Polymorphisms in Host Immunity-Modulating Genes and Risk of Invasive Aspergillosis: Results from the AspBIOmics Consortium.

Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12Brs3212227 and IFNγrs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγrs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFNγrs2069705 SNPs was stronger in allo-HSCT (IL4Rrs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγrs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγrs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057; P value for 96 h of treatment with phytohemagglutinin [PPHA-96 h], 0.036; PLPS+PHA-96 h = 0.030; PPHA-72 h = 0.045; PLPS+PHA-72 h = 0.018; PLPS-96 h = 0.058; PLPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P-2 log likehood ratio test = 5.2 · 10(-4) and P50.000 permutation test = 9.34 · 10(-5)). These findings suggest that the IFNγrs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.

Human platelet-specific antigens frequencies in the Argentinean population.

The frequencies of several human platelet antigens (HPAs) vary between different populations and are a major determinant for the prevalence of HPA alloimmunization and its clinical associated entities. The aim of this study was to characterize the allele frequencies of seven HPA systems in two different ethnic groups from the Argentinean city of Rosario, the major population and a minority Amerindian group recently arrived from the north of the country, the Tobas. A total of 192 healthy unrelated individuals from blood donors and hospital staff from the Hospital Italiano Garibaldi and 27 unrelated Toba Amerindians were genotyped for HPA-1, -2, -3, -4, -5, -6 and -15 systems by polymerase chain reaction with sequence specific primers (PCR-SSP). The present data showed that the distribution of the HPA alleles among Argentineans from Rosario is quite similar to that reported among Europeans. The frequencies seen in Tobas, although limited by the small number of aboriginal samples studied, are similar to those reported for other Amerindians populations. Statistically significant differences were found for the genotype distribution of HPA-1, -3, -5 and -15 between both groups, indicating important differences in the potential risk of HPA alloimmunization associated to transfusion and pregnancy. The study of these polymorphisms represents the first step in the elucidation of pathological conditions that are underdiagnosed in our population. It allowed us to establish a panel of characterized blood donors necessary for the serological work out and as a source for compatible platelets transfusion.

HNA-1a, HNA-1b and HNA-1c gene frequencies in Argentineans.

Human neutrophil antigens (HNA) are polymorphic structures located in the neutrophil membrane. The neutrophil-specific antigens HNA-1a (NA1), 1b (NA2) and 1c (SH) are well-recognized allotypic forms of FcgammaRIIIb and the most frequent targets of neutrophil alloantibodies. The aim of this study was to determine the gene frequencies of the neutrophil-specific antigens belonging to the HNA-1 system in blood donors and Toba Amerindians from Rosario, Argentina. Two hundred and eighteen unrelated healthy Argentinean blood donors and Toba Amerindians from Rosario were typed for HNA-1a, HNA-1b and HNA-1c using polymerase chain reaction with sequence-specific primers. For the Argentinean blood donors, the HNA-1a and HNA-1b gene frequencies were 0.44 and 0.56 and for the Amerindians Toba were 0.77 and 0.23, respectively. The HNA-1c antigen is present in 4.7% (gene frequency=0.023) of the blood donors but in none of the Amerindian individuals. The present data showed that the HNA-1 allele frequencies in the major population and the Toba Amerindians from Rosario are similar to those described in European and others distant Amerindians populations, respectively.

Time-course study of histological and genetic patterns of differentiation in human engineered oral mucosa.

The lack of sufficient oral mucosa available for intra-oral grafting is a major surgical problem, and new sources of oral tissues for clinical use are needed. In this regard, some models of engineered oral mucosa have been reported to date, but little is known about the structural and genetic mechanisms that occur during the process of development and maturation of these tissue substitutes. We have carried out a time-course study of the genes and morphological patterns of cell and tissue differentiation that develop in oral mucosa constructs after 3, 7, 11 and 21 days of development. Our electron microscopy and microarray analyses demonstrated that the oral mucosa constructs generated by tissue engineering undergo a progressive process of cell differentiation with the sequential formation and maturation of several layers of epithelium (with expression of stratifin, sciellin, involucrin, trichohyalin and kallikrein 7), intercellular junctions (with expression of plakophilin, desmocollin, desmoglein and cadherins), cytokeratins, a basement membrane (laminins, collagen IV) and the extracellular matrix (biglycan, matrix metalloproteinases). In conclusion, although the level and type of keratinization developed in vitro could be different, the oral mucosa substitutes were very similar to the native tissues.

