Evaluation of Polysaccharide Typhim Vi Antibody Response as a predictor of Humoral Immunodeficiency in Haematological Malignancies.

An increasing healthcare challenge in the management of haematological malignancy (HM) is secondary immunodeficiency. From January 2019, the EMA included the evaluation of specific antibody (Ab) responses to better select patients for immunoglobulin replacement therapy (IgRT). We evaluated Ab responses to pneumococcal and Salmonella typhi pure polysaccharide immunization in a cohort of 42 HM patients and 24 healthy-controls. Pre-post specific Ab concentrations were measured by ELISA at 4 weeks. Globally, significantly lower Typhim Vi (TV) seroprevalence (9%) compared to 23-valent pneumococcal polysaccharide vaccine (PPV) (76%) (p <0.001) was observed. TV non responders (88%) were higher than PPV non responders (62%) (p <0.0001) and correlated better to infectious history. By ROC analysis, pre-post 5-fold TV increase was the best cut-off to discriminate HM with recurrent infections and controls (sensitivity 91%, specificity 100%). Despite the small sample cohort, our results suggest that specific anti-S typhi Ab response is a useful complementary assay in the diagnosis and management decision of SID to HM.

Typhim vi immunization assists to discriminate primary antibody responses in hematological malignancies.

Assessment of specific antibody (Ab) production to polysaccharide antigens is clinically relevant, identifying patients at risk for infection by encapsulated bacteria and thus enabling a more rigorous selection of patients that can benefit of immunoglobulin replacement therapy. Classically, the gold-standard test is the measurement of antibody production to pure polysaccharide pneumococcal (PPV) immunization. Several factors, including introduction of conjugate vaccination schedule, serotyping analysis, high baseline Ab levels, have hindered the evaluation of polysaccharide antigens. This is even more difficult in secondary immunodeficiencies (SID), where patients can show secondary responses despite lack of primary antibody responses and present with recurrent or severe infections. Assessment of specific Ab production to pure Salmonella typhi Vi polysaccharide (TV) immunization has been proposed as a complementary test to PPV, given its low seroprevalence. To set the optimal cut-off value for PPV and TV response in SID, we tested different biostatistical methodologies, including ROC analysis, Youden index, Union index and Closest-topleft in a cohort of 42 SID patients and 24 healthy controls. The statistically chosen cut-offs value pre-post TV Ab ratio was ≥5, (sensitivity of 90%, specificity of 100%) and a postvaccination TV concentration of 28.5 U/mL (sensitivity of 90%, specificity of 95%), showing relevant clinical correlate.

[Incidence and clinical characteristics of maculopapular exanthemas of viral aetiology]. / Incidencia y características clínicas de los exantemas maculopapulares de etiología viral.

OBJECTIVE: To estimate the incidence of maculo-papular viral exanthemas and to describe the epidemiological and clinical patterns. DESIGN: Observational descriptive study with a sample design. PARTICIPANTS AND SETTING: 154 practitioners from the Castilla y León Sentinel Network with a surveilled population of 23 237 people-year under 15 years old, notified in 2002 the cases of diseases by means of a standard form with the variables and inclusion and exclusion criteria. MAIN MEASUREMENTS: It was included the maculo-papular exanthemas associated to a presumable systemic virus disease in patients under 15 years old. It was excluded the infectious mononucleose, the chickenpox, and other non viral infections or exanthemas. RESULTS: 368 cases were notified which represent a incidence rate of 158.37 cases per 10 000 (95% CI, 142.31-174.42). The incidence was maximum under four years old, more than 350 per 10 000, decreasing significantly in children over this age. Erythema infectiousum presented the highest rate, followed by exanthema subitum. The exanthemas caused by measles or rubella were insignificants. CONCLUSIONS: Childhood exanthematous diseases of presumable viral etiology have an important incidence in primary care, although the majorities are banal and self-limited diseases. Clinical characteristics supported the suspicion diagnosis, which was consistent with the observed epidemiological description and expected presentations of each disease. Although serological analysis could diminish the uncertainly on notification and control of diseases submited to especial programs of vaccination and eradication, they would not improve substantially the diagnosis and treatment of these patients.

