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INTRODUCTION AND OBJECTIVES: Transplant renal artery stenosis (TRAS) is a vascular complication after kidney transplantation which estimated incidence is 13%. It could cause refractory arterial hypertension, kidney dysfunction and premature death in transplant recipients. METHODS: We carried out a retrospective study including every patient who underwent renal transplantation between 2014 and 2020. They were evaluated with a systematic post-transplant renal Doppler ultrasound. To identify independent risk factors for transplant renal artery stenosis we performed a multivariate analysis. RESULTS: Seven hundred twenty-four kidney transplants were included, 12% ââwere living donors and 88% were deceased donors. The mean age was 54.8 in recipients and 53 in donors. Transplant renal artery stenosis was diagnosed in 70 (10%) recipients, the majority in the first 6 months after surgery. 51% of patients with transplant renal artery stenosis were managed conservatively. The multivariate analysis showed diabetes mellitus, graft rejection, arterial resuture and donor body mass index as independent risk factors for transplant renal artery stenosis. Survival of the grafts with transplant renal artery stenosis was 98% at 6 months and 95% at two years. CONCLUSIONS: The systematic performance of Doppler ultrasound in the immediate post-transplant period diagnosed 10% of transplant renal artery stenosis in our cohort. Despite the above risk factors, an adequate monitoring and treatment could avoid the increased risk of graft loss in patients with transplant renal artery stenosis.
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Obstrução da Artéria Renal , Humanos , Pessoa de Meia-Idade , Obstrução da Artéria Renal/diagnóstico por imagem , Obstrução da Artéria Renal/epidemiologia , Obstrução da Artéria Renal/etiologia , Incidência , Estudos Retrospectivos , Resultado do Tratamento , Fatores de Risco , Ultrassonografia Doppler/efeitos adversosRESUMO
The milk fat globule membrane (MFGM) provides infants and adults with several health benefits. These are not derived solely from its unique composition, but also from arrangement of lipids in the MFGM that, in the case of newborns, could reach the intestine partially intact. Fluorochromes associated with lipid derivatives were used to prove a fusion process between the MFGM and the cellular membrane of differentiated Caco-2 cells. To explore the mechanism of this interaction, incubations of MFGM with Caco-2 cells were carried out in the presence of fusogenic agents or compounds that block other MFGM interaction pathways with cells. Confocal fluorescence microscopy provided visual evidence of the fusion process. Lastly, determination on the lipid profile of cells after their interaction with MFGM indicated a metabolic rearrangement of lipids leading to accumulation of triacylglycerols.
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Glicolipídeos , Glicoproteínas , Recém-Nascido , Adulto , Lactente , Humanos , Células CACO-2 , Membrana Celular/metabolismoRESUMO
Plasmodium falciparum (Pf) malaria continues to cause considerable morbidity and mortality worldwide. The circumsporozoite protein (CSP) is a particularly attractive candidate for designing vaccines that target sporozoites-the first vertebrate stage in a malaria infection. Current PfCSP-based vaccines, however, do not include epitopes that have recently been shown to be the target of potent neutralizing antibodies. We report the design of a SpyCatcher-mi3-nanoparticle-based vaccine presenting multiple copies of a chimeric PfCSP (cPfCSP) antigen that incorporates these important "T1/junctional" epitopes as well as a reduced number of (NANP)n repeats. cPfCSP-SpyCatcher-mi3 was immunogenic in mice eliciting high and durable IgG antibody levels as well as a balanced antibody response against the T1/junctional region and the (NANP)n repeats. Notably, the antibody concentration elicited by immunization was significantly greater than the reported protective threshold defined in a murine challenge model. Refocusing the immune response toward functionally relevant subdominant epitopes to induce a more balanced and durable immune response may enable the design of a more effective second generation PfCSP-based vaccine.
