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1.
Int J Mol Sci ; 20(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067838

RESUMO

BACKGROUND: Squamous intraepithelial lesions/cervical intraepithelial neoplasias (SIL/CIN) are high-risk human papilloma virus (hrHPV)-related lesions which are considered as high grade (HSIL/CIN2-3) or low grade (LSIL/CIN1) lesions according to their risk of progression to cervical cancer (CC). Most HSIL/CIN2-3 are considered as transforming hrHPV infections, so truly CC precursors, although some clear spontaneously. hrHPV testing has a high sensitivity for the detection of HSIL/CIN2-3 but a relatively low specificity for identifying transforming lesions. We aimed to determine whether the combination of CADM1, MAL and miR124 promoter methylation status assessed in histological samples can be used as a biomarker in the identification of transforming HSIL/CIN lesions. DESIGN: 131 cervical biopsies, including 8 cases with no lesion and a negative hrHPV test result (control group), 19 low-grade (L)SIL/CIN1, 30 HSIL/CIN2, 60 HSIL/CIN3, and 14 CC were prospectively collected. hrHPV was detected and genotyped using the polymerase chain reaction (PCR)-based technique SPF10 HPV LIPA. A multiplex quantitative methylation-specific PCR (qMSP) was used to identify the methylation status of the CADM1, MAL, and miR124 promoter genes. RESULTS: Significantly higher methylation levels of CADM1, MAL and miR-124 were found in HSIL/CIN2-3 and CC compared with normal and LSIL lesions. DNA methylation of at least one gene was detected in 12.5% (1/8) of normal samples, 31.5% (6/19) of LSIL/CIN1, 83.3% (25/30) of HSIL/CIN2, 81.6% (49/60) of HSIL/CIN3 and 100% (14/14) of CC (p < 0.001). The sensitivity and specificity for HSIL/CIN2-3 and CC of having at least one methylated gene were 84.6% and 74.0%, respectively. The sensitivity and specificity of the combination of at least one methylated gene and a positive hrHPV test were 80.7% and 85.1% for HSIL/CIN2-3 and CC, respectively. CONCLUSIONS: The methylation rate of CADM1, MAL and miR124 increases with the severity of the lesion. Further research is warranted to evaluate the usefulness of these biomarkers for the identification of transforming HSIL/CIN.


Assuntos
Biomarcadores Tumorais/genética , Molécula 1 de Adesão Celular/genética , Metilação de DNA , MicroRNAs/genética , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Lesões Intraepiteliais Escamosas Cervicais/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Lesões Intraepiteliais Escamosas Cervicais/patologia
2.
Histopathology ; 75(6): 799-812, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30861172

RESUMO

AIMS: The clinical implications of the programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) axis in patients with post-transplant lymphoproliferative disorders are largely unknown, and its association with Epstein-Barr virus (EBV) status and PD-L1 copy number alterations (CNAs) has not been thoroughly studied. METHODS AND RESULTS: PD1/PD-L1 expression was studied in 50 adult post-transplant lymphoproliferative disorders, and the correlations with PD-L1 CNAs, EBV, clinicopathological features and outcome were evaluated. Thirty-seven (74%) cases were classified as diffuse large B-cell lymphoma (DLBCL), nine (18%) cases were classified as polymorphic, and four (8%) cases were classified as classic Hodgkin lymphoma. Thirty-four cases were EBV-positive, with 29 of 34 (85%) having latency II or III, and 15 of 34 (44%) having viral replication. PD-L1 expression in tumour cells and tumour-associated macrophages was observed in 30 (60%) and 37 (74%) cases, respectively. PD1 positivity was seen in 16 (32%) cases. PD-L1 expression was associated with EBV with latency II or III (P = 0.001) and organ rejection (P = 0.04), and, in DLBCL, with non-germinal centre type DLBCL (P < 0.001). Cases with PD-L1-positive tumour cells showed a higher number of PD-L1 CNAs than PD-L1-negative cases (P = 0.001). Patients with EBV/latency III/replication and simultaneous PD-L1 expression showed the worst overall survival (P < 0.001). CONCLUSIONS: The PD1/PD-L1 axis is deregulated in post-transplant lymphoproliferative disorders, with frequent PD-L1 expression and PD1 negativity. PD-L1 expression is associated with EBV latency II or III and PD-L1 CNAs, and probably reflects a proinflammatory tumour microenvironment. The combined analysis of EBV status and PD-L1 expression may help to identify deeply immunosuppressed patients who can benefit from immune reconstitution approaches.

