ABSTRACT
Typical Kunitz proteins (I2 family of the MEROPS database, Kunitz-A family) are metazoan competitive inhibitors of serine peptidases that form tight complexes of 1:1 stoichiometry, mimicking substrates. The cestode Echinococcus granulosus, the dog tapeworm causing cystic echinococcosis in humans and livestock, encodes an expanded family of monodomain Kunitz proteins, some of which are secreted to the dog host interface. The Kunitz protein EgKU-7 contains, in addition to the Kunitz domain with the anti-peptidase loop comprising a critical arginine, a C-terminal extension of â¼20 amino acids. Kinetic, electrophoretic, and mass spectrometry studies using EgKU-7, a C-terminally truncated variant, and a mutant in which the critical arginine was substituted by alanine, show that EgKU-7 is a tight inhibitor of bovine and canine trypsins with the unusual property of possessing two instead of one site of interaction with the peptidases. One site resides in the anti-peptidase loop and is partially hydrolyzed by bovine but not canine trypsins, suggesting specificity for the target enzymes. The other site is located in the C-terminal extension. This extension can be hydrolyzed in a particular arginine by cationic bovine and canine trypsins but not by anionic canine trypsin. This is the first time to our knowledge that a monodomain Kunitz-A protein is reported to have two interaction sites with its target. Considering that putative orthologs of EgKU-7 are present in other cestodes, our finding unveils a novel piece in the repertoire of peptidase-inhibitor interactions and adds new notes to the evolutionary host-parasite concerto.
Subject(s)
Echinococcus granulosus , Helminth Proteins , Echinococcus granulosus/enzymology , Echinococcus granulosus/genetics , Echinococcus granulosus/metabolism , Animals , Dogs , Helminth Proteins/metabolism , Helminth Proteins/genetics , Helminth Proteins/chemistry , Trypsin Inhibitors/metabolism , Trypsin Inhibitors/chemistry , Cattle , Amino Acid Sequence , Trypsin/chemistry , Trypsin/metabolismABSTRACT
La mononucleosis infecciosa es una enfermedad infectocontagiosa causada por el virus de Epstein-Barr, que afecta principalmente a personas jóvenes, se caracteriza por presencia de fiebre, faringitis y linfadenopatía, generalmente autolimitada, de 1-2 semanas de evolución. Se presenta el caso de un paciente masculino de 22 años con historia de 1 mes de evolución de fiebre y cefalea al que posteriormente se añade odinofagia, adenopatía cervical posterior y exantema generalizado. En analítica laboratorial se constata leucocitosis con neutrofilia. Entre sus estudios complementarios retorna IgM para virus de Epstein-Barr positivo.
Infectious mononucleosis is an infectious disease caused by the Epstein-Barr virus, which mainly affects young people. It is characterized by the presence of fever, pharyngitis and lymphadenopathy, generally self-limited, lasting 1-2 weeks. The case of a 22-year-old male patient with a 1-month history of fever and headache is presented to which odynophagia, posterior cervical lymphadenopathy, and generalized rash are later added. Laboratory analysis revealed leukocytosis with neutrophilia. Among his complementary studies, IgM for Epstein-Barr virus was positive.
Subject(s)
Myelodysplastic Syndromes , Humans , Child , Methylation , Myelodysplastic Syndromes/genetics , Prognosis , Biomarkers , DNA MethylationABSTRACT
Congenital anomalies (CA) affect 3-5% of newborns, representing the second-leading cause of infant mortality in Argentina. Multiple congenital anomalies (MCA) have a prevalence of 2.26/1000 births in newborns, while congenital heart diseases (CHD) are the most frequent CA with a prevalence of 4.06/1000 births. The aim of this study was to identify the genetic causes in Argentinian patients with MCA and isolated CHD. We recruited 366 patients (172 with MCA and 194 with isolated CHD) born between June 2015 and August 2019 at public hospitals. DNA from peripheral blood was obtained from all patients, while karyotyping was performed in patients with MCA. Samples from patients presenting conotruncal CHD or DiGeorge phenotype (n = 137) were studied using MLPA. Ninety-three samples were studied by array-CGH and 18 by targeted or exome next-generation sequencing (NGS). A total of 240 patients were successfully studied using at least one technique. Cytogenetic abnormalities were observed in 13 patients, while 18 had clinically relevant imbalances detected by array-CGH. After MLPA, 26 patients presented 22q11 deletions or duplications and one presented a TBX1 gene deletion. Following NGS analysis, 12 patients presented pathogenic or likely pathogenic genetic variants, five of them, found in KAT6B, SHH, MYH11, MYH7 and EP300 genes, are novel. Using an algorithm that combines molecular techniques with clinical and genetic assessment, we determined the genetic contribution in 27.5% of the analyzed patients.