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Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 has prompted increased attention to coronavirus biology and immunopathology, but the T-cell response to seasonal coronaviruses remains largely uncharacterized. Here we report the repertoire of viral peptides that are naturally processed and presented upon infection of a model cell line with seasonal coronavirus OC43. We identified MHC-bound peptides derived from each of the viral structural proteins (spike, nucleoprotein, hemagglutinin-esterase, membrane, and envelope) as well as non-structural proteins nsp3, nsp5, nsp6, and nsp12. Eighty MHC-II bound peptides corresponding to 14 distinct OC43-derived epitopes were identified, including many at very high abundance within the overall MHC-II peptidome. Fewer and less abundant MHC-I bound OC43-derived peptides were observed, possibly due to MHC-I downregulation induced by OC43 infection. The MHC-II peptides elicited low-abundance recall T-cell responses in most donors tested. In vitro assays confirmed that the peptides were recognized by CD4+ T cells and identified the presenting HLA alleles. T-cell responses cross-reactive between OC43, SARS-CoV-2, and the other seasonal coronaviruses were confirmed in samples of peripheral blood and peptide-expanded T-cell lines. Among the validated epitopes, spike protein S903-917 presented by DPA1*01:03/DPB1*04:01 and S1085-1099 presented by DRB1*15:01 shared substantial homology to other human coronaviruses, including SARS-CoV-2, and were targeted by cross-reactive CD4 T cells. Nucleoprotein N54-68 and hemagglutinin-esterase HE128-142 presented by DRB1*15:01 and HE259-273 presented by DPA1*01:03/DPB1*04:01 are immunodominant epitopes with low coronavirus homology that are not cross-reactive with SARS-CoV-2. Overall, the set of naturally processed and presented OC43 epitopes comprise both OC43-specific and human coronavirus cross-reactive epitopes, which can be used to follow CD4 T-cell cross-reactivity after infection or vaccination, and to guide selection of epitopes for inclusion in pan-coronavirus vaccines.
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COVID-19 , Coronavirus Humano OC43 , Humanos , SARS-CoV-2 , Linfócitos T CD4-Positivos , Epitopos de Linfócito T , Hemaglutininas , Estações do Ano , Esterases , Glicoproteína da Espícula de CoronavírusRESUMO
BACKGROUND: Evaluating the performance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological assays and clearly articulating the utility of selected antigens, isotypes, and thresholds is crucial to understanding the prevalence of infection within selected communities. METHODS: This cross-sectional study, implemented in 2020, screened PCRconfirmed coronavirus disease 2019 patients (n 86), banked prepandemic and negative samples (n 96), healthcare workers and family members (n 552), and university employees (n 327) for antiSARS-CoV-2 receptor-binding domain, trimeric spike protein, and nucleocapsid protein immunoglobulin (Ig)G and IgA antibodies with a laboratory-developed enzyme-linked immunosorbent assay and tested how antigen, isotype and threshold choices affected the seroprevalence outcomes. The following threshold methods were evaluated: (i) mean 3 standard deviations of the negative controls; (ii) 100 specificity for each antigen-isotype combination; and (iii) the maximal Youden index. RESULTS: We found vastly different seroprevalence estimates depending on selected antigens and isotypes and the applied threshold method, ranging from 0.0 to 85.4. Subsequently, we maximized specificity and reported a seroprevalence, based on more than one antigen, ranging from 9.3 to 25.9. CONCLUSIONS: This study revealed the importance of evaluating serosurvey tools for antigen-, isotype-, and threshold-specific sensitivity and specificity, to interpret qualitative serosurvey outcomes reliably and consistently across studies.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , Estudos Soroepidemiológicos , Estudos Transversais , Proteínas do Nucleocapsídeo , Ensaio de Imunoadsorção Enzimática/métodos , Sensibilidade e Especificidade , Imunoglobulina G , Anticorpos Antivirais , Glicoproteína da Espícula de CoronavírusRESUMO
Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 has prompted increased attention to coronavirus biology and immunopathology, but identification and characterization of the T cell response to seasonal human coronaviruses remain largely uncharacterized. Here we report the repertoire of viral peptides that are naturally processed and presented upon infection of a model cell line with seasonal human coronavirus OC43. We identified MHC-I and MHC-II bound peptides derived from the viral spike, nucleocapsid, hemagglutinin-esterase, 3C-like proteinase, and envelope proteins. Only three MHC-I bound OC43-derived peptides were observed, possibly due to the potent MHC-I downregulation induced by OC43 infection. By contrast, 80 MHC-II bound peptides corresponding to 14 distinct OC43-derived epitopes were identified, including many at very high abundance within the overall MHC-II peptidome. These peptides elicited low-abundance recall T cell responses in most donors tested. In vitro assays confirmed that the peptides were recognized by CD4+ T cells and identified the presenting HLA alleles. T cell responses cross-reactive between OC43, SARS-CoV-2, and the other seasonal coronaviruses were confirmed in samples of peripheral blood and peptide-expanded T cell lines. Among the validated epitopes, S 903-917 presented by DPA1*01:03/DPB1*04:01 and S 1085-1099 presented by DRB1*15:01 shared substantial homology to other human coronaviruses, including SARS-CoV-2, and were targeted by cross-reactive CD4 T cells. N 54-68 and HE 128-142 presented by DRB1*15:01 and HE 259-273 presented by DPA1*01:03/DPB1*04:01 are immunodominant epitopes with low coronavirus homology that are not cross-reactive with SARS-CoV-2. Overall, the set of naturally processed and presented OC43 epitopes comprise both OC43-specific and human coronavirus cross-reactive epitopes, which can be used to follow T cell cross-reactivity after infection or vaccination and could aid in the selection of epitopes for inclusion in pan-coronavirus vaccines. Author Summary: There is much current interest in cellular immune responses to seasonal common-cold coronaviruses because of their possible role in mediating protection against SARS-CoV-2 infection or pathology. However, identification of relevant T cell epitopes and systematic studies of the T cell responses responding to these viruses are scarce. We conducted a study to identify naturally processed and presented MHC-I and MHC-II epitopes from human cells infected with the seasonal coronavirus HCoV-OC43, and to characterize the T cell responses associated with these epitopes. We found epitopes specific to the seasonal coronaviruses, as well as epitopes cross-reactive between HCoV-OC43 and SARS-CoV-2. These epitopes should be useful in following immune responses to seasonal coronaviruses and identifying their roles in COVID-19 vaccination, infection, and pathogenesis.
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A diet rich in saturated fat and carbohydrates causes low-grade chronic inflammation in several organs, including the liver, ultimately driving nonalcoholic steatohepatitis. In this setting, environment-driven lipotoxicity and glucotoxicity induce liver damage, which promotes dendritic cell activation and generates a major histocompatibility complex class II (MHC-II) immunopeptidome enriched with peptides derived from proteins involved in cellular metabolism, oxidative phosphorylation, and the stress responses. Here, we demonstrated that lipotoxicity and glucotoxicity, as driven by a high-fat and high-fructose (HFHF) diet, promoted MHC-II presentation of nested T and B cell epitopes from protein disulfide isomerase family A member 3 (PDIA3), which is involved in immunogenic cell death. Increased MHC-II presentation of PDIA3 peptides was associated with antigen-specific proliferation of hepatic CD4+ immune infiltrates and isotype switch of anti-PDIA3 antibodies from IgM to IgG3, indicative of cellular and humoral PDIA3 autoreactivity. Passive transfer of PDIA3-specific T cells or PDIA3-specific antibodies also exacerbated hepatocyte death, as determined by increased hepatic transaminases detected in the sera of mice subjected to an HFHF but not control diet. Increased humoral responses to PDIA3 were also observed in patients with chronic inflammatory liver conditions, including autoimmune hepatitis, primary biliary cholangitis, and type 2 diabetes. Together, our data indicated that metabolic insults caused by an HFHF diet elicited liver damage and promoted pathogenic immune autoreactivity driven by T and B cell PDIA3 epitopes.