3.
Nefrología (Madrid) ; 38(5): 503-513, sept.-oct. 2018. tab, graf
Artigo em Inglês | IBECS | ID: ibc-177635

RESUMO

Introduction: Kidney donor shortage requires expanding donor selection criteria, as well as use of objective tools to minimize the percentage of discarded organs. Some donor pre-transplant variables such as age, standard/expanded criteria donor (SCD/ECD) definition and calculation of the Kidney Donor Profile Index (KDPI), have demonstrated correlations with patient and graft outcomes. We aimed to establish the accuracy of the three models to determine the prognostic value of kidney transplantation (KT) major outcomes. Material and methods: We performed a retrospective study in deceased donor KTs at our institution. Unadjusted Cox and Kaplan-Meier survival, and multivariate Cox analyses were fitted to analyze the impact of donor age, SCD/ECD and KDPI on outcomes. Results: 389 KTs were included. Mean donor age was 53.6 ± 15.2 years; 163 (41.9%) came from ECD; mean KDPI was 69.4 ± 23.4%. Median follow-up was 51.9 months. The unadjusted Cox and Kaplan–Meier showed that the three prognostic variables of interest were related to increased risk of patient death, graft failure and death-censored graft failure. However, in the multivariate analysis only KDPI was related to a higher risk of graft failure (HR 1.03 [95% CI 1.01-1.05]; p = 0.014). Conclusions: SCD/ECD classification did not provide significant prognostic information about patient and graft outcomes. KDPI was linearly related to a higher risk of graft failure, providing a better assessment. More studies are needed before using KDPI as a tool to discard or accept kidneys for transplantation


Introducción: La escasez de donantes de riñón requiere una ampliación de los criterios de selección de donantes, así como el uso de herramientas objetivas para minimizar el porcentaje de órganos descartados. Algunas variables pretrasplante del donante, como la edad, la definición de donante con criterios de selección estándar/ampliados (standard/expanded criteria donor [SCD/ECD]) y el cálculo del índice del perfil de donante renal (Kidney Donor Profile Index [KDPI]) han demostrado correlación con los resultados del paciente y el injerto. Nuestro objetivo fue evaluar la precisión de 3 modelos diferentes para determinar el valor pronostico en los resultados del trasplante renal. Materiales y métodos: Llevamos a cabo un estudio retrospectivo de TR de donantes fallecidos en nuestro centro. Se realizó un analisis de supervivencia mediante curvas de Kaplan-Meir y Cox no ajustado, ai como un analisis multivariante de Cox para analizar el impacto de la edad del donante, la definición SCD/ECD y el índice KDPI sobre los resultados. Resultados: Se incluyeron 389 TR. La media de edad de los donantes era de 53,6 ± 15,2 años; 163 (41,9%) procedían de donantes ECD; el índice KDPI medio era de 69,4 ± 23,4%. La mediana de seguimiento era de 51,9 meses. Los análisis de Kaplan-Meier y de Cox no ajustado mostraron que las 3 variables pronósticas de interés estaban relacionadas con un mayor riesgo de muerte del paciente, fracaso del injerto y fracaso del injerto censurado por la muerte. Sin embargo, en el análisis multivariable solamente el índice KDPI estuvo relacionado con un mayor riesgo de fracaso del injerto (HR: 1,03 [IC 95%: 1,01-1,05]; p = 0,014). Conclusiones: La clasificación SCD/ECD no proporcionó información pronóstica significativa sobre los desenlaces del paciente y el injerto. El índice KDPI estuvo linealmente relacionado con un mayor riesgo de fracaso del injerto, por lo que ofrecía una mejor evaluación. Es necesario realizar más estudios antes de usar el índice KDPI como herramienta para descartar o aceptar riñones para trasplante