[Variations in transfusion practice in Spain]. / Variaciones en la práctica de la transfusión en España.

OBJECTIVES: 1) To study the variations in the use of erythrocyte, platelet and plasma transfusion in Spain between regions, within a single region (Andalusia), and between hospitals; and 2) To determine any correlation between transfusion and blood donor rates within these areas. MATERIAL AND METHODS: The data were gathered from the Administrations of 17 regions, 8 Andalusian provinces, and 30 Andalusian hospitals. The variables selected for the study were the rates of donation, the rates of transfusion of each component/1000 inhabitants, and the rates of transfusion/1000 hospital stays. RESULTS: Among regions, the greatest variability was in platelet transfusion [Variation coefficient (VC) = 54.8%] and the least was in erythrocyte transfusion (VC = 21.2%). Donation rates correlated (r) strongly with erythrocyte and platelet transfusion rates, but not with those for plasma. Among the Andalusian provinces there was also a greater variability in the transfusion of platelets (VC = 61.3%) and a lesser one in erythrocyte transfusion (VC = 19.5%), and the correlation with donation rates was positive and significant for all the components (for erythrocytes, r = 0.93). CONCLUSIONS: There are significant variations in transfusion practice in Spain at all the levels we analysed. Variations are greatest in platelet transfusion, followed by erythrocyte and finally plasma transfusion. Blood donation rates correlate strongly with transfusion rates for most of the components.

How some attitudes, beliefs and motivations of Spanish blood donors evolve over time.

OBJECTIVES: To determine whether the attitudes, beliefs and motivations of blood donors evolve over time. MATERIALS AND METHODS: Using questionnaires a 7-year longitudinal study of a cohort of 126 donors was performed to gather their sociodemographic characteristics and their attitudes, beliefs and motivations relating to blood donation. RESULTS: Changes were observed in a large number of beliefs and attitudes, with a reduction in fear about donation and in the need for rewards and recognition, and an increase in comfort during donation and in attitudes of duty and solidarity. However, the motivations of 65% of the sample did not change. CONCLUSION: With the passage of time, donors' attitudes and beliefs evolve in a way that is favourable to blood donation and their motivations remain stable.

Altruism and payment in blood donation.

Paid blood donation still has its defenders, who cite economic doctrines denying the existence of altruism per se, the inability of most countries with exclusively voluntary donations to achieve self-sufficiency and the supposedly successful use of selected groups of paid donors. This paper argues that blood donation is an example of genuine altruism where the altruistic behaviour is incorporated into the self as a role. Unpaid donation is proven to be much safer for receivers and supply problems can be attributed fundamentally to inefficiencies in the organization of transfusion services. Voluntary and non-remunerated donation may be sufficient for a country/region to cover all its blood product needs, but requires an efficient organization and the elimination of "spurious altruism", nonmonetary forms of compensation that harm the social image of voluntary donation and obstruct its further development.

[Attitudes, beliefs, and motivations in blood donors and non-donors]. / Actitudes, creencias y motivaciones en donantes y no donantes de sangre.

OBJECTIVE: To know and compare the beliefs, attitudes and motivations of donors and non-donors in relation with blood donation. MATERIAL AND METHODS: Transversal study by questionnaires administered to 197 blood donors and 303 non-donors. The questionnaires gathered: sociodemographic data, beliefs and attitudes (using a Likert scale), and motivations and demotivations (using upon questions). The responses were analysed using different descriptive analyses and bivariant tests, and factorial analysis and discriminant analysis were performed as multivariant analyses. RESULTS: The donor group had a mean age of 37.8 years, were 58.4 female and 41.6% male, and had made 6.02 donations. The non-donor group had a mean age of 39.8 years and were 53.8% female and 46.2 male. Regarding attitudes and beliefs, the donor group showed more confidence in the good conditions in which donations are performed, had less fears about the possibility that donation can affect health, their attitudes were generally less egotistical, and they had less fears about possible commercialisation of the blood. Both groups believed that blood banks and society itself give inadequate compensation to donors, but this belief was significantly greater among non-donors. Regarding the motivations of donors, the highest proportion were related with a sense of solidarity or duty (26.4%), followed by issues related with information or pressure (23.4%), and the possible personal or family benefits that donation might bring (21.8%). The initial motivations of most donors (75.9%) had not varied with the passage of time, and the factors found to be most demotivating for donation had to do with problems of access and comfort (74.6%). We would highlight that most non-donors denied any worries about blood donation (70.9%) and did not agree that those who need blood should be those who pay for it (92.8%). For non-donors, lack of information (43.6%) and different fears (32.3%) were the principal factors discouraging them from donating. Finally, discriminant analysis selected 11 of the items as providing 75.6% of correct discrimination between the one population and the other. CONCLUSIONS: Donors and non-donors reveal very different beliefs, attitudes and motivations towards blood donation, and the questionnaire employed in this study permits a high degree of discrimination between the two groups. The attitudes of non-donors towards donation are generally less favourable, but allow us to think that a high percentage of these could be changed with the right conditions.