Subject(s)
Abnormalities, Multiple , Heart Defects, Congenital , Abnormalities, Multiple/genetics , Algorithms , Genetic Testing , Heart Defects, Congenital/genetics , Histone Acetyltransferases , Humans , KaryotypingABSTRACT
Resumen: Introducción: la cirugía micrográfica de Mohs es una técnica quirúrgica especializada para el tratamiento del cáncer de piel no melanoma. La histopatología cumple un rol fundamental, y la elección de la tinción es un punto de controversia. Objetivos: comparar el rendimiento de las tinciones de hematoxilina y eosina (HyE) versus azul de toluidina (AT) durante la cirugía. Método: estudio observacional, descriptivo y transversal a partir de noviembre de 2017 hasta mayo de 2018. Se incluyeron las láminas empleadas durante la cirugía en el período mencionado. Estas fueron analizadas por el cirujano de Mohs, tres residentes y una dermopatóloga. Se valoró el rendimiento de ambas tinciones, teniendo en cuenta las características celulares y los elementos del estroma. Resultados: se estudiaron 23 tumores (16 carcinomas basocelulares y 7 carcinomas espinocelulares). Al observarse al microscopio óptico tanto con la tinción de AT como con HyE no se encontraron diferencias significativas entre ambos grupos en lo global, sólo en algunas características, especialmente con la HyE. Conclusiones: es el primer trabajo en Uruguay que compara la eficacia de las dos tinciones durante la cirugía micrográfica de Mohs. Como conclusión tanto la tinción de HyE como el AT son muy buenas técnicas para el diagnóstico de carcinomas cutáneos.
Abstract: Introduction: Mohs micrographic surgery is a specialized surgical technique used to treat nonmelanoma carcinoma. Histopathology plays a vital role in the diagnosis of this condition, and the choice staining method is controversial. Objective: to compare results in the use of hematoxylin and eosin (H&E) versus Toluidine blue (TB) staining during surgery. Method: observational, descriptive and transversal study conducted from November, 2017 until May, 2018 of the slides used during surgeries in the selected period. Slides were analysed by the Mohs surgeon, 3 residents and a dermopathologist to evaluate the results of both staining methods, in consideration of cell features and stromal elements. Results: 23 tumors were analysed (16 Basal Cell carcinomas and 7 Squamous Cell Carcinoma). Microscopic observation of slides prepared with Toluidine blue and hematoxylin and eosin stains did not show significant global differences between both groups, except in terms of a few characteristics, in particular with hematoxylin and eosin stains. Conclusions: this was the first study in Uruguay to evaluate the effectiveness of both staining methods during Mohs micrographic surgery, and it concluded that both Toluidine blue and hematoxylin and eosin stains are very good techniques in evaluating skin-cancer.
Resumo: Introdução: a cirurgia micrográfica de Mohs é uma técnica cirúrgica especializada para o tratamento do câncer de pele não melanoma. A histopatologia desempenha um papel fundamental, onde a escolha da coloração é um ponto de controvérsia. Objetivos: comparar o desempenho das colorações de hematoxilina e eosina versus azul de toluidina durante a cirurgia. Método: estudo observacional, descritivo e transversal de novembro de 2017 a maio de 2018. Foram incluídas as lâminas utilizadas durante as cirurgias no referido período. Estas foram analisadas pelo cirurgião especializado na técnica de Mohs, 3 residentes e um dermatopatologista onde foi avaliado o desempenho de ambas as colorações, levando em consideração as características celulares e os elementos do estroma. Resultados: foram estudados 23 tumores (16 carcinomas basocelulares e 7 carcinomas espinocelulares). Quando observados ao microscópio de luz para coloração AT e H&E, não foram encontradas diferenças significativas entre os dois grupos em geral, apenas em algumas características, especialmente com o H&E. Conclusões: é o primeiro estudo no Uruguai que compara a eficácia dos 2 corantes durante a cirurgia micrográfica de Mohs. Em conclusão, tanto a coloração com hematoxilina e eosina quanto com azul de toluidina são técnicas muito boas para o diagnóstico de carcinomas de pele.
Subject(s)
Mohs SurgeryABSTRACT
The role of circumcision in partially protecting against sexually transmitted infections (STIs) and other dermatoses has been documented. Neonatal circumcision is not routinely practiced in South America. Although it is logical to assume that male genital dermatoses are more prevalent in Hispanic men, they are underrepresented in the existing literature. Objective: To describe the epidemiological characteristics from our male genital dermatology unit in Montevideo (Uruguay), the diagnoses, and correlate them with circumcision status and comorbidities. Methods: A retrospective observational cohort study was conducted. A dermatologist and urologist evaluated all patients using standard questionnaires. In 3 years and 8 months, 269 patients were seen. Median age was 41, prevalence of neonatal circumcision was 0.7%, HIV was 4.2%, STIs were 24.9%, non-STIs were 63.9%, and both (STI + non-STI) were 11.2%. Most frequent entities: eczema/balanoposthitis (27.1%), condyloma (24.9%), and lichen sclerosus (15.6%). Data correlating circumcision and other diagnoses did not reach statistical significance. HIV was positively associated with other STIs (p < 0.05), and an association with balanoposthitis was seen; however, it did not reach statistical significance (p < 0.1). Main limitation was small sample size. This is the first study of its kind based on Hispanic patients. Collaboration between specialties proved to be fundamental. Further studies are needed in this demographic to find an association between circumcision, comorbidities, and genital dermatoses.
