New αIIbß3 variants in 28 Turkish Glanzmann patients; structural hypothesis for complex activation by residues variations in I-EGF domains.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by impaired platelet aggregation due to defects in integrin αIIbß3, a fibrinogen receptor. Platelet phenotypes and allelic variations in 28 Turkish GT patients are reported. Platelets αIIbß3 expression was evaluated by flow cytometry. Sequence analyzes of ITGA2B and ITGB3 genes allowed identifying nine variants. Non-sense variation effect on αIIbß3 expression was studied by using transfected cell lines. 3D molecular dynamics (MDs) simulations allowed characterizing structural alterations. Five new alleles were described. αIIb:p.Gly423Asp, p.Asp560Ala and p.Tyr784Cys substitutions impaired αIIbß3 expression. The αIIb:p.Gly128Val substitution allowed normal expression; however, the corresponding NM_000419.3:c.476G>T variation would create a cryptic donor splicing site altering mRNA processing. The ß3:p.Gly540Asp substitution allowed αIIbß3 expression in HEK-293 cells but induced its constitutive activation likely by impairing αIIb and ß3 legs interaction. The substitution alters the ß3 I-EGF-3 domain flexibility as shown by MDs simulations. GT variations are mostly unique although the NM_000419.3:c.1752 + 2 T > C and NM_000212.2:c.1697 G > A variations identified in 4 and 8 families, respectively, might be a current cause of GT in Turkey. MD simulations suggested how some subtle structural variations in the ß3 I-EGF domains might induce constitutive activation of αIIbß3 without altering the global domain structure.

Performance, body fat reserves and plasma metabolites in Brown Swiss dairy cows: Indoor feeding versus pasture-based feeding.

Feeding dairy cows indoors or on pasture affects not only labour, machinery and housing costs, but also animals' performance and metabolism. This study investigates the effects of indoor feeding (IF) with a partial-mixed ration (PMR) versus pasture-based feeding (PF) on milk production, fertility, backfat thickness (BFT), body weight (BW) loss and energy metabolism of Brown Swiss (BS) dairy cows with similar genetic production potential. The IF herd consisted of 13 cows fed a PMR composed of maize and grass silage plus protein concentrate according to each cow's requirements. The PF herd consisted of 14 cows offered barn-ventilated hay ad libitum after calving from January until March and grazed on semi-continuous pastures during the vegetation period. The IF cows produced more energy-corrected milk (ECM) per standard lactation (9,407 vs. 5,960 kg; p < .01), more milk fat (378 vs. 227 kg; p < .01) and milk protein (326 vs. 215 kg; p < .01). The calving interval (377 vs. 405 days; p < .01) and time empty (86 vs. 118 days; p < .01) were shorter in the PF compared to IF, possibly also due to different selection criteria for maintaining the respective seasonal calving rhythm. The empty body fat loss calculated according to BCS until its nadir was higher in IF cows (IF: 10.4 vs. PF: 4.8 MJ/day; p < .01), but no differences were noted in total body fat loss estimated via BFT (p = .24). However, PF had lower blood glucose concentration at all investigated time points, but no differences occurred in serum non-esterified fatty acid and ß-hydroxybutyrate concentrations post-partum. In conclusion, BS cows were equally well suited for the IF with PMR and the PF system investigated here without developing a prominent metabolic load despite differences in nutrient supply. As such, investigated BS dairy cows in our trial seem to have a high capacity for metabolic adaptation to different production systems.

Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome.

Patients with Wiskott-Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760 ) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242 ), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS.

Does body size of dairy cows, at constant ratio of maintenance to production requirements, affect productivity in a pasture-based production system?

