Association between TLR2/TLR4 gene polymorphisms and COPD phenotype in a Greek cohort.

BACKGROUND: Considering that the innate immune system plays a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD), we hypothesized that functional single-nucleotide polymorphisms (SNPs) of innate immune genes affect the disease phenotype and prognosis. AIM: To elucidate the contribution of common functional TLR2 and TLR4 SNPs and genotypic deficiency of the mannose-binding lectin (MBL) protein, both as single parameters and in combination, in Greek COPD patients. RESULTS: In a cohort of 114 Greek COPD patients, we confirmed that the presence of TLR4-D299G or TLR4-T399I SNPs was significantly associated with an earlier COPD stage (p = 0.003 and p = 0.009, respectively). In comparison, the absence of any analyzed polymorphism, including those of TLR2-R753Q and genotypic MBL deficiency, was significantly associated with a more severe disease phenotype, characterized by more frequent exacerbations (p = 0.045). CONCLUSION: Our findings support the notion that the presence of innate immune SNPs, such as functional polymorphisms of TLRs along with MBL deficiency, might exert a protective effect on the COPD phenotype, similar with other immune-mediated disorders.

International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency.

BACKGROUND: The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1-INH-HAE. METHODS: During an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting. RESULTS: The symptoms of C1-INH-HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1-INH-HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1-INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1-INH-HAE family member should be screened for C1-INH deficiency. Pediatric patients should always carry a C1-INH-HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma-derived C1-INH, recombinant C1-INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center. CONCLUSIONS: The pediatric-focused international consensus for the diagnosis and management of C1-INH-HAE patients was created.

F12-46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema.

The factors influencing the heterogeneous clinical manifestation of hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) represent one of the oldest unsolved problems of the disease. Considering that factor XII (FXII) levels may affect bradykinin production, we investigated the contribution of the functional promoter polymorphism F12-46C/T in disease phenotype. We studied 258 C1-INH-HAE patients from 113 European families, and we explored possible associations of F12-46C/T with clinical features and the SERPING1 mutational status. Given that our cohort consisted of related subjects, we implemented generalized estimating equations (GEEs), an extension of the generalized linear model accounting for the within-subject correlation. F12-46C/T carriers exhibited a significantly delayed disease onset (P < 0.001) and did not need long-term treatment (P = 0.02). In a GEE linear regression model, the presence of F12-46C/T was significantly associated with a 7-year delay in disease onset (P < 0.0001) regardless of SERPING1 mutational status. It is concluded that F12-46C/T carriage acts as an independent modifier of C1-INH-HAE severity.

Breast cancer risk in relation to most prevalent IgE specific antibodies: a case control study in Greece.

BACKGROUND: This study aims to explore the debatable role of allergy in breast cancer (BC) by using country-specific biological markers, namely levels of the most prevalent allergen-specific immunoglobulin E in Greece. PATIENTS AND METHODS: Blood samples and clinical information were collected over a 30-month period from 103 women with histologically-confirmed BC and 103 controls from two university hospitals in Athens. Allergen-specific IgE, against the 12 prevailing allergens in Greece were determined; thereafter, a score comprising the sum of the individual values for this battery of serological IgE determinations was created. Bivariate and multiple logistic regression analyses were undertaken using case-control status as the outcome and IgE-scores as the predictor variable, controlling for socio-demographic, gynecological and lifestyle confounders. RESULTS: The serum IgE score seemed to be positively related to BC (OR: approximately 1.73; CI: 0.95-3.14; p-value: 0.07). A positive correlation between serological evidence and allergic history among controls was also found (p-value: 0.06). CONCLUSION: This investigation suggests an IgE-mediated allergic response among women with BC in comparison to their controls. The finding needs confirmation by immuno-epidemiological investigation to clarify the directionality of this association and whether laboratory-ascertained atopy can be considered as a risk-marker of susceptibility in the development of BC.

Immunoepigenetics: the unseen side of cancer immunoediting.