Subject(s)
Circumcision, Male , Dermatology , Adult , Genitalia , Hispanic or Latino , Humans , Infant, Newborn , Male , Retrospective StudiesABSTRACT
Background: Oculocutaneous albinism (OCA) is a Mendelian disorder characterized by hypopigmentation of the skin, hair, and eyes, hypoplastic fovea, and low vision, known to be caused by mutations in the Tyrosinase (TYR) gene. Among the known TYR variants, some reduce but do not completely eliminate tyrosinase activity, allowing residual production of melanin and resulting in a contradictory assignment as either pathogenic or benign, preventing a precise clinical diagnostic.Materials and Methods: In the present work, we performed Whole Exome Sequencing and subsequent Sanger sequencing in a young male clinically diagnosed with OCA.Results: Whole-exome sequencing analysis revealed the identification of two variants in trans in TYR. The first, corresponds to a known pathogenic variant G47D, while the second S192Y, was considered a polymorphism due to its relatively high frequency in the European population.Conclusion: The lack of other pathogenic variants in TYR, the reported reduced enzymatic activity (ca. 40% respect to wt) for S192Y, together with the structural in-silico analysis strongly suggest that both reported variants are jointly disease-causing and that S192Y should be considered as likely pathogenic, especially when it is found in trans with a null variant.
Subject(s)
Albinism, Oculocutaneous/genetics , Monophenol Monooxygenase/genetics , Mutation, Missense/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Albinism, Oculocutaneous/diagnosis , Amino Acid Sequence , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Male , Molecular Sequence Data , Pedigree , Exome SequencingABSTRACT
The genus Echinococcus of cestode parasites includes important pathogens of humans and livestock animals. Transcriptomic and genomic studies on E. granulosus and E. multilocularis uncovered striking expansion of monodomain Kunitz proteins. This expansion is accompanied by the specialization of some family members away from the ancestral protease inhibition function to fulfill cation channel blockade functions. Since cation channels are involved in immune processes, we tested the effects on macrophage physiology of two E. granulosus Kunitz-type inhibitors of voltage-activated cation channels (Kv) that are close paralogs. Both inhibitors, EgKU-1 and EgKU-4, inhibited production of the Th1/Th17 cytokine subunit IL-12/23p40 by macrophages stimulated with the TLR4 agonist LPS. In addition, EgKU-4 but not EgKU-1 inhibited production of the inflammatory cytokine IL-6. These activities were not displayed by EgKU-3, a family member that is a protease inhibitor without known activity on cation channels. EgKU-4 potently inhibited macrophage proliferation in response to M-CSF, whereas EgKU-1 displayed similar activity but with much lower potency, similar to EgKU-3. We discuss structural differences, including a heavily cationic C-terminal extension present in EgKU-4 but not in EgKU-1, that may explain the differential activities of the two close paralogs.
Subject(s)
Echinococcus granulosus/chemistry , Helminth Proteins/pharmacology , Interleukin-12/antagonists & inhibitors , Interleukin-6/antagonists & inhibitors , Macrophages/drug effects , Proteinase Inhibitory Proteins, Secretory/pharmacology , Animals , Cell Proliferation/drug effects , Gene Expression Regulation , Helminth Proteins/isolation & purification , Interleukin-10/genetics , Interleukin-10/immunology , Interleukin-12/genetics , Interleukin-12/immunology , Interleukin-6/genetics , Interleukin-6/immunology , Kv1.3 Potassium Channel/genetics , Kv1.3 Potassium Channel/immunology , Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Macrophage Colony-Stimulating Factor/pharmacology , Macrophages/cytology , Macrophages/immunology , Mice , Mice, Inbred C57BL , Primary Cell Culture , Proteinase Inhibitory Proteins, Secretory/isolation & purification , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/immunologyABSTRACT
The choice of alternative donors for HCT for patients without an HLA-matched related donor depends on several factors. We compared major HCT outcomes in 212 consecutive children transplanted at 11 centers in Brazil for acute leukemia or MDS from an HLA-matched unrelated donor (MUD, n = 95), mismatched unrelated donor (MMUD, n = 47) or unrelated umbilical cord blood (UCB, n = 70). Most had ALL (61%), bone marrow (57%) as the graft source and 95% received a MAC regimen. The 3-year OS probability were 57, 55, and 37% after HCT from MUD, MMUD, and UCB, respectively (HR 1.68, 95%CI 1.07-2.63; P = .02). In comparison with MUD, OS was similar after transplantation of a ≥ 6/8 HLA-matched or a high cell dose (>5 × 107 TNC/kg) CB unit (HR 1.41, 95%CI 0.88-2.27; P = .15). NRM was higher for UCB (HR 3.90, 95%CI 1.43-10.7; P = .01) but not for MMUD (HR 1.03, 95%CI 0.53-2.00; P > .20). Advanced disease (HR 2.05, 95%CI 1.26-3.33; P < .001) and UCB with high probability of being < 6/8 HLA-matched (HR 5.34, 95%CI 2.0-13.9; P < .001) were associated with higher mortality. Relapse and acute GVHD were similar among groups, while PGF was higher among UCB transplants (P = .002) and chronic GVHD among MMUD group (HR 2.88, 95% CI 1.05-7.88; P = .04). Our results suggest that in Brazil HCT outcomes performed with MMUD and MUD donors were comparable, while with UCB units < 6/8 HLA-matched were associated with higher NRM for children with acute leukemia or MDS.