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Transplante de Rim , Medição de Risco/métodos , Seleção do Doador/métodos , Estudos Retrospectivos , Estimativa de Kaplan-Meier , Fatores Etários , Estudos de Coortes , Prognóstico , Espanha
4.
Am J Clin Pathol ; 150(5): 432-440, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30052715

RESUMO

Objectives: To assess the prognostic value of human papillomavirus (HPV) 16/18 genotyping and p16/Ki-67 dual staining cytology in high-risk HPV (hrHPV)-positive women with no lesion or minor abnormalities. Methods: We evaluated progression to high-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia grades 2 to 3 or cervical cancer (HSIL/CIN2+), persistence/regression of hrHPV infection in women referred to colposcopy showing hrHPV infection, histology diagnosis different from HSIL/CIN2+, and negative cytology. HPV 16/18 genotyping and dual staining were performed in liquid-based cytologic specimens obtained on the first visit. Results: Progression was observed in 16 (8.0%) of 200 women. Those with HPV 16/18 infection had an increased risk of progression compared with women infected by other hrHPV types, and they also showed more persistence. However, no association was observed between progression or persistence and the result of the dual staining. Conclusions: HPV 16/18-positive women with no lesions or minor abnormalities are at high risk of progression to HSIL/CIN2+ and hrHPV persistence.


Assuntos
Neoplasia Intraepitelial Cervical/diagnóstico , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Infecções por Papillomavirus/diagnóstico , Lesões Intraepiteliais Escamosas Cervicais/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Biomarcadores/metabolismo , Neoplasia Intraepitelial Cervical/metabolismo , Neoplasia Intraepitelial Cervical/virologia , Colposcopia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Progressão da Doença , Feminino , Genótipo , Humanos , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Prognóstico , Estudos Prospectivos , Espanha , Lesões Intraepiteliais Escamosas Cervicais/metabolismo , Lesões Intraepiteliais Escamosas Cervicais/virologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia
5.
Nefrologia ; 38(5): 503-513, 2018.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29884503

RESUMO

INTRODUCTION: Kidney donor shortage requires expanding donor selection criteria, as well as use of objective tools to minimize the percentage of discarded organs. Some donor pre-transplant variables such as age, standard/expanded criteria donor (SCD/ECD) definition and calculation of the Kidney Donor Profile Index (KDPI), have demonstrated correlations with patient and graft outcomes. We aimed to establish the accuracy of the three models to determine the prognostic value of kidney transplantation (KT) major outcomes. MATERIAL AND METHODS: We performed a retrospective study in deceased donor KTs at our institution. Unadjusted Cox and Kaplan-Meier survival, and multivariate Cox analyses were fitted to analyze the impact of donor age, SCD/ECD and KDPI on outcomes. RESULTS: 389 KTs were included. Mean donor age was 53.6±15.2 years; 163 (41.9%) came from ECD; mean KDPI was 69.4±23.4%. Median follow-up was 51.9 months. The unadjusted Cox and Kaplan-Meier showed that the three prognostic variables of interest were related to increased risk of patient death, graft failure and death-censored graft failure. However, in the multivariate analysis only KDPI was related to a higher risk of graft failure (HR 1.03 [95% CI 1.01-1.05]; p=0.014). CONCLUSIONS: SCD/ECD classification did not provide significant prognostic information about patient and graft outcomes. KDPI was linearly related to a higher risk of graft failure, providing a better assessment. More studies are needed before using KDPI as a tool to discard or accept kidneys for transplantation.