This study compared productivity of dairy cows with different body weight (BW), but a constant ratio of maintenance to production requirements in their first lactation, in a pasture-based production system with spring calving. Two herds, Herd L (13 and 14 large cows in 2003 and 2004 respectively; average BW after calving, 721 kg) and Herd S (16 small cows in both years; 606 kg) [Correction added after online publication 14 January 2011: 16 small cows in both years; 621 kg was changed to 16 small cows in both years; 606 kg], all in their second or following lactations, were each allocated 6 ha of pasture and rotationally grazed on 10 parallel paddocks with equal herbage offer and nutritional values. Winter hay, harvested from the same pastures, was offered ad libitum in the indoor periods in a tied stall barn. Each herd received, per lactation and year, approximately 2000 kg dry matter (DM) of concentrates and of fodder beets, equally distributed to every individual. Indoors, the L-cows ingested more DM than the S-cows (18.7 vs. 16.3 kg DM/cow per day; p < 0.01), but DM intake per 100 kg of metabolic BW was similar (13.0 vs. 13.1 kg DM/cow per day). Estimates based on the n-alkane technique gave similar results on pasture (17.9 vs. 15.5 kg DM/cow per day; p < 0.001). Roughage intakes per 100 kg of metabolic BW, at 13.5 kg DM/cow per day, were similar. Mean annual yield of energy-corrected milk (ECM)/ha was slightly higher for the S-herd than the L-herd (13,026 vs. 12,284 kg) but was associated with a higher stocking rate (on average +20%) for the S-herd. Feed conversion efficiency (1.2 vs. 1.3 kg ECM/kg DM intake) and overall milk production efficiency (45.3 vs. 47.3 kg ECM/kg metabolic BW) were similar in L- and S-cows. Thus, both dairy cow types were equally efficient in utilising pasture-based forage.

[Thirty years of platelet immunology in fetal and neonatal alloimmune thrombocytopenia management, current situation]. / Trente ans d'immunologie plaquettaire dans la prise en charge des thrombopénies fœtales et néonatales allo-immunes, état des lieux.

Fetal and neonatal allo-immune thrombocytopenia (FNAIT) is considered as a rare disease due to the incidence (1/1000-1/2000 births). The major complication of severe thrombocytopenia is bleeding and particularly intra-cranial hemorrhage and neurologic sequelae following. Serology and molecular biology developments have reconfigured the platelet immunology diagnosis. Anti-HPA-1a allo-immunisation is responsible for more than 80% FNAIT cases with a high recurrence rate of severe bleeding complications. Therapeutic management has changed over the coming years from an invasive concept associating fetal blood sampling and in utero platelet transfusion to a non invasive treatment by intravenous immunoglobulins injection (IVIg). The purpose of this article is to provide an update on FNAIT management in the light of current developments over the past 30years.

Cab4b, the first human platelet antigen carried by glycoprotein IX discovered in a context of severe neonatal thrombocytopenia.

Essentials Life-threatening maternofetal thrombocytopenias mostly depend on αIIb ß3 antigens. We performed serological, genomic and in vitro studies of two life-threatening thrombocytopenias. Identification of a c.368C>T variation leading to Pro123Leu substitution in GPIX. A rare GPIX variant reported in a genomic database define a new alloantigen. SUMMARY: Background After three miscarriages, a 39-year-old woman gave birth, with a 1-year interval, to two severely thrombocytopenic neonates (4 ×109 L-1 and 33 ×109 L-1 ) with intracranial hemorrhages. Transfusion of platelet concentrates corrected the thrombocytopenia. The outcome was favorable for the first child, but the second one died 10 days after cesarean delivery (31 weeks of gestation + 6 days). Methods Serologic studies were performed with mAb-specific immobilization of platelet antigens and flow cytometry techniques. Human platelet alloantigen (HPA) genotyping was performed with the BioArray HPA BeadChip and PCR-sequence-specific primer techniques. Genomic DNA was studied by direct sequencing of PCR products. The mutant glycoprotein (GP) was expressed in transiently transfected HEK293 cells. Results In MAIPA assay, the maternal serum faintly reacted with GPIbIX from paternal and child 1 platelets, but not with maternal or panel platelets. No maternofetal incompatibility was found in the 22 known HPA systems, tested except for HPA-1b in child 2. A new alloantigen carried by GPIbIX was suspected. Genomic sequencing revealed a paternal GPIX variation (NM_000174.4:c.368C>T). The father and children were heterozygous and incompatible with the mother, who was NM_000174.4:c.368C homozygous. The maternal serum reacted with the GPIX NP_000165.1:p.Leu123 form coexpressed with GPIb in transfected HEK293 cells. The NM_000174.4:c.368T allele (rs202229101) has a minor allele frequency of 0.0002, and was not detected in 120 French subjects (families with fetal and neonatal alloimmune thrombocytopenia [FNAIT]), suggesting that it is rarely implicated in alloimmunization. Conclusion The NP_000165.1:p.Leu123 allele named Cab4b is the first platelet alloantigen described on GPIX. In the absence of other known maternofetal incompatibility, the child 1 case suggests that anti-Cab4b alloantibodies can induce severe thrombocytopenias.