Subject(s)
Cord Blood Stem Cell Transplantation/methods , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/therapy , Brazil/epidemiology , Child , Female , Graft Survival , Humans , Incidence , Leukemia, Myeloid, Acute/epidemiology , Male , Myelodysplastic Syndromes/epidemiology , Retrospective Studies , Treatment OutcomeABSTRACT
CONTEXT: 21-hydroxylase deficiency is the most common cause of Congenital Adrenal Hyperplasia. It presents as severe or classical forms-salt wasting and simple virilizing-and a mild or nonclassical (NC). Several studies have reported the frequency of pathogenic variants in different populations, although few of them included a large number of NC patients. OBJECTIVE: To analyse the CYP21A2 gene defects in a large cohort of Argentine patients. DESIGN: Molecular characterization of 628 patients (168 classical, 460 nonclassical, representing 1203 nonrelated alleles), 398 relatives, 126 partners. METHODS: Genetic variants were assessed by allele-specific PCR, PCR-RFLP or direct sequencing. Deletions, duplications and large gene conversions (LGC) were studied by Southern blot/MLPA or long-range PCR. Biological implications of novel variants were analysed by structure-based in silico studies. RESULTS: The most frequent pathogenic variants were p.V282L (58%) in NC alleles and c.293-13C>G (31.8%) and p.I173N (21.1%) in classical. Deletions and LGC were found at low frequency (6.2%), 57 alleles had rare pathogenic variants, and 3 had novel variants: p.(S166F); p.(P189R), p.(R436L). Genotype-phenotype correlation was observed in 98.6% of the cases, 11 asymptomatic first-degree relatives had pathogenic variants in both alleles, and 21/126 partners were carriers. CONCLUSIONS: We conducted a comprehensive genetic characterization of the largest cohort of 21-hydroxylase patients from the region. In particular, we add to the molecular characterization of a large number of NC patients and to the estimation of the disease carrier's frequency in our population.
Subject(s)
Adrenal Hyperplasia, Congenital , Adrenal Hyperplasia, Congenital/genetics , Alleles , Genotype , Humans , Mutation , Phenotype , Steroid 21-Hydroxylase/geneticsABSTRACT
OBJECTIVE: To present the development of the first custom gene panel for the diagnosis of male and female infertility in Latin America. METHODS: We developed a next-generation sequencing (NGS) panel that assesses genes associated with infertility. The panel targeted exons and their flanking regions. Selected introns in the CFTR gene were also included. The FMR1 gene and Y chromosome microdeletions were analyzed with other recommended methodologies. An in-house developed bioinformatic pipeline was applied for the interpretation of the results. Clear infertility phenotypes, idiopathic infertility, and samples with known pathogenic variants were evaluated. RESULTS: A total of 75 genes were selected based on female (primary ovarian insufficiency, risk of ovarian hyperstimulation syndrome, recurrent pregnancy loss, oocyte maturation defects, and embryo development arrest) and male conditions (azoospermia, severe oligospermia, asthenozoospermia, and teratozoospermia). The panel designed was used to assess 25 DNA samples. Two of the variants found were classified as pathogenic and enable the diagnosis of a woman with secondary amenorrhea and a man with oligoasthenoteratozoospermia. Targeted NGS assay metrics resulted in a mean of 180X coverage, with more than 98% of the bases covered ≥20X. CONCLUSION: Our custom gene sequencing panel designed for the diagnosis of male and female infertility caused by genetic defects revealed the underlying genetic cause of some cases of infertility. The panel will allow us to develop more precise approaches in assisted reproduction.