Cancer immunosurveillance representing, till recently, the explanatory framework relating cancer and the immune system, does not convincingly explain tumor escape. At the beginning of the decade, a new theory emerged, namely the immunoediting theory, and it comprehensively defines the role of the immune system in carcinogenesis. The core of this theory embraces the concept that the immune system on the one hand protects the body from cancer and on the other it shapes the immunogenicity of these cancers, thus presents a persuasive rationalization of the resistance of tumors against the immune response. With the immune system playing, in this context, such a pivotal role in shaping the tumor immune profile and in subsequent oncogenesis, it seems rather paradoxical to accept the immunocompetent host's immune system as a constant moiety. While DNA mutations of immune genes create a rather polymorphic condition, their frequency is much lower than that of other genetic events. Of these, epigenetic alterations give rise to new epialleles, which can reach up to 100% per locus. Bearing in mind that cancer is characterized by a tremendous amount of epigenetic aberrations, in both gene and global level, it is reasonable to postulate that, for the same unknown causes, analogous aberrations could affect the immune genes. Should this be the case, the relation between oncogenesis and the immune system appears much more dynamic and complex. Such an immunoepigenetic approach to carcinogenesis could improve our understanding of a series of common cancer-related aspects, such as environmental risk factors, effectiveness of demethylating agents, failure of current immunotherapies, etc. Moreover, this immunoepigenetic paradigm will take the current perception of the immune system and cancer interrelation further and beyond, constituting that the immunoresistant cancer cell phenotype is not shaped by the immune system acting as a steady and rigid evolutionary pressure, but rather as an extremely dynamic variable.

Complement: an inflammatory pathway fulfilling multiple roles at the interface of innate immunity and development.

Complement has been long perceived as an innate immune system that plays a pivotal role in the maintenance of host defense against infectious agents and the propagation of pro-inflammatory responses in the context of human disease. Complement activation has been associated with the onset of acute inflammatory reactions leading to complications such as acute graft rejection, local tissue injury and multi-organ failure. However, recent studies have indicated that various complement activation products may exert a beneficial effect by contributing to critical developmental and regenerative processes. Appreciating this extraordinary 'versatility' of complement proteins provides a framework for revisiting the design of effective complement therapeutics. A balanced strategy will have to consider limiting the detrimental proinflammatory effects of complement while preserving those activities that promote tissue repair and regeneration, cell survival and early development.

Beyond the Ingelfinger Rule: the intellectual property ethics after the end of biomedical journals' monopoly.

According to the so-called Ingelfinger Rule (IR), biomedical journals do not accept for publication papers which have already been publicized elsewhere. This rule was subjected to fierce criticism which was mainly based on the fact that authors transfer the intellectual rights of their work to the journals. With the emergence of the Internet, the scientific community has a golden opportunity to re-evaluate the IR concept. Scientists no longer have to depend on the debatable benefits (i.e. publicity and review) stemming from journal publications; rather they can be free to explore novel communication opportunities and, subsequently, to tackle the emerging intellectual property issues. This approach should take into account the tight bond between applied research and the world economy, the need for teamwork instead of individual effort for effective scientific research, and the added value of journal publications. Based on such an analysis, it would appear that the inherent characteristics of the Internet promote a re-assessment of the intellectual property theory on three levels: the cognitive (the way in which knowledge is made up from its building blocks), the morphological (the use of hypertext) and finally the sociological (the formation of virtual scientific communities). It is concluded that publishing on the Internet necessitates a different approach to the question of intellectual property based on the primal values of science. This can be achieved only if the scientific community embraces and nourishes the academic nature of the Internet as well as laying down the rules to control the dissemination of ideas without the intervention of non-scientific third parties.

Non-indexed medical journals in the Web: new perspectives in the medical literature.

Many medical journals, publishing in national languages, meet serious financial problems and difficulties when they attempt to become indexed in the international indices. Obviously, this not only affects the scientific quality of non-indexed medical journals (NIMJs) but also affects the awareness of the scientific community of topics with apparently local but potentially broader scientific significance. This is a reality for over 100 Greek medical journals, none of which has a life longer than 30 years or more than 2000 subscribers. Among them, the 'Archives of Hellenic Medicine' (AHM) is published and sponsored by the Athens Medical Society (the oldest medical society in Greece founded in 1835). This peer-reviewed Journal is being published for 13 years, bimonthly, in Greek. Attempting to overcome the above mentioned problems and to be involved in the process of discovering the most effective way of scientific 'skywriting', 2 years ago, the AHM entered full-text in the Web and it was decided that up to 500% of its volume should be covered by English-language papers. As a result, the AHM are now included in the main Web lists of medical journals and their home page is linked in many academic pages having approximately 500 hits/month. Furthermore, 45 retrievals of AHM's English-language papers or English abstracts of Greek-language articles were reported by e-mail response from abroad. Considered apart from the paper-publishing, the expenses of the digital publishing of the AHM are about half of those of paper-publishing, as they were before the appearance of the Journal in the Web. Up to now, about 40% of the Journal's digital publishing cost is covered by advertisements included in its pages and by a modification of its paper-publishing policy. It is concluded that the international scientific community is not indifferent for information published in NIMJs. Medical national minorities working abroad express special interest for this type of information. The Web makes the NIMJs accessible to these potential readers, who would never have the chance to acquire them in their printed form.