[Platelet transfusion role in neonatal immune thrombocytopenia]. / Place de la transfusion plaquettaire dans les thrombopénies immunes néonatales.

Neonatal immune thrombocytopenia represent less than 5% of cases of early thrombocytopenia (early-onset<72hours post-delivery). As in adults, thrombocytopenia in neonates is defined as a platelet count less than 150G/L. They are either auto- or allo-immune. Thrombocytopenia resulting from transplacental passage of maternal antibodies directed to platelet membrane glycoproteins can be severe. The major complication of severe thrombocytopenia is bleeding and particularly intra-cranial haemorrhage and neurologic sequelea following. However, auto- and allo-immune thrombocytopenia have very different characteristics including the treatment management. In fact, this treatment is based on platelet transfusion associated or not to intravenous immunoglobulin administration. The purpose of this article is to remind platelet transfusion's place in neonatal immune thrombocytopenia in terms of recently published French guidelines and international practices.

[Blood representations associated to chronic transfused patients: Symbolic interpretations and ethical perspectives]. / Lectures des représentations du sang chez les receveurs chroniques de produits sanguins labiles : interprétations symboliques et perspectives éthiques.

Since the beginning of the 20th century, major technological developments have been made in blood transfusion. Although numerous sociological studies have been conducted on donors, few have highlighted transfused patients, and in this case, the attention has almost exclusively been focused on transfusion risks in patients. Conversely, blood representations associated with the chronically transfused patients have not really been explored in the literature. Based on interviews conducted among chronically transfused patients (patients with hemoglobinopathy, malignant hemopathy or cancer), this present study enables to understand their needs and their expectations through their symbolic representations and their interpretations of blood transfusion, raising tensions as well ethical perspectives.

Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II.

As a result of the t(11;22)(q24;q12) chromosomal translocation characterizing the Ewing family of tumors (ET), the amino terminal portion of EWS, an RNA binding protein of unknown function, is fused to the DNA-binding domain of the ets transcription factor Fli1. The hybrid EWS-Fli1 protein acts as a strong transcriptional activator and, in contrast to wildtype Fli1, is a potent transforming agent. Similar rearrangements involving EWS or the highly homologous TLS with various transcription factors have been found in several types of human tumors. Employing yeast two-hybrid cloning we isolated the seventh largest subunit of human RNA polymerase II (hsRPB7) as a protein that specifically interacts with the amino terminus of EWS. This association was confirmed by in vitro immunocoprecipitation. In nuclear extracts, hsRPB7 was found to copurify with EWS-Fli1 but not with Fli1. Overexpression of recombinant hsRPB7 specifically increased gene activation by EWS-chimeric transcription factors. Replacement of the EWS portion by hsRPB7 in the oncogenic fusion protein restored the transactivating potential of the chimera. Our results suggest that the interaction of the amino terminus of EWS with hsRPB7 contributes to the transactivation function of EWS-Fli1 and, since hsRPB7 has characteristics of a regulatory subunit of RNA polymerase II, may influence promoter selectivity.