Subject(s)
Genetic Testing/methods , High-Throughput Nucleotide Sequencing , Infertility , Female , Humans , Infertility/diagnosis , Infertility/genetics , Latin America , Male , Mutation/genetics , Polymorphism, Single Nucleotide/genetics , Sequence Analysis, DNAABSTRACT
PURPOSE: The aim of this study was to analyse the expression profiles of DNMT1, DNMT3A, DNMT3B (components of DNA methylation machinery), TET2 and APOBEC3B (components of DNA demethylation machinery) in pediatric MDS patients and investigate their associations with MDS subtypes, cytogenetics, evolution to acute myeloid leukemia (AML) and p15INK4B methylation level. PATIENTS AND METHODS: The expressions of DNMT1, DNMT3A, DNMT3B, TET2, and APOBEC3B were evaluated in 39 pediatric MDS patients by real-time quantitative PCR (qPCR). The quantification of p15INK4B methylation levels (MtL) was performed in 20 pediatric MDS patients by pyrosequencing. Mann-Whitney test was used to evaluate possible differences between the expression levels of selected in patients and donors, according to MDS subtypes, karyotypes, evolution to AML and p15INK4B MtL. The correlations between the expression levels of the different genes were assessed by Spearman rank correlation coefficient. RESULTS: We found that DNMTs expression levels were higher in pediatric MDS compared to donors [DNMT1 (p<0.03), DNMT3A (p<0.03), DNMT3B (p<0.02)]. TET2 and APOBEC3B expression levels did not show a statistically significant difference between pediatric patients and donors. Considering MDS subtypes, patients at initial stage presented DNMT1 overexpression (p<0.01), while DNMT3A (p<0.02) and DNMT3B (p<0.007) were overexpressed in advanced subtypes. TET2 and APOBEC3B expression did not differ in MDS subtypes. DNMT1 (p<0.03), DNMT3B (p<0.03), and APOBEC3B (p<0.04) expression was higher in patients with normal karyotypes, while patients with abnormal karyotypes showed higher DNMT3A expression (p<0.03). Karyotypes had no association with TET2 expression. DNMTs overexpression was observed in patients who showed disease evolution. A positive correlation was found between DNMTs expression and between APOBEC3B and DNMT3A/DNMT3B. However, TET2 expression was not correlated with DNMTs or APOBEC3B. p15INK4B MtL was higher in pediatric MDS patients compared with donors (p<0.03) and its hypermethylation was associated with increased DNMT1 expression (p<0.009). CONCLUSION: Our results suggest that the overexpression of DNMTs and an imbalance between the expressions of the DNA methylation/demethylation machinery components play an important role in MDS development and evolution to AML. These results have clinical implications indicating the importance of DNMTs inhibitors for preventing or delaying the progression to leukemia in pediatric MDS patients.
ABSTRACT
Pediatric myelodysplastic syndrome (MDS) is an uncommon disease and little is known about the molecular alterations of its development and evolution to acute myeloid leukemia (AML). The Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2 (PCR2). It is a histone methyltransferase, that targets lysine 27 of histone 3. This methylated H3-K27 is usually associated with the silencing of genes that are involved in fundamental cellular processes, such as cell proliferation and differentiation. There are only few studies showing the status of EZH2 expression in patients with MDS and they were performed in adult MDS patients. The aim of this study was to analyze the EZH2 expression in pediatric patients with MDS and its association with karyotypes and evolution to acute myeloid leukemia (AML). We conducted the first study of EZH2 expression in pediatric patients with MDS. Considering the EZH2 expression levels in 42 patients and 17 healthy pediatric donors, it was possible to define three groups of expression in patients: low, intermediate, and high. The intermediate level encompassed patients with normal karyotypes, low level included patients with monosomy 7 and del(7q) and high level included patients with trisomy 8 and del(11q) (p < 0.0001). Comparing the leukemic evolution, the low expression group presented disease evolution in 100% (8/8) of the cases, the intermediate expression group showed disease evolution in 4.34% (1/23) and in the high expression group, 63.63% (7/11) patients showed evolution from MDS to AML (p < 0.0001). It is important to note that low and high EZH2 expression are associated with leukemic evolution, however low expression showed a stronger association with evolution from MDS to AML than the high expression. Our results suggest a scale of measure for EZH2 expression in pediatric MDS, where aberrant EZH2 expression may be a potential biomarker of disease evolution.