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Autoimunidade , Diabetes Mellitus Tipo 2 , Fígado , Isomerases de Dissulfetos de Proteínas , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Epitopos , Antígenos de Histocompatibilidade Classe II , Fígado/patologia , Camundongos , Peptídeos , Isomerases de Dissulfetos de Proteínas/imunologia , Isomerases de Dissulfetos de Proteínas/metabolismoRESUMO
Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can affect T cell response in COVID-19. We studied T cell responses to SARS-CoV-2 and HCoVs in convalescent COVID-19 donors and identified a highly conserved SARS-CoV-2 sequence, S811-831, with overlapping epitopes presented by common MHC class II proteins HLA-DQ5 and HLA-DP4. These epitopes are recognized by low-abundance CD4 T cells from convalescent COVID-19 donors, mRNA vaccine recipients, and uninfected donors. TCR sequencing revealed a diverse repertoire with public TCRs. T cell cross-reactivity is driven by the high conservation across human and animal coronaviruses of T cell contact residues in both HLA-DQ5 and HLA-DP4 binding frames, with distinct patterns of HCoV cross-reactivity explained by MHC class II binding preferences and substitutions at secondary TCR contact sites. These data highlight S811-831 as a highly conserved CD4 T cell epitope broadly recognized across human populations.
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COVID-19 , SARS-CoV-2 , Alelos , Linfócitos T CD4-Positivos , Vacinas contra COVID-19 , Epitopos de Linfócito T , Antígenos HLA , Humanos , Receptores de Antígenos de Linfócitos T , Vacinas de mRNARESUMO
The roles of Wnt/ß-catenin signaling in regulating the morphology and microstructure of craniomaxillofacial (CMF) bones was explored using mice carrying a constitutively active form of ß-catenin in activating Dmp1-expressing cells (e.g., daßcatOt mice). By postnatal day 24, daßcatOt mice exhibited midfacial truncations coupled with maxillary and mandibular hyperostosis that progressively worsened with age. Mechanistic insights into the basis for the hyperostotic facial phenotype were gained through molecular and cellular analyses, which revealed that constitutively activated ß-catenin in Dmp1-expressing cells resulted in an increase in osteoblast number and an increased rate of mineral apposition. An increase in osteoblasts was accompanied by an increase in osteocytes, but they failed to mature. The resulting CMF bone matrix also had an abundance of osteoid, and in locations where compact lamellar bone typically forms, it was replaced by porous, woven bone. The hyperostotic facial phenotype was progressive. These findings identify for the first time a ligand-independent positive feedback loop whereby unrestrained Wnt/ß-catenin signaling results in a CMF phenotype of progressive hyperostosis combined with architecturally abnormal, poorly mineralized matrix that is reminiscent of craniotubular disorders in humans.
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Hiperostose , beta Catenina , Animais , Camundongos , Osteoblastos/metabolismo , Osteócitos/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Malaria remains a major cause of morbidity and mortality worldwide with 219 million infections and 435,000 deaths predominantly in Africa. The infective Plasmodium sporozoite is the target of a potent humoral immune response that can protect murine, simian and human hosts against challenge by malaria-infected mosquitoes. Early murine studies demonstrated that sporozoites or subunit vaccines based on the sporozoite major surface antigen, the circumsporozoite (CS) protein, elicit antibodies that primarily target the central repeat region of the CS protein. In the current murine studies, using monoclonal antibodies and polyclonal sera obtained following immunization with P. falciparum sporozoites or synthetic repeat peptides, we demonstrate differences in the ability of these antibodies to recognize the major and minor repeats contained in the central repeat region. The biological relevance of these differences in fine specificity was explored using a transgenic P. berghei rodent parasite expressing the P. falciparum CS repeat region. In these in vitro and in vivo studies, we demonstrate that the minor repeat region, comprised of three copies of alternating NANP and NVDP tetramer repeats, contains an epitope recognized by sporozoite-neutralizing antibodies. In contrast, murine monoclonal antibodies specific for the major CS repeats (NANP)n could be isolated from peptide-immunized mice that had limited or no sporozoite-neutralizing activity. These studies highlight the importance of assessing the fine specificity and functions of antirepeat antibodies elicited by P. falciparum CS-based vaccines and suggest that the design of immunogens to increase antibody responses to minor CS repeats may enhance vaccine efficacy.