Cloning of a novel human ELF-1-related ETS transcription factor, ELFR, its characterization and chromosomal assignment relative to ELF-1.

The ETS gene family encodes a group of proteins that function as transcription factors under physiological conditions and, if aberrantly expressed, can lead to cellular transformation. ETS transcription factors are characterized by a unique conserved DNA binding domain. A subset of these proteins is rearranged with EWS in Ewing tumors (ET). We recently described a spectrum of ETS genes coexpressed with EWS-FLI1 in an ETcell line to define proteins that potentially compete in target site selection. We now report on the cloning and characterization of a novel ETS family member, ELFR, displaying 92% homology to ELF-1 in its DNA binding domain while diverging in the rest of the protein. ELFR expression was found in a very tissue restricted pattern with the highest abundancy in placenta. We also report the chromosomal assignment of ELFR and ELF-1 to Xq26 and 13q13, respectively, by means of fluorescence in-situ hybridization (FISH).

Shear stress abnormalities contribute to endothelial dysfunction in hypertension but not in type II diabetes.

BACKGROUND: The relative contribution of the various hemodynamic and metabolic mechanisms leading to endothelial dysfunction may be different in specific vascular diseases. Since shear stress is one of the main mechanical stimuli of endothelial cells, the aim of this study was to investigate its contribution to endothelial dysfunction in two distinct vascular diseases, hypertension and type II diabetes. SUBJECTS AND METHODS: We measured the radial artery diameter at baseline, after ischemic vasodilation and after nitroglycerin vasodilation in 16 untreated patients with high blood pressure, in 15 type II normotensive diabetic patients and in 17 healthy controls. Wall shear stress was evaluated by simultaneous measurements of whole blood viscosity and blood flow velocity. RESULTS: In diabetic patients, whole blood viscosity was significantly higher whereas wall shear stress was similar compared to controls. In hypertensive patients, whole blood viscosity was higher and wall shear stress was lower than in controls. Endothelium-dependent vasodilation was impaired in both hypertensive and diabetic patients (P < 0.01) after adjustment for age, sex, body mass index and postnitroglycerin vasodilation. When adjustments were made for maximal systolic shear stress, endothelium-dependent vasodilation remained lower in the diabetic patients (P < 0.01), but not in those with high blood pressure compared to controls. CONCLUSIONS: In hypertension, endothelium-dependent vasodilation is mainly due to a chronic decrease in shear stress (the most important physiological stimulus of the endothelial cells) with no major intrinsic endothelial cell dysfunction. In contrast, in diabetics, the lower endothelium-dependent vasodilation was not the result of an altered shear stress.

Los problemas auditivos aumentan el riesgo de deterioro cognitivo en adultos mayores chilenos / Hearing impairments increase the risk of cognitive impairment in older Chilean adults

RESUMEN Introducción: Estudios previos han asociado la pérdida auditiva con un acelerado deterioro cognitivo durante el envejecimiento; no obstante, esta asociación no ha sido estudiada en adultos mayores chilenos. Objetivo: Investigar la asociación entre la discapacidad auditiva y la sospecha de deterioro cognitivo a través del cuestionario Mini Mental State Examination (MMSE, versión abreviada) en esta población. Material y método: Se incluyeron 1.384 adultos mayores de 60 años de la encuesta nacional de salud 2009-2010. Un puntaje <13 puntos en el MMSE se consideró sospecha de deterioro cognitivo. La discapacidad auditiva se determinó a través de un cuestionario de tamizaje autorreportado de tres preguntas. La asociación entre estas dos variables se investigó mediante análisis de regresión logística. Resultados: Se identificó una asociación significativa entre el MMSE alterado y cada una de las discapacidades auditivas estudiadas. A su vez, existió una tendencia a aumentar en 59% la probabilidad de desarrollar deterioro cognitivo en la medida que aumentaron las discapacidades auditivas (OR: 1,59 [95% IC: 1,38 a 1,82], p <0,0001). Conclusión: La disminución de la percepción auditiva es un factor de riesgo para el desarrollo de deterioro cognitivo y posteriormente demencia. La creación de políticas públicas, orientadas al tamizaje temprano en población de riesgo, podría ser una solución efectiva para prevenir las consecuencias asociadas con esta condición.

