each of the 17 patients with ABPA (13 proven and 4 probable ABPA) and from 3 patients with Aspergillus bronchitis and rhinosinusitis. One serum sample for the 45 patients without ABPA was tested. The sensitivity of specific IgE detection against rAspf4 calculated per patient (92.3%) was significantly higher (P < 0.05) than that of rAspf6 (53.8%). When rAspf4 IgE detection was associated with anti-Aspergillus IgG enzyme-linked immunosorbent assay (ELISA) and precipitin detection, the sensitivity rose to 100%. The specificities of rAspf4 and rAspf6 IgE detection were 93.7% and 91.6%, respectively. Other diagnostic criteria had slightly lower specificities (87.5% for anti-Aspergillus IgG ELISA, 89.6% for precipitins, 84.4% for total IgE, and 85.0% for positive A. fumigatus culture in sputum). In conclusion, this retrospective study showed the relevance of rAspf4 IgE detection, in combination with other biological markers (Aspergillus IgG ELISA, precipitins, and total IgE), for improving the biological diagnosis of ABPA.Allergic bronchopulmonary aspergillosis (ABPA) is a frequent complication in patients with cystic fibrosis that causes significant respiratory morbidity (1, 13, 18). The exact prevalence of ABPA is not clearly known; however, it ranges from 2 to 25% in patients with cystic fibrosis (22). ABPA may lead to acute worsening of the respiratory condition and ongoing decline in lung function. Without adequate treatment, ABPA ultimately progresses to a chronic state with lung fibrosis. ABPA is a hypersensitivity pulmonary disease associated with inflammatory destruction of airways in response to Aspergillus allergens (23). Thus, chronic airway colonization with Aspergillus induces strong inflammatory responses with high IgE levels (20). The factors leading to ABPA are not clearly understood, but it is believed that Aspergillus-specific, IgE-mediated type I hypersensitivity reactions and specific IgG-mediated type III hypersensitivity reactions play central roles in the pathogenesis of ABPA (18). Furthermore, host factors, including individual susceptibility, may contribute to the immunopathogenesis of ABPA. Early diagnosis and treatment of ABPA are important to prevent serious and potentially irreversible lung damage (9).ABPA is defined by five major diagnostic criteria, according to the Cystic Fibrosis Foundation Consensus Conference (19, 23): (i) acute or subacute clinical deterioration and decline in pulmonary function not attributable to another etiology, (ii) elevated serum IgE concentrations, (iii) immediate prick test reactivity to Aspergillus antigen or presence of specific IgE antibodies to Aspergillus fumigatus, (iv) precipitating antibodies to A. fumigatus or elevated serum IgG antibodies to A. fumigatus, and (v) history of pulmonary infiltrates (transient or fixed) and central bronchiectasis. Minor diagnostic criteria include repeated detection of Aspergillus species in sputum samples, a history of expectoration of brown plugs or flecks, and late skin reactivity to Aspergillus antigens. Despite these criteria, diagnosis of ABPA in cystic fibrosis patients remains particularly difficult (3, 16, 21, 22). Therefore, as stated in the most recent consensus document on the diagnosis and therapy of ABPA in cystic fibrosis patients (19), serological findings should strongly contribute to the confirmation or exclusion of clinically suspected ABPA.The demonstration that some recombinant antigens are specifically expressed only in hyphae explains why an IgE response to these antigens may occur in ABPA patients but not in A. fumigatus-sensitized patients. Thus, cloning, characterization, production, and clinical evaluation of A. fumigatus allergens have been major advances in the diagnosis of ABPA and help in the understanding of the pathophysiological mechanisms underlying the disease (9). The rAspf1, rAspf2, rAspf3, rAspf4, and rAspf6 recombinant allergens have been evaluated for their diagnostic performance in several serological studies concerning patients with both asthma and cystic fibrosis, with or without ABPA, and showed high specificity for the detection of A. fumigatus sensitization, as well as ABPA (14). Serological investigations involving rAspf4 and rAspf6 showed that allergen-specific IgE levels against these proteins increased almost exclusively in samples from patients with ABPA (9). However, de Oliveira et al. (10) showed that the determination of the IgE response against A. fumigatus recombinant antigens in asthmatic patients with immediate cutaneous reactivity to A. fumigatus was not helpful in diagnosing ABPA or in detecting sensitization to fungi.The aim of the present study was to evaluate the efficiencies of two recombinant allergens (rAspf4 and rAspf6) in IgE detection, combined with anti-Aspergillus IgG, precipitins, total serum IgE concentration, and fungal culture of sputum.     

Monascus ruber: Invasive Gastric Infection Caused by Dried and Salted Fish Consumption

We report a case of invasive gastric infection caused by Monascus ruber observed in a patient from French Guiana with gastric adenocarcinoma. The originality of this case is that, first, this invasive mycosis is extremely rare and, second, the probable mode of infection was by the consumption of Monascus ruber-contaminated food.