Assuntos
Seleção do Doador/normas , Transplante de Rim , Fatores Etários , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha
6.
Kidney Blood Press Res ; 43(1): 34-44, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29393217

RESUMO

BACKGROUND/AIMS: Recurrent acute kidney injury (AKI) is common among patients after a first hospitalized AKI. However, little is known about the prognosis of recurrent AKI episodes in chronic kidney disease (CKD) development, cardiovascular events and mortality. METHODS: A retrospective study included patients admitted to our Hospital from 2000 to 2010. AKI was defined according to the Acute Dialysis Quality Initiative criteria. In the follow-up period after the first AKI episode, clinical, laboratory data and the number of repeated AKI episodes, etiology and severity were recorded. RESULTS: Among the 359 AKI survivor patients included, 250 new AKI episodes were observed in 122 patients (34%). Variables independently associated to new episodes were: type 2 DM [OR 1.2, 95%CI 1.2-3.8, p=0.001], ischemic heart disease [OR 1.9; 95%CI 1.1-3.6, p=0.012], and SCr at the first AKI event>2,6 mg/dl [OR 1.2; 95%CI 1.03-1.42, p=0.02]. Development of CKD during four years follow-up was more frequent in patients with recurrent AKI, HR [2.2 (95% CI: 1.09-4.3, p=0.003)] and 44% of recurrent AKI patients who developed CKD occurred during the first 6 months after the initial event. Cardiovascular events were more frequent among patients with recurrent AKI patients than in those with one AKI episode (47.2% vs 24%, p=0.001). Mortality at 4 years was higher in the patient subgroup with several episodes of AKI as compared with those with a single episode [HR: 4.5 (95% CI 2.7-7.5) p<0.001]. CONCLUSION: Episodes of recurrent AKI have a high potential to be associated with relevant complications such as cardiovascular events, mortality and CKD development.


Assuntos
Lesão Renal Aguda/complicações , Doenças Cardiovasculares/etiologia , Insuficiência Renal Crônica/etiologia , Lesão Renal Aguda/mortalidade , Lesão Renal Aguda/patologia , Adulto , Idoso , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Recidiva , Estudos Retrospectivos , Terapêutica
7.
Clin Exp Nephrol ; 22(1): 61-67, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28551821

RESUMO

BACKGROUND: Severe acute kidney injury (AKI) is associated with chronic kidney disease (CKD), cardiovascular events and increased mortality. However, little is known about the prognosis in hospitalized population suffering from non-severe AKI episodes. The aim of this study is to determine the impact of non-severe AKI episodes in cardiovascular events, mortality and CKD, on short and long term. METHODS: Retrospective cohort study to 360 patients who met the criteria for diagnosis of AKI according ADQI guidelines with full recovery of renal function after the AKI episode, admitted between January 2000 and December 2010 in our hospital. Follow-up was 4 years after the diagnosis of AKI. Covariates included demographic variables, baseline creatinine and diagnosis of comorbidities. RESULTS: 360 AKI survivor patients were included. Twenty five of them (6.7%) had developed CKD after 1-year follow-up. Hypertension (OR 1.62; 95% CI 1.2-2.6, p < 0.05) and serum creatinine >2.6 mg/dL in AKI (OR 1.7; 95% CI 1.2-3.7, p < 0.05) were independent risk factors. After 4-year follow-up, 40 patients (18.3%) had developed CKD; age >66 years was an independent risk factor (OR 1.03, 95% CI 1.03-1.06, p < 0.05). Mortality rate at 4 years was 25.3% and was significantly higher in CKD patients (OR 4.3, 95% CI 1.13-4.90, p < 0.05) and patients >66 years (OR 1.12, 95% CI 1.02-1.06, p < 0.05). The incidence of cardiovascular events also was higher in CKD patients than in non-CKD patients (62.7 vs. 21.7%, p < 0.05). CONCLUSION: Even after fully recovered non-severe AKI episodes, some patients develop CKD and those have an increase in the incidence of cardiovascular events and long-term mortality.