ABSTRACT Introduction: Hearing loss has been associated with an accelerated cognitive impairment during ageing. However, this association has not been investigated in older Chilean adults. Aim: To investigate the association between hearing impairment and cognitive impairment, using the Mini-Mental State Examination (MMSE, abridged version), in the Chilean population. Material and methods: 1,384 older adults aged ≥60 years, from 2009-2010 Chilean national health survey, were included. <13 points in the MMSE were considered suspicion of cognitive impairment. Hearing impairment was determined through a questionnaire including 3 domains. The association between cognitive and hearing loss was investigated using logistic regression. Results: An association between MMSE and each hearing disabilities studied was identified. As hearing impairments increased, the odd for cognitive impairment incremented by 59% (OR: 1.59 [95% IC: 1.38 a 1.82], p <0.0001). Conclusion: Hearing loss is a risk factor to develop cognitive impairment, which could translate into a high risk of dementia. Public politics implementation, focused in an early screening, could be an effective approach to prevent the complications associated with this hearing loss in older adults.

[Transfusion transmitted bacterial infectious (TTBI) with blood component accountability score 2: Retrospective analysis of the French e-fit database 2000-2007. Groupe de travail­validation des IBTT (Working group for validation of transfusion-transmitted bacterial infections)]. / Les infections bactériennes transmises par transfusion avec imputabilité 2 du PSL : analyse rétrospective de la base e-FIT de 2000 à 2007.

PURPOSE OF THE STUDY: Transfusion transmitted bacterial infection is an adverse reaction occurring in a patient during blood transfusion and due to the presence of bacteria in the blood component. For each transfusion transmitted bacterial infection suspicion, clinical and biological investigations should allow to either affirm the accountability of the transfused product in the occurrence of the infection (accountability score 4) or exclude it (accountability score 0). However, among 60,175 adverse reaction sheets extracted from the French e-FIT database (AFSSAPS), 143 are classified as transfusion transmitted bacterial infection diagnosis and 97 of them show a score of accountability 2 (possible). This study aims to analyze these 97 adverse reaction sheets and search for the reasons that led the haemovigilance network actors not to refine the degree of accountability in line with an exclusion or a confirmation of transfusion origin. METHOD: During collective reading sessions, each adverse reaction sheet among the 97 extracted was re-analyzed with an accountability criteria grid, built beforehand, and proposed in the technical guide sheet for transfusion transmitted bacterial infection (e-Fit AFSSAPS). RESULTS: Among the 97 analyzed adverse reaction sheets with a score accountability of 2: 12.4 % were considered as "non-analysable"; 54% were reclassified in another diagnosis category: non haemolytic febrile reaction (n=12), unknown diagnosis (n=17); patient infection before transfusion (n=23); blood component's "smear" (n=9); retrograde contamination of blood component (n=5). Finally, only 18.5% adverse reaction sheets (n=18) were maintained with a true diagnosis of transfusion transmitted bacterial infection an accountability score of 2. These cases were in agreement with those described in number 2, 3 or 4 in the annex sheet "Fiche Technique TTBI". 70% of adverse reaction sheets reclassified under another diagnosis as transfusion transmitted bacterial infection had been declared between 2000 and 2004. In order to improve transfusion transmitted bacterial infection suspicions diagnosis approach and to guide the French haemovigilance network in the investigations following a transfusion transmitted bacterial infection suspicion, the group propose recommendations after each adverse reaction sheets category analysis. CONCLUSION: The improvement measures taken as part of the French haemovigilance declaration framework allowed to perfect the data quality of transfusion transmitted bacterial infection. Progresses are still to be made to improve clinical and biological declaration, in order to precise the accountability of a blood component in the occurrence of an adverse transfusion transmitted bacterial infection effect. Tracking transfusion transmitted bacterial infection notifications by a group of experts at the national level is still recommended.