Epidemiology, serological markers, and hepatic disease of anti-HCV ELISA-2-positive blood donors.

The epidemiology associated with hepatitis C virus (HCV) infection, serologic reactivity, and hepatic disease related to anti-HCV-positive donors of Granada were researched. From 1990 through 1993, medical and epidemiological information and anti-HCV and HCV RNA testing were evaluated in 46,741 blood donors. Serum samples were obtained for anti-HCV ELISA and RIBA and HCV RNA determination. A liver biopsy was conducted in all anti-HCV positives by confirmatory second-generation RIBA to analyze the hepatic lesion and the presence of HCV RNA. The anti-HCV prevalence was 1.12%. A total of 228 anti-HCV second-generation ELISA positive blood donors were analyzed. Intrafamiliar transmission rate was 1.7%. Transfusion and intravenous drug abuse (IVDA) antecedents were associated with a higher risk of seroconversion. A RIBA-positive result was related to high second- and third-generation ELISA ratios (90%), HCV RNA positivity (89%), and elevated alanine aminotransferase (ALT) levels (88%). Approximately 50% of donors with normal ALT levels had high ELISA ratios and second-generation RIBA and HCV RNA positive results. Of the second-generation RIBA indeterminate results, 42% and 82% of the c22 and 33% and 100% of the c100 reactivities were third-generation RIBA and HCV RNA positive, respectively. Liver biopsy was conducted in 85 donors, 74% of whom had a chronic hepatitis and 83% had detectable HCV RNA levels. Chronic hepatitis was diagnosed in 88% vs 43% of donors with elevated and normal alanine aminotransferase levels, respectively. ELISA and confirmatory HCV RNA determinations should be routinely employed in donor screening. A liver biopsy should be conducted in patients with elevated ALT levels and normal ALT levels when viremic.

[Prospective study of the incidence of post-transfusion hepatitis after the exclusion of donors positive for anti-HCV ELISA 2]. / Estudio prospectivo de la incidencia de hepatitis postransfusional después de la exclusión de los donantes anti-VHC ELISA 2 positivos.

BACKGROUND: The incidence of post transfusional hepatitis (PTH) after the exclusion of anti-HCV ELISA 2 positive donors is not well known. The aim of this study was to determine the incidence and type of PTH in 113 post transfused patients. METHODS: A post transfusional follow up was performed for at least one year with periodic controls of transaminase levels. When an increase in GPT level compatible with PTH was demonstrated investigation of all the virus related with the transfusion was carried out in both the donor and the transfused subject: HAV, HCV, HEV, HBV and CMV. RESULTS: Four cases (3.5%) were detected which fulfilled the PTH criteria with the following characteristics: short period of time between transfusion and the increase in GPT level, moderate GPT increase, moderate clinical expression and good evolution. In all the cases the viral study was negative and other non viral possibilities were eliminated. CONCLUSIONS: Transfusions are currently relatively safe and the increase in transaminases may not be related with transfusion.

[Prevalence of antibodies against CMV in Grenada]. / Prevalencia de anticuerpos frente a CMV en Granada.

The prevalence of anti-CMV antibodies was studied on 1,552 serum samples by means of latex passive haemagglutination method. Of all the sera studied, 1,084 were positive (69.8%). Amongst them, 523 samples came from women and 561 from men, which represent 74.7% and 65.8%, respectively. Regarding to age, 62.3% of the positive samples were from people under 30 years and 91.3% from subjects over that age. The screening of anti-CMV antibodies is especially important in blood and organ donors, where the high percentage of positivity makes it difficult to select negative blood donations. Thus, taking into account the cost-effectiveness, and the results of this study, the search for CMV-negative blood must be exerted preferentially on the group of blood donors under 30 years of age, regardless of sex.