Mhc-E polymorphism in Pongidae primates: the same allele is found in two different species.

Mhc-E intron 1, exon 2, intron 2, and exon 3 from pygmy chimpanzee (Pan paniscus), chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla) and orangutan (Pongo pygmaeus) have been sequenced; six new Mhc-E alleles have been obtained but sequence changes are only placed either in introns or in synonymous exonic bases. One pygmy chimpanzee Mhc-E DNA sequence is identical to another sequence from chimpanzee; the fact that no variation is found also at the intronic level suggests that these two species of chimpanzee may have recently separated and/or that both of them might only represent subspecies. Mhc-E phylogenetic trees separate two evolutionary groups: Pongidae, including humans, and Cercopithecinae; this is also found by studying another non-classical class I gene, Mhc-G. The Mhc-E alleles' invariance at the protein level supports that strong selective forces are operating at the Mhc-E locus, as has also been found in both Cercopithecinae and humans. These allelic and evolutionary data suggest an altogether different functionality for HLA-E (and also HLA-G) compared with classical class I proteins: i.e., sending negative (tolerogenic) signals to NK and T cells.

Phylogeny and rapid northern and southern hemisphere speciation of goldfinches during the Miocene and Pliocene epochs.

Mitochondrial cytochrome b (cyt b) from 25 out of 31 extant goldfinches, siskins, greenfinches and redpolls (genus Carduelis) has been sequenced from living samples taken around the world, specimens have also been photographed. Phylogenetic analysis consistently gave the same groups of birds, and this grouping was generally related to geographical proximity. It has been supposed that Pleistocene glaciations played a crucial role in the origin of extant diversity and distribution of Northern Hemisphere vertebrates. Molecular comparison of most extant songbird species belonging to the genus Carduelis does not support this assertion. The fossil record of chicken and pheasant divergence time has been used to calibrate the molecular clock; cyt b DNA dendrograms suggest that speciation in Carduelinae birds occurred during the Miocene and Pliocene Epochs (9-2 million years ago) in both the Northern and Southern Hemispheres. Only about 4% average amount of nucleotide substitution per lineage is found between the most distant Carduelis species; this suggests a remarkably rapid radiation when compared with the radiation of other passerine songbird genera. In addition, a continuum of small songbird speciation may be found during the Miocene Epoch in parallel with speciation of other orders (i.e. Galliformes, chicken/pheasant). Pleistocene glaciations may have been important in subspeciation (i.e. Eastern European grey-headed goldfinches/Western European black-headed goldfinches) and also in ice-induced vicariance (isolation) (i.e. siskin in Western Europe vs. siskin in Far East Asia) around the world. European isolated Serinus citrinella (citril finch) is not a canary, but a true goldfinch. South American siskins have quickly radiated in the last 4 million years coinciding with the emergence of the Isthmus of Panama; probably, a North American siskin related to C. notata invaded a suitable and varied biotope (the South American island) for Carduelis birds. North American goldfinches may be renamed as siskins, because they have a distant genetic relationship with European goldfinches. Genus Acanthis could be dropped, and thus redpolls should be separated from twite and linnet, the latter (Europeans) probably being related to American goldfinches. Also, reproductive barriers are observed between closely related species and not between other more distant ones. Finally, a tentative classification for genus Carduelis species is suggested.

Description of two Mhc-C-related sequences in the New World monkey Saguinus oedipus.