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Some genetic disorders are associated with distinctive facial features, which can aid in diagnosis. While considerable advances have been made in identifying causal genes, relatively little progress has been made toward understanding how a particular genotype results in a characteristic craniofacial phenotype. An example is sclerosteosis/van Buchem disease, which is caused by mutations in the Wnt inhibitor sclerostin (SOST). Affected patients have a high bone mass coupled with a distinctive appearance where the mandible is enlarged and the maxilla is foreshortened. Here, mice carrying a null mutation in Sost were analyzed using quantitative micro-computed tomographic (µCT) imaging and histomorphometric analyses to determine the extent to which the size and shape of craniofacial skeleton were altered. Sost-/- mice exhibited a significant increase in appositional bone growth, which increased the height and width of the mandible and reduced the diameters of foramina. In vivo fluorochrome labeling, histology, and immunohistochemical analyses indicated that excessive bone deposition in the premaxillary suture mesenchyme curtailed overall growth, leading to midfacial hypoplasia. The amount of bone extracellular matrix produced by Sost-/- cells was significantly increased; as a consequence, osteoid seams were evident throughout the facial skeleton. Collectively, these analyses revealed a remarkable fidelity between human characteristics of sclerosteosis/van Buchem disease and the Sost-/- phenotype and provide clues into the conserved role for sclerostin signaling in modulating craniofacial morphology.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Morfogenéticas Ósseas , Hiperostose , Animais , Proteínas Morfogenéticas Ósseas/genética , Marcadores Genéticos/genética , Humanos , Camundongos , FenótipoRESUMO
Quantification of cell-secreted molecules, e.g., cytokines, is fundamental to the characterization of immune responses. Cytokine capture assays that use engineered antibodies to anchor the secreted molecules to the secreting cells are widely used to characterize immune responses because they allow both sensitive identification and recovery of viable responding cells. However, if the cytokines diffuse away from the secreting cells, non-secreting cells will also be identified as responding cells. Here we encapsulate immune cells in microfluidic droplets and perform in-droplet cytokine capture assays to limit the diffusion of the secreted cytokines. We use microfluidic devices to rapidly encapsulate single natural killer NK-92 MI cells and their target K562 cells into microfluidic droplets. We perform in-droplet IFN-γ capture assays and demonstrate that NK-92 MI cells recognize target cells within droplets and become activated to secrete IFN-γ. Droplet encapsulation prevents diffusion of secreted products to neighboring cells and dramatically reduces both false positives and false negatives, relative to assays performed without droplets. In a sample containing 1% true positives, encapsulation reduces, from 94% to 2%, the number of true-positive cells appearing as negatives; in a sample containing 50% true positives, the number of non-stimulated cells appearing as positives is reduced from 98% to 1%. After cells are released from the droplets, secreted cytokine remains captured onto secreting immune cells, enabling FACS-isolation of populations highly enriched for activated effector immune cells. Droplet encapsulation can be used to reduce background and improve detection of any single-cell secretion assay.