Subject(s)
Biomarkers, Tumor/biosynthesis , Enhancer of Zeste Homolog 2 Protein/biosynthesis , Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute/metabolism , Myelodysplastic Syndromes/metabolism , Neoplasm Proteins/biosynthesis , Adolescent , Biomarkers, Tumor/genetics , Child , Child, Preschool , Enhancer of Zeste Homolog 2 Protein/genetics , Female , Humans , Infant , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Male , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Neoplasm Proteins/geneticsABSTRACT
BACKGROUND: Cartilage-hair hypoplasia is a rare autosomal recessive disease, which is characterized by metaphyseal chondrodysplasia and thin hair. It can be accompanied by immunological disorders in varying degrees. CLINICAL CASE: The case of a 35-month-old girl is described. Since her birth, with growth restriction, she has developed pneumonia eleven times, malabsorption syndrome and aganglionic megacolon, which is why she was diagnosed with cartilage-hair hypoplasia, with expression of non-severe combined immunodeficiency. The decision was to proceed with hematopoietic stem cell transplantation. At the time of this report, the patient was free from infectious processes. CONCLUSION: Cartilage-hair hypoplasia is a condition with diverse clinical features and different degrees of immunodeficiency. As part of the treatment, it is possible to perform haematopoietic stem cell transplantation.
Antecedentes: La hipoplasia cartílago-cabello es una enfermedad autosómica recesiva poco frecuente, caracterizada por condrodisplasia metafisaria y cabello fino. Puede estar acompañada de alteraciones inmunológicas en distintos grados. Caso clínico: Niña de 35 meses de edad, quien desde su nacimiento mostró restricción del crecimiento; desarrolló 11 cuadros de neumonía, síndrome de malabsorción y megacolon agangliónico, por lo que se diagnosticó hipoplasia cartílago-cabello, con expresión de inmunodeficiencia combinada no severa. Se decidió trasplante de células madre hematopoyéticas. Al momento de este informe, la paciente estaba libre de procesos infecciosos. Conclusión: La hipoplasia cartílago-cabello es un padecimiento con rasgos clínicos y distintos grados de inmunodeficiencia. Como parte del tratamiento es posible realizar trasplante de células madre hematopoyéticas.
Subject(s)
Hair/abnormalities , Hirschsprung Disease/diagnosis , Osteochondrodysplasias/congenital , Primary Immunodeficiency Diseases/diagnosis , Child, Preschool , Female , Humans , Osteochondrodysplasias/diagnosis , PhenotypeABSTRACT
BACKGROUND: The horn fly Haematobia irritans is a blood-sucking ectoparasite responsible for substantial economic loss of livestock. Like other hematophagous arthropods species, the successful blood-feeding of H. irritans is highly dependent on the modulation of the host's hemostasis and immune system. Here, we evaluated the biological activity of hematobin (HTB), a protein recently identified in the H. irritans saliva, on macrophage biology. The goal was to understand the putative interactions between the components of H. irritans saliva and the early host immune responses. RESULTS: Thioglycolate-elicited peritoneal macrophages from BALB/c mice were stimulated by lipopolysaccharide (LPS) plus interferon-γ (IFN-γ) in the presence or absence of recombinant HTB. The presence of the salivary protein in the cultures inhibited nitric oxide production and decreased the inducible nitric oxide synthase (iNOS) expression induced by LPS plus IFN-γ. The tumor necrosis factor-α (TNF-α) and interleukin-12p40 (IL-12p40) levels were also reduced in the macrophages pre-incubated with HTB; these findings correlated to the decreased NF-κB expression. The biological activities described here were not associated with changes in annexin V binding to macrophages suggesting that HTB does not induce cell death. In addition, the activity of HTB seems to be specific to macrophages because no changes were observed in lymphocyte proliferation or cytokine production. CONCLUSIONS: We describe here the first bioactive salivary protein of H. irritans. We characterized its ability to modulate macrophage inflammatory response, and the results can help explain how horn flies modulate the host immune system to feed on blood.
Subject(s)
Diptera/metabolism , Inflammation/metabolism , Insect Proteins/metabolism , Insect Proteins/pharmacology , Macrophages, Peritoneal/drug effects , Amino Acid Sequence , Animals , Cells, Cultured , Cytokines , Dinoprostone , Gene Expression Regulation/drug effects , Lymphocytes/drug effects , Mice , Mice, Inbred BALB C , Nitric Oxide , Nitric Oxide Synthase Type II , Spleen/cytologyABSTRACT
BACKGROUND: Latex-fruit syndrome (LFS) is characterized by allergy to latex and plants. Papain, chymopapain, caricaine and class I chitinases are papaya's most allergenic proteins. The similarity between latex hevein epitopes and papaya class I chitinases might explain the latex-papaya syndrome (LPS). OBJECTIVE: To describe the clinical characteristics of patients with LPS. METHODS: Cross-sectional, observational, descriptive study where 11 patients diagnosed with latex allergy by skin prick test and clinically diagnosed with papaya-induced anaphylaxis were included. The results were analyzed with descriptive statistics. RESULTS: Out of 11 patients with LPS, 72.7% were females (7 to 46 years), all with a history of papaya-induced anaphylaxis, identified by medical history and medical notes plus latex-positive skin prick tests, with 63.3% exhibiting anaphylaxis in the skin prick tests. Risk factors included multiple surgeries, another allergic disease, and being employed in the field of health; 63.6% were allergic to to other foods, 45.4% to medications, 45.4% had allergic rhinitis and 27.3% had asthma. CONCLUSIONS: Hypersensitivity to papaya increases the risk of anaphylaxis in patients with latex allergy and, therefore, mortality. Clinical data is the main diagnostic tool. Education for the management of anaphylaxis with adrenaline self-administration is essential.