[Detection of B19 parvovirus in plasma pools before solvent-detergent treatment of plasma: AFSSAPS and EFS Aquitaine-Limousin's experience]. / Détection du génome viral du parvovirus B19 dans les pools de plasmas servant à la préparation du plasma frais congelé traité pour viro-atténuation par solvant-détergent : expérience de l'Afssaps et de l'EFS Aquitaine-Limousin.

Since 1998, the Aquitaine-Limousin branch of the French Blood Institute has set up a parvovirus B19 (PV B19) systematic screening on each unit of plasma to be treated by solvent-detergent procedure for virus inactivation. Parvovirus B19 nucleic acid systematic testing in plasma pools became mandatory since 2005 (European monograph "Human plasma" - pooled and treated for virus inactivation). The French competent state authority (AFSSAPS) has decided to introduce this test as a part of the external quality control of labile blood products. This process is related to the harmonization of quality control practice realised on blood products in Europe even if the human plasma pooled and treated for virus inactivation by solvent-detergent is considered in France as a blood labile component. Implementation of this test required a validation step and a close cooperation between AFSSAPS and Aquitaine-Limousin blood transfusion centre. Validation consisted in perfecting a semi-quantitative, real-time nucleic acid testing method with automated extraction. This collaborative study leads us to control 1642 plasma pools. All the results were under the threshold of 10,0 IU/microL. AFSSAPS's results were in agreement with those of Aquitaine-Limousin's blood transfusion center who carry out the parvovirus B19 screening both on fresh frozen plasma units composing the pool and on plasma pools.

A recombination based method to rapidly assess specificity of two-hybrid clones in yeast.

The yeast two-hybrid system is frequently used to identify protein-protein interactions. Confirming the specificity of candidate clones requires separation and isolation of yeast plasmids, propagation in bacteria and testing combinations of DNA-binding and activation domain hybrids in yeast. In order to simplify this procedure, we developed a rapid method based on PCR amplification of library insert DNAs and in vivo cloning into the activation domain hybrid vector. Reporter gene activity is assayed in parallel for combinations with different DNA-binding domain hybrids. Further characterization of inserts does not require plasmid isolation and intermediate hosts.

T cell receptor vbeta repertoire in bronchoalveolar lavage in Wegener's granulomatosis and sarcoidosis.

BACKGROUND: Lymphocytic alveolitis is a common feature of Wegener's granulomatosis (WG) and sarcoidosis. In pulmonary sarcoidosis analysis of the T cell receptor (TCR) configuration disclosed a biased TCR repertoire in cells obtained by bronchoalveolar lavage (BAL), suggesting that the pulmonary T cell population contains an oligoclonal, probably antigenically selected component. We examined whether this is also a feature of WG. METHODS: The distribution of 16 TCR Vbeta phenotypes on BAL cells was compared with the distribution on autologous blood cells in 8 WG patients with lymphocytic alveolitis. A control group was composed of 5 patients with active pulmonary sarcoidosis. The two groups were comparable with respect to the lymphocyte count in BAL and the distribution of the CD4+ and CD8+ T cell subsets in BAL and the blood. Overutilization of individual Vbeta phenotypes on BAL cells was considered to be significant when the percentage of positive cells in BAL doubled than in the blood and the frequency in BAL was at least 10% of total BAL T cells. RESULTS: All 5 sarcoidosis patients showed substantial overutilization of individual Vbeta families in BAL as compared with the blood. By contrast, only 2 of the 8 WG patients showed overutilization of individual Vbeta phenotypes in BAL. CONCLUSIONS: These findings do not suggest that the T cell population in BAL of WG patients contains a prominent oligoclonal component. While BAL is a convenient approach to obtain T cells from a site of active disease, BAL cells do not appear to be good material for the isolation of clonally selected T cells in WG.