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Dispositivos Lab-On-A-Chip , Microfluídica , Citocinas , Células Matadoras NaturaisRESUMO
INTRODUCCIÓN: la marcha es una actividad compleja, que requiere de un balance estricto, donde toda la extremidad inferior actúa de manera conjunta para realizar el movimiento y donde el pie es la única parte que actúa sobre el suelo. Por ello cualquier alteración anatómica y biomecánica del pie repercute en la ambulación. OBJETIVO: determinar el grado de correlación funcional radiológica en pacientes tratados mediante osteotomía de scarf. MATERIAL Y MÉTODOS: rstudio correlacional y transversal. Se estudiaron 78 pacientes con diagnóstico de hallux valgus. Se realizó la valoración funcional (Escala AOFAS) y radiológica de todos los pacientes con hallux valgus operados mediante la osteotomía de scarf; se estableció además la correlación entre la valoración funcional y radiológica de cada paciente mediante la prueba de chi cuadrado. RESULTADOS: habiéndose obtenido el valor crítico de Chi cuadrado (X2 c = 12.992), se comprobó que este es menor que el valor del Chi cuadrado calculado, tanto para el ángulo metatarso-falángico (X2 = 40.715) y el ángulo inter-metatarsiano (X2 = 16.539); lo que significa que la hipótesis nula no se aceptó (Los resultados funcionales no se correlacionan con los resultados radiológicos de manera inversamente proporcional). CONCLUSIÓN: se determinó un grado de correlación inverso entre los resultados funcionales y radiológicos en pacientes tratados mediante osteotomía de scarf; α = 0.05; p = 0.95. Significa que a mayor gradación de hallux valgus (leve, moderado y severo), menor es el puntaje de la escala AOFAS (pobre, aceptable, bueno y excelente).
INTRODUCTION: walking is a complex activity, requiring a strict balance, where the entire lower limb acts together to perform the movement and where the foot is the only part that acts on the ground. Therefore, any anatomical and biomechanical alteration of the foot has an impact on the ambulation. OBJECTIVE: to determine the degree of functional radiological correlation in patients treated by the scarf osteotomy. MATERIAL AND METHODS: correlational and cross-sectional study. 78 patients diagnosed with hallux valgus were studied. Functional and radiological (AOFAS Scale) assessment was performed on all patients with hallux valgus operated by scarf osteotomy; the correlation between each patient's functional and radiological assessment was also established using the squared chi test. RESULTS: having obtained the critical value of Chi squared ((X2c x 12,992), it was found that this is less than the value of the Chi calculated square, both for the phalangeal metatarsus angle (X2 x 40.715) and the inter-metatarsal angle (X2 x 16,539); which means that the null hypothesis was not accepted (Functional results do not correlate with radiological results inversely proportional). CONCLUSION: a degree of reverse correlation between functional and radiological results was determined in patients treated with scarf osteotomy; α = 0.05; p = 0.95. meaning that the greater the gradation of hallux valgus (mild, moderate and severe), the lower the AOFAS scale score (poor, acceptable, good and excellent).
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Osteotomia , Ossos do Metatarso/anatomia & histologia , Hallux Valgus , Traumatologia/métodosRESUMO
INTRODUCCIÓN: una gran parte de la población adulta padece dolor de hombro en algún momento de su vida. Dejando aparte las enfermedades neoplásicas, sistémicas y traumáticas directas, una de las causas de dolor de hombro es la patología inflamatoria o degenerativa del manguito rotador, que puede ser responsable de una limitación funcional importante adulto. OBJETIVO: determinar el grado de correlación clínica y ultrasonográfica con los hallazgos intra-operatorios en pacientes con diagnóstico de ruptura de manguito rotador en el servicio de Traumatología del Hospital Obrero Nº 1, durante el periodo 2010 2014. MATERIAL Y MÉTODOS: estudio descriptivo transversal y analítico. Se estudiaron 56 pacientes de ambos sexos, internados en el servicio de Traumatología y Ortopedia del Hospital Obrero Nº1, durante el periodo del 1° de enero del 2010 al 31 de diciembre del año 2014. Se realizó la valoración clínica (maniobra de Jobe y manobra de Yocum) y ultrasonográfica y se compararon los resultados con los hallazgos intra-operatorios, para determinar la validez y la seguridad de la clínica y la ecografía. RESULTADOS: se determina que el test diagnóstico clínico tiene mayor validez (Sensibilidad: 92,7-87,8% y Especificidad: 73,3-60%) y seguridad (Valor Predictivo Positivo: 90,5-85,7% y Valor Predictivo Negativo: 78,6-64,3%) que el test diagnóstico ultrasonográfico (Sensibilidad: 85,4%, Especificidad: 66,7%, Valor Predictivo Positivo: 87,5% y Valor Predictivo Negativo: 62,5%). CONCLUSIÓN: se determina que existe una correlación clínica y ultrasonográfica con los hallazgos intra-operatorios en pacientes con diagnóstico de ruptura de manguito rotador en el servicio de Traumatología del Hospital Obrero Nº 1