Antecedentes: El síndrome látex-fruta (SLF) se caracteriza por alergia al látex y vegetales. La papaína, quimopapaína, caricaína y las quitinasas clase I son las proteínas más alergénicas de la papaya. La similitud entre epítopos de heveína del látex y las quitinasas clase I de la papaya puede explicar el síndrome látex-papaya (SLP). Objetivo: Describir las características clínicas de pacientes con SLP. Métodos: Estudio transversal, observacional y descriptivo en el que se incluyeron 11 pacientes con diagnóstico por punción cutánea de alergia al látex y diagnóstico clínico de anafilaxia a papaya. Los resultados fueron analizados con estadística descriptiva. Resultados: De 11 pacientes con SLP, 72.7 % fue del sexo femenino (7 a 46 años), todos con antecedente de anafilaxia a papaya, identificada por historia clínica y notas médicas más pruebas cutáneas positivas a látex; 63.3 % presentó anafilaxia en las pruebas cutáneas. Los factores de riesgo fueron múltiples cirugías, otra enfermedad alérgica y ser empleado en el ámbito de la salud; 63.6 % tenía alergia a otros alimentos, 45.4 % a medicamentos, 45.4 % rinitis alérgica y 27.3 % asma. Conclusiones: La hipersensibilidad a la papaya incrementa el riesgo de anafilaxia en individuos con alergia al látex, por tanto, la mortalidad. La clínica es la herramienta principal para el diagnóstico. La educación para el manejo de la anafilaxia con autoadministración de adrenalina es fundamental.
Subject(s)
Carica , Food Hypersensitivity/diagnosis , Latex Hypersensitivity/diagnosis , Adolescent , Adult , Anaphylaxis/etiology , Carica/adverse effects , Child , Cross-Sectional Studies , Female , Food Hypersensitivity/complications , Food Hypersensitivity/etiology , Humans , Male , Middle Aged , Skin Tests , Syndrome , Young AdultABSTRACT
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of adrenal steroidogenesis. Disorders in steroid 21-hydroxylation account for over 95% of patients with CAH. Clinically, the 21-hydroxylase deficiency has been classified in a broad spectrum of clinical forms, ranging from severe or classical, to mild late onset or non-classical. Known allelic variants in the disease causing CYP21A2 gene are spread among different sources. Until recently, most variants reported have been identified in the clinical setting, which presumably bias described variants to pathogenic ones, as those found in the CYPAlleles database. Nevertheless, a large number of variants are being described in massive genome projects, many of which are found in dbSNP, but lack functional implications and/or their phenotypic effect. In this work, we gathered a total of 1,340 GVs in the CYP21A2 gene, from which 899 variants were unique and 230 have an effect on human health, and compiled all this information in an integrated database. We also connected CYP21A2 sequence information to phenotypic effects for all available mutations, including double mutants in cis. Data compiled in the present work could help physicians in the genetic counseling of families affected with 21-hydroxylase deficiency.
Subject(s)
Databases, Genetic , Genetic Variation , Mutation , Steroid 21-Hydroxylase/genetics , Adrenal Hyperplasia, Congenital/diagnosis , Adrenal Hyperplasia, Congenital/genetics , Alleles , Genetic Association Studies , Genotype , Humans , PhenotypeABSTRACT
Primary immunodeficiencies (PIDs) are low-incidence diseases caused by defects in genes involved in the development, maintenance, and regulation of the immune system. Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency of adulthood. It has an approximate prevalence of 1 in 25 000-50 000 in the general population, with a delay in diagnosis between 6-7 years. The clinical manifestations of CVID constitute six main categories: infections, pulmonary complications, granulomatous or polyclonal lymphocytic disease, autoimmunity, gastrointestinal diseases and malignancy Most patients must have at least one of the following clinical manifestations (infection, autoimmunity, lymphoproliferation). However, the diagnosis of CVID can be conferred in asymptomatic patients, especially in familial cases. Secondary causes of hypogammaglobulinemia should be ruled out in any patient meeting the diagnostic criteria for CVID, as the treatment may be totally different from that required for CVID. Because CVID comprises a heterogeneous group of syndromes with poor primary antibody production, the potential number of entities within this group is unknown. Patients with CVID suffer from various complications that are considered prognostic. In the absence of clear guidelines for their search, it is recommended that lymphoproliferative disease, lung disease, liver disease and autoimmunity be investigated intentionally during the initial evaluation. The intervals in which they should be performed are not clear, but several evaluations may be required per year, according to the clinical evolution of the patient.