Two new Mhc class I partial exon 1, intron 1, exon 2, intron 2 and partial exon 3 DNA sequences from the New World monkey Saguinus oedipus (Saoe) are described. These two sequences show certain Mhc-C sequence-specific changes. The only difference between these two new sequences is a productive substitution at position 152 [GCG (Ala)-->GAG (Glu)]. This change occurs in a position which in Mhc classical class I molecules affects the interaction between the peptide and the T-cell receptor. A dendrogram with Mhc sequences from different loci and different species was constructed, which clearly shows that these two new sequences cluster closer to Mhc-C sequences than to others. These data suggest that the new sequences may be related to the Mhc-C locus, and they have been named Mhc-Saoe-CR*01 and -CR*02. However, they share only a few of the conserved residues (from gorilla to human) of Mhc-C sequences, which suggests that the relationships with an ancestor of the Mhc-C lineage are very distant or that these two sequences are products of convergent evolution to perform a C locus related function. Furthermore, in the fragment of DNA sequenced, there is a loss of two invariant residues conserved in antigen-presenting molecules from reptiles to humans; thus, it is unlikely that these two Mhc-C-like sequences have an antigen-presenting function, or even that they are two alleles of a pseudogene; however, the G + C percentage (86.1%) at the third base of codons approaches that of an expressed gene in Saoe. It is concluded that Mhc molecules with C-locus characteristics existed in primates 50 million years ago and that this does not support a more recent origin of Mhc-C genes.

Transcription and weak expression of HLA-DRB6: a gene with anomalies in exon 1 and other regions.

HLA-DRB6 is one of the human major histocompatibility complex (MHC) genes present in DR1, DR2, and DR10 haplotypes (approximately 26% of individuals). It shows several anomalies in human and non-human primates, including exon 2 stop codons (non-randomly grouped between codons 74 and 94) and a promoter region, and an exon 1 coming from an inserted retrovirus. It has been shown that not only chimpanzee but also human Mhc-DRB6 lack the usual 3' untranslated (UT) polyadenylation signal, and in the present work it was found that the human DRB6 gene coming from an HLA-DR2 haplotype is effectively transcribed after transfection in mouse L cells, and that HLA-DRB6 molecules may be expressed on the cell surface. DRB6 transcription level is remarkably lower in human than in chimpanzee. Moreover, their exons 1 (both taken from the 3'LTR region of a mammary tumor retrovirus) are also different; this shows that these viral insertions may be an important mechanism for different evolutionary changes in orthologous genes of different species. The pathways by which DRB6 molecules may be expressed on the membrane are unclear but other examples of truncated protein expression have also been described, even within the human major histocompatibility complex (i. e., in HLA-G). Finally, the presence of mature HLA-DRB6 mRNA molecules supports the notion that splicing may take place even in the absence of a canonical 3'UT polyadenylation signal.

Allelic diversity at the primate Mhc-G locus: exon 3 bears stop codons in all Cercopithecinae sequences.

Twenty-seven major histocompatibility complex (Mhc)-G exon 2, exon 3, and exon 2 and 3 allelic sequences were obtained together with 12 different intron 2 sequences. Homo sapiens, Pan troglodytes, Pan paniscus, Gorilla gorilla, Pongo pygmaeus, Macaca fascicularis, Macaca mulatta, and Cercopithecus aethiops individuals were studied. Polymorphism does not follow the classical pattern of three hypervariable regions per domain and is found in all species studied; exon 3 (equivalent to the alpha 2 protein domain) shows stop codons in the Cercopithecinae group but not in the Pongidae and human groups. Dendrograms show that cotton top tamarin (Saguinus oedipus) Mhc-G sequences are closer to Homo sapiens and Pongidae than to Cercopithecinae, probably due to the stop codons existing at exon 3 of the latter. There is a clear trans-species evolution of allelism in Cercopithecinae and also in exon 2 of all the other apes studied, but a generation of allelism within each species may be present on exon 3 sequences. This discrepancy may be due to the preferential use of exon 2 over exon 3 at the mRNA splicing level within each species in order to obtain the appropriate functional G product. Mhc-G intron 2 shows conserved motifs in all species studied, particularly a 23 base pair deletion between positions 161 and 183 which is locus specific, and some of the invariant residues, important for peptide presentation, conserved in classical class I molecules from fish and reptiles to humans were not found in Mhc-G alleles; the intron 2 dendrogram also shows a particular pattern of allelism within each species. In summary, Mhc-G has substantial differences from other classical class I genes: polymorphism patterns, tissue distribution, gene structure, splicing variability, and probably an allelism variability within each species at exon 3. The G proteins may also be different. This indicates that the Mhc-G function may not be peptide presentation to the clonotypic T-cell receptor.