INTRODUCTION: a great part of the adult population suffers shoulder pain at some moment of life. Leaving aside direct neoplastic systems and traumatic diseases, one of the causes of pain of shoulder is the inflammatory or degenerative pathology of the muff rotator, which can result in an important functional limitation. OBJECTIVE: determining the degree of clinical and ultrasonographic correlation with the intra-operative findings in patients with yielding-point diagnosis of muff rotator in the service of Traumatology of the Hospital Obrero Nº 1, during the period 2010 2014. MATERIAL AND METHODS: cross-sectional descriptive and analytical study. 56 patients of both sexes were surveyed, inpatients in the service of Traumatology y Orthopedic of the Hospital Obrero Nº 1, during the period January 1 of 2010 to December 31 of 2014. The clinical assessment was carried out (maneuver of Jobe and maneuver of Yocum) and ultrasonographic and the results were compared with the intra operative findings, in order to determine the value and security of the clinic and the echography. RESULTS: it is determined that the diagnostic test has higher validity (Sensitivity: 92,7-87,8% and specificity: 73,3-60%) and certainty (Positive Predictive Value: 90,5-85,7% and Negative Predictive Value: 78,6-64,3%) than the diagnostic ultrasonographic test (Sensitivity: 85.4%, Specificity: 66.7%, Positive Predictive Value: 87.5% and Negative Predictive Value: 62.5%). CONCLUSIONS: it is determined that there is a clinical and ultrasonographic correlation with the intra operative findings in patients with yielding-point diagnosis of muff rotator at the service of Traumatology of the Hospital Obrero Nº 1
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Humanos , Animais , Masculino , Ultrassonografia/instrumentação , Manguito Rotador/diagnóstico por imagem , Traumatologia/métodos , TendinopatiaRESUMO
OBJECTIVE: Investigate role of dose/duration of zoledronic acid (ZOL), a powerful anti-resorptive (pAR), on prevalence of medication-related osteonecrosis of the jaw (MRONJ) in rice rats (Oryzomys palustris), a species with natural susceptibility to food impaction-induced localized periodontitis (FILP). We hypothesize that ZOL induces MRONJ lesions in rice rats with FILP, and that the prevalence of MRONJ rises with increasing dose and duration of ZOL treatment. METHODS: We performed a toxicology experiment with clinically-relevant doses of ZOL in female rats (N=230) fed standard (STD) rodent chow. At age 4weeks (baseline), 12 rats were necropsied. The rest were randomized into five groups that began to receive 0, 8, 20, 50 or 125µg/kg ZOL IV/q 4weeks. After 12, 18, 24 and 30weeks, subgroups (N=9-16) from each of the dose groups were necropsied. High-resolution macroscopic photos of all jaw quadrants were given a gross quadrant grade (GQG) (0-4 or MRONJ) that classified FILP lesion severity and determined presence of gross MRONJ. Quadrants with GQG≥1 were examined histopathologically. Logistic regression analysis (ZOL dose/duration) of MRONJ prevalence was completed. RESULTS: We found: 1) 75% of 0µg/kg ZOL rats developed FILP lesions; 2) baseline rats and rats treated with 0µg/kg ZOL had no MRONJ; 3) 29 gross MRONJ cases were identified; 4) all gross MRONJ cases were confirmed histopathologically by the observation of exposed necrotic bone, and 53 new cases were discovered (total=82); 5) ZOL dose (P<0.001), but not duration (P=0.326), was a significant predictor of MRONJ prevalence; 6) 13% prevalence of gross MRONJ among all rats, with 22% prevalence among rats exposed to ZOL oncologic doses (20-125µg/kg); 7) 38% prevalence of histopathologic MRONJ among all rats, with 73% prevalence among rats exposed to ZOL oncologic doses. CONCLUSIONS: This is the first experiment to show a dose response relationship between clinically relevant doses of ZOL and MRONJ prevalence.