The effect of blood transfusion on 51Cr-red blood cells surface-counting data in homozygous beta-thalassaemia.

The effect of blood transfusion on 51Cr-red blood cells surface-counting patterns was studied in 22 patients with homozygous beta-thalassaemia being transfused during erythrocyte survival study. Surface-counting patterns of 15 thalassaemics who had not been submitted to blood transfusion during the erythrocyte survival study were served as controls. In 17 of the transfused patients (group A), spleen excess counts (SEC) appeared decreasing after blood transfusion, reaching a minimum (about 50% of the initial value) 3-4 days later, and increasing thereafter to reach again their initial value on 8th to 10th posttransfusion day. The SEC pattern of the remaining 5 transfused patients (group B) presented a continuously ascending curve. Corresponding changes were observed in excess liver counts and heart counts patterns. As a result of these changes spleen/liver ratio (S/L) was found significantly affected by blood transfusion in the majority of thalassaemic patients which were transfused during the erythrocyte survival study. Furthermore, the mean age of group A patients (12.1 +/- 5.5 years) has been found to be significantly lower than that of group B (21.8 +/- 3.3 years). On the contrary, in the control group the SEC pattern appeared permanently increasing and the S/L was found unaltered during the whole duration of the erythrocyte survival study. In conclusion, as far as the surface-counting data represent indexes for splenectomy in thalassaemic patients, the results of this study signify that the influence of blood transfusion on these has to be taken into account.

Kinetics of heat-damaged homologous erythrocytes. A five-compartmental analysis.

A new theoretical five-compartmental model (5CM) was developed for analysis of the clearance of heat-damaged erythroctes (HDE) labelled with chromium 51. Besides the HDE-spleen interaction, this new model also takes into account the interaction between extrasplenic reticuloendothelial (RES) sites and HDE, i.e. the hepatic clearance of fragmented erythrocytes (FE). Accordingly, HDE clearance curves are analysed into three exponential components, the fastest of which describes the RES-FE interaction, whereas the others describe the splenic clearance of spherocytes. Therefore, an estimation of the effective liver blood flow for HDE (ELBF) was achieved, along with a series of parameters describing splenic function. The 5CM proved to be more efficient than a previously proposed three-compartmental model (3CM) in the mathematical description of HDE clearance. Comparison was made by applying both models to 37 experimental curves obtained from 20 patients with congenital hemolytic anemias. The values for the splenic function parameters calculated by 5CM analysis and the strong correlations observed among them offer evidence that this model provides an adequate approximation to the real conditions under which HDE clearance takes place. Furthermore, a detailed quantitative analysis of the pooling of spherocytes within the spleen was attempted in this work, and this phenomenon was found to compete with splenic irreversible spherocyte trapping. The ELBF proved to be closely correlated with the hemodynamic splenic parameters, following first-order kinetics, as do low-dose colloids.

Partial splenic embolisation for hypersplenism of thalassaemia major: five year follow up.

Six patients with thalassaemia major were treated by partial splenic embolisation as an alternative to splenectomy and followed up for five years. Results were compared with those in a matched control group of seven patients treated by splenectomy. All patients treated by partial splenic embolisation showed a reduction in blood transfusion requirements comparable with those in the controls and which remained unchanged over the five years. Serious infections that commonly occur in patients splenectomised for thalassaemia did not occur after embolisation, presumably owing to preservation of some immune function by the splenic remnant. By contrast with the change in platelet counts seen after splenectomy, platelet counts remained normal after partial splenic embolisation, so reducing the risk of thromboses. On the other hand, pre-existing leucopenia and thrombocytopenia were corrected after embolisation. It is concluded that partial splenic embolisation provides an alternative to splenectomy for thalassaemia major and is equally effective and much safer.