Las inmunodeficiencias primarias (IDP) son enfermedades de baja incidencia, causadas por defectos en genes involucrados en el desarrollo, mantenimiento y regulación del sistema inmune. La inmunodeficiencia común variable (IDCV) es la inmunodeficiencia sintomática más común de la edad adulta. Tiene una prevalencia aproximada de 1 en 25 000 a 50 000 sujetos de la población general, con un retraso en el diagnóstico entre seis y siete años. Las manifestaciones clínicas de la IDCV, constituyen seis categorías principales: infecciones, complicaciones pulmonares, enfermedad granulomatosa o linfocítica policlonal, autoinmunidad, enfermedades gastrointestinales y neoplasias. La mayoría de los pacientes debe tener al menos una de las siguientes manifestaciones clínicas (infección, autoinmunidad, linfoproliferación). No obstante, el diagnóstico de IDCV puede ser formulado en pacientes asintomáticos especialmente en casos familiares. Las causas secundarias de hipogammaglobulinemia deben ser descartadas en cualquier paciente que reúna los criterios diagnósticos para IDCV, ya que el tratamiento puede ser totalmente diferente al que se requiere para la IDCV. Debido a que la IDCV comprende un grupo heterogéneo de síndromes con producción deficiente de anticuerpos de tipo primario, el número potencial de entidades dentro de este grupo se desconoce.Los pacientes con IDCV sufren diversas complicaciones que se consideran pronósticas. En ausencia de directrices claras de su búsqueda se recomienda que durante la evaluación inicial se indague intencionadamente enfermedad linfoproliferativa, enfermedad pulmonar, hepática y autoinmunidad. Los intervalos en los cuales deben realizarse no están claros, pero se pueden requerir varias evaluaciones al año, de acuerdo con la evolución clínica del paciente.
Subject(s)
Common Variable Immunodeficiency , Adult , Algorithms , Common Variable Immunodeficiency/classification , Common Variable Immunodeficiency/complications , Common Variable Immunodeficiency/diagnosis , Common Variable Immunodeficiency/therapy , HumansABSTRACT
The premutation state of FMR1 (Fragile X Mental Retardation 1) has been associated with primary ovarian insufficiency (POI), and is the most common known genetic cause for 46,XX patients. Nevertheless, very few studies have analyzed its frequency in Latin American populations. Additionally, a relationship between alleles carrying a cryptic microdeletion in the 5'UTR of FMR2 and the onset of POI has only been studied in one population. Our aim was to analyze the incidence of FMR1 premutations and putative microdeletions in exon 1 of FMR2 in a cohort of Argentinean women with POI. We studied 133 patients and 84 controls. Fluorescent PCR was performed, and the FMR2 exon 1 was further sequenced in samples presenting less than 11 repeats. We found the frequency of FMR1 premutations to be 6.7% and 2.9% for familial and sporadic patients, respectively. Among controls, 1/84 women presented a premutation. In addition, although we did not find microdeletions in FMR2, we observed a change (T >C) adjacent to the repeats in two sisters with POI. Given the repetitive nature of the sequence involved, we could not ascertain whether this represents a single nucleotide polymorphism (SNP) or a deletion. Therefore, a relationship between FMR2 and POI could not be established for our population.
ABSTRACT
BACKGROUND: Drug hypersensitivity is defined as any unfavorable reaction that occurs after the administration of any drug. It may or may not be mediated by the involvement of the immune system. Epidemiological data related to drug hypersensitivity reactions in our country are scarce. OBJECTIVE: To determine the prevalence of drug hypersensitivity in a group of young adults, as well as to identify associated factors. METHODS: A structured questionnaire was applied to young people aged 18 to 25 years. The instrument was oriented to identify reactions of drug hypersensitivity, as well as the most prevalent drugs involved. In addition, a personal and family history of atopic diseases was included. Analysis for associations between variables was been done through logistic regression. RESULTS: The prevalence of drug hypersensitivity reactions was 12% (144 of 1,200). The antibiotics were the agents most related to hypersensitivity reactions (9.8%) followed by nonsteroidal anti-inflammatory drugs (1.6%). Factors associated with drug hypersensitivity were a personal history of asthma, odds ratio (OR) 3.15 (95% confidence interval [CI], 1.44-6.91), maternal and paternal history of drug hypersensitivity, OR 2.33 (95% CI, 1.21-4.48) and OR 3.11 (95% CI, 1.22-7.92), respectively. CONCLUSION: The results of this research show that drug hypersensitivity in young adults is a highly prevalent event and it is associated with personal history of asthma and history of drug hypersensitivity in parents.