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Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/epidemiologia , Periodontite/complicações , Ácido Zoledrônico/efeitos adversos , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/patologia , Peso Corporal , Reabsorção Óssea/patologia , Relação Dose-Resposta a Droga , Feminino , Fêmur/patologia , Osteócitos/patologia , Periodontite/patologia , Prevalência , Sigmodontinae , Resultado do TratamentoRESUMO
Multiple myeloma (MM) causes lytic bone lesions due to increased bone resorption and concomitant marked suppression of bone formation. Sclerostin (Scl), an osteocyte-derived inhibitor of Wnt/ß-catenin signaling, is elevated in MM patient sera and increased in osteocytes in MM-bearing mice. We show here that genetic deletion of Sost, the gene encoding Scl, prevented MM-induced bone disease in an immune-deficient mouse model of early MM, and that administration of anti-Scl antibody (Scl-Ab) increased bone mass and decreases osteolysis in immune-competent mice with established MM. Sost/Scl inhibition increased osteoblast numbers, stimulated new bone formation and decreased osteoclast number in MM-colonized bone. Further, Sost/Scl inhibition did not affect tumor growth in vivo or anti-myeloma drug efficacy in vitro. These results identify the osteocyte as a major contributor to the deleterious effects of MM in bone and osteocyte-derived Scl as a promising target for the treatment of established MM-induced bone disease. Further, Scl did not interfere with efficacy of chemotherapy for MM, suggesting that combined treatment with anti-myeloma drugs and Scl-Ab should effectively control MM growth and bone disease, providing new avenues to effectively control MM and bone disease in patients with active MM.
Assuntos
Doenças Ósseas/etiologia , Doenças Ósseas/prevenção & controle , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/genética , Deleção de Genes , Mieloma Múltiplo/complicações , Mieloma Múltiplo/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Biomarcadores , Doenças Ósseas/diagnóstico , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Bortezomib/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/farmacologia , Modelos Animais de Doenças , Progressão da Doença , Marcadores Genéticos/genética , Humanos , Camundongos , Camundongos Knockout , Mieloma Múltiplo/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , OsteóliseRESUMO
OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.
Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Desprescrições , Fatores Imunológicos/uso terapêutico , Infliximab/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Colite Ulcerativa/fisiopatologia , Colo , Constrição Patológica , Doença de Crohn/fisiopatologia , Progressão da Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Seguimentos , Humanos , Íleo , Incidência , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Mesalamina/uso terapêutico , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Proteção , Recidiva , Indução de Remissão , Retratamento , Estudos Retrospectivos , Fatores de Risco , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto JovemRESUMO
The most widespread Plasmodium species, Plasmodium vivax, poses a significant public health threat. An effective vaccine is needed to reduce global malaria burden. Of the erythrocytic stage vaccine candidates, the 19 kDa fragment of the P. vivax Merozoite Surface Protein 1 (PvMSP119) is one of the most promising. Our group has previously defined several promiscuous T helper epitopes within the PvMSP1 protein, with features that allow them to bind multiple MHC class II alleles. We describe here a P. vivax recombinant modular chimera based on MSP1 (PvRMC-MSP1) that includes defined T cell epitopes genetically fused to PvMSP119. This vaccine candidate preserved structural elements of the native PvMSP119 and elicited cytophilic antibody responses, and CD4+ and CD8+ T cells capable of recognizing PvMSP119. Although CD8+ T cells that recognize blood stage antigens have been reported to control blood infection, CD8+ T cell responses induced by P. falciparum or P. vivax vaccine candidates based on MSP119 have not been reported. To our knowledge, this is the first time a protein based subunit vaccine has been able to induce CD8+ T cell against PvMSP119. The PvRMC-MSP1 protein was also recognized by naturally acquired antibodies from individuals living in malaria endemic areas with an antibody profile associated with protection from infection. These features make PvRMC-MSP1 a promising vaccine candidate.