Vacuna de polisacárido meningocócico del grupo C conjugada con toxoide tetánico. Un meta-análisis de la inmunogenicidad, seguridad y posología / Group C Meningococcal Polysaccharide-Tetanus Toxoid Conjugate Vaccine. A Meta-Analysis of Immunogenicity, Safety and Posology

La vacuna que contiene polisacárido de meningococodel grupo C de-O-acetilado, conjugada con toxoidetetánico (GCMP-TT), se ha autorizado en 32países y se ha incorporado en un programa de vacunaciónrutinaria en el Reino Unido. Rápidamentese ha acumulado una gran experiencia, que es elobjeto de este meta-análisis, sobre la inmunogenicidad,seguridad y posología de GCMP-TT, así comosobre su impacto epidemiológico. GCMP-TT ha demostradoser efectiva tras una dosis única en individuosmayores de 12 meses de edad y su posologíainicial especificaba tres dosis en lactantes. Sin embargo,según un ensayo clínico reciente, la posologíase redujo a dos dosis en lactantes. La tasa deprotección recogida, definida como la proporción deindividuos con títulos de anticuerpos bactericidas ensuero (SBA) ≥1:8, fue del 99,4% (CI, 98.2-99.9%) ensiete estudios clínicos que abarcan todos los gruposde edad. Se han demostrado respuestas fuertes aGCMP-TT con respecto a SBA, niveles de IgG y deavidez a los anticuerpos. En la farmacovigilanciadespués de la comercialización, que abarca >12 x106 GCMP-TT dosis distribuidas por todo el mundo,la vacuna ha sido bien tolerada con una tasa de incidenciade 0,01% para todos los tipos de efectos adversosmás comúnmente encontrados. Después deuna campaña de vacunación general en el ReinoUnido, en la que a los niños de 5-8 años se les dioprimeramente GCMP-TT, se observó una disminucióndel 93% en la incidencia de enfermedad meningocócica.A la vista de esta inmunogenicidad, seguridady adaptación potencial al uso en lactantes enprogramas de posología reducida, la vacuna GCMPTTmarca un mayor avance sobre las vacunas depolisacárido predecesoras en la prevención de enfermedadmeningocócica C

A conjugate vaccine comprised of de-O-acetylatedgroup C meningococcal polysaccharide coupledto tetanus toxoid (GCMP-TT) has been licensed in32 countries and incorporated in a comprehensiveUK vaccination program. Extensive evidence, formingthe subject of this meta-analysis, has rapidlyaccumulated on the immunogenicity, safety and posologyof GCMP-TT as well as its epidemiologicalimpact. GCMP-TT has been shown effective after asingle dose in individuals > 12 months of age, andinitial posology specified three doses in infants. However,based on a recent clinical trial, posology wasreduced to two doses in infants. Pooled protectionrate, defined as proportion of subjects with serumbactericidal antibody (SBA) levels 1:8, was 99.4%(CI, 98.2-99.9%) in 7 clinical trials covering all agegroups. Robust responses to GCMP-TT have been demonstrated with respect to SBA, IgG levels andantibody avidity. In post-marketing pharmacosurveillanceencompassing > 12*106 GCMP-TT doses distributedworldwide, the vaccine has been well toleratedwith an incidence rate of 0.01% for all the mostcommonly encountered types of adverse events. Aftera catch-up UK vaccination campaign where 5-8year old children were primarily given GCMP-TT, a93% decline in meningococcal disease incidencewas observed. In view of its immunogenicity, safetyand potential suitability for use among infants in reduceddose schedules, GCMP-TT appears to marka major advance over predecessor polysaccharidevaccines for the prevention of meningococcal C disease