Allelic diversity at the primate MHC-DMB locus: presence of a conserved tyrosine inhibitory motif in the cytoplasmic tail.

Ten new primate Mhc-DMB complete cDNA sequences have been obtained in chimpanzee (n=four), gorilla (n=three) and orangutan (n=three); this gene has not been previously studied in these species. Exonic allelism has been recorded all along the molecule domains and also in the leader peptide, but not in the transmembrane segment. An analysis of the residues critical in the conformation of the Mhc-DR peptide-binding site was done in order to look for a Mhc-DR homologue site; synonymous substitutions are favoured in this homologous HLA-DM region. This is another finding that supports the possibility that DM could not be typically presenting molecules. The immunoreceptor inhibition motif Tyr 230-Thr/Ser 231-Pro 232-Leu 233 (ITIM) is invariantly present in apes for at least 15 million years, and may have a double function: 1) To direct DMB-DMA molecules from the endoplasmic reticulum or cell surface towards the endosomal/lysosomal class II compartment and 2) to send an inhibitory signal to the cell in order to stop synthesis of unnecessary HLA-DR molecules, once all available antigenic peptides are loaded. Other molecules, like NK-cell receptors and Fc receptors, bear this type of tyrosine-based inhibitory motifs in order to switch off specific cell functions. DMB molecules (as previously shown in C4d molecules) do not present species-specific motifs in common chimpanzee, suggesting that this species is very close to gorilla or man; also, DMB, like C4d molecules, do not show a trans-species evolution pattern, suggesting the existence of extensive homogenization of DMB genes within each species or a recent generation of alleles. Finally, a clade grouping human and gorilla DMB cDNA sequences is obtained using a dendrogram (as for C4d trees); this is in contrast to others' results that obtain a human/chimpanzee clade using different DNA sequences.

El complejo TCR/CD3: especificidad con flexibilidad / TCR/CD3 complex: specificity with flexibility

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Enfermedad de Creutzfeldt-Jakob de presentación rápidamente progresiva / Creutzfeldt-Jackob disease with rapidly progressive presentation

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Incidencia y características clínicas de los exantemas maculopapulares de etiología viral / Incidence and clinical characteristics of maculopapular exanthemas of viral aetiology

Objetivo. Estimar la incidencia de exantemas maculopapulares de presumible etiología viral y describir las características epidemiológicas y clínicas. Diseño. Estudio observacional, descriptivo, de diseño muestral. Participantes y emplazamiento. Ciento cincuenta y cuatro médicos integrantes de la Red de Médicos Centinelas de Castilla y León, en una población vigilada de 23.237 personas-año menores de 15 años, notificaron durante el año 2001 los casos de la enfermedad a través de una ficha estándar que contenía las variables requeridas y los criterios de inclusión y exclusión.Mediciones principales. Se incluyeron los exantemas maculopapulares asociados a enfermedad sistémica de presumible etiología viral en menores de 15 años. Se excluyeron la mononucleosis infecciosa, la varicela y otras infecciones o exantemas no virales. Resultados. Se notificaron 368 casos, que suponen una tasa de incidencia de 158,37 casos por 10.000 (IC del 95 por ciento, 142,31174,42). La incidencia fue máxima en los menores de 4 años, superior a 350 por 10.000, reduciéndose significativamente en los niños mayores de esa edad. El eritema infeccioso presentó la tasa más elevada, seguido del exantema súbito. Los exantemas ocasionados por sospecha de sarampión o rubéola fueron insignificantes. Conclusiones. Las enfermedades exantemáticas en la infancia de presumible etiología viral tienen una incidencia importante en atención primaria, si bien la mayoría son enfermedades leves y autolimitadas. Las características clínicas fundamentaron el diagnóstico de sospecha etiológico, que fue coherente con la descripción epidemiológica observada y las manifestaciones esperadas para cada enfermedad. Si bien los análisis serológicos permitirían disminuir la incertidumbre en la notificación y el control de enfermedades sometidas a programas especiales de vacunación y eliminación, no mejorarían sustancialmente el diagnóstico y tratamiento de estos pacientes (AU)