Assuntos
Lesão Renal Aguda/mortalidade , Lesão Renal Aguda/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Comorbidade , Creatinina/sangue , Feminino , Seguimentos , Humanos , Incidência , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Insuficiência Renal Crônica/complicações , Fatores de Risco , Resultado do Tratamento
8.
Adv Anat Pathol ; 24(4): 201-214, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28590952

RESUMO

Human papillomavirus (HPV) is involved in one of the at least 2 pathways leading to vulvar squamous cell carcinoma (VSCC). Inactivation of p53 and retinoblastoma by the viral products E6 and E7 is involved in malignant transformation. The percentage of HPV-positive VSCCs ranges from 18% to 75%, depending on the geographical area. HPV-associated tumors affect relatively young women and arise from high-grade intraepithelial lesions, identical to other HPV-associated premalignant lesions of the anogenital tract. HPV-independent tumors tend to affect older women and usually arise in a background of inflammatory skin disorders and a subtle variant of in situ lesion called differentiated vulvar intraepithelial neoplasia. HPV-positive tumors tend to be of basaloid or warty types, whereas HPV-independent tumors tend to be of keratinizing type, but there is frequent overlap between histologic types. There is no conclusive evidence yet on the best strategy in terms of determining HPV attribution. HPV DNA detection is generally considered the gold standard although there is some concern about misclassification when using this technique alone. p16 immunostaining has shown to be an excellent surrogate marker of HPV infection. Positive results for both techniques are considered the best evidence for HPV-association. The prognostic role of HPV in VSCC is still contradictory, but increasing evidence suggests that HPV-associated tumors are less aggressive. Currently, there are no differences in treatment between HPV-associated and HPV-independent VSCC, but novel immunological strategies based on anti-HPV antigens are being evaluated in clinical trials.


Assuntos
Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/patologia , Neoplasias Vulvares/epidemiologia , Neoplasias Vulvares/virologia , Carcinoma in Situ/epidemiologia , Carcinoma in Situ/virologia , Feminino , Humanos , Infecções por Papillomavirus/diagnóstico , Prognóstico , Neoplasias Vulvares/patologia
10.
J Crit Care ; 37: 19-23, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27610587

RESUMO

PURPOSE: Zika virus (ZIKV) infection is an emerging global threat and a public health problem in the Americas. Guillain-Barré syndrome (GBS) has been recently associated to ZIKV. This report presents a case series of GBS possibly associated to ZIKV. METHODS: Clinical and demographic data from patients with GBS treated in 5 intensive care units and with recent history of ZIKV in Cúcuta, Colombia were collected from December 1 2015 to April 30 2016. Electrophysiological examination, lumbar puncture, and reverse transcriptase-polymerase chain reaction for ZIKV were performed in 14, 10, and 1 patients, respectively. RESULTS: Nineteen patients with GBS and a recent history of acute viral syndrome compatible with ZIKV infection were studied (mean age, 44 years; range, 17-78). Neurologic symptoms developed at a median of 10 days after the onset of the viral symptoms. Albuminocytological dissociation was found in 8 cases. Electrophysiological criteria for acute motor axonal neuropathy were found in all patients tested. Five patients met level 1, 8 patients level 2, and 6 patients level 3 of diagnostic certainty for GBS in the Brighton classification. Fifteen patients required respiratory assistance, 16 received intravenous immunoglobulins, and 3 had plasmapheresis. Seventy-nine percent of patients were in Hughes GBS disability scale 4 to 5 at discharge and no patients died during the observation period. Acute ZIKV infection, confirmed by reverse transcriptase-polymerase chain reaction, was observed for 1 patient. CONCLUSIONS: All cases of this GBS outbreak had a recent history ZIKV infection, reinforcing existing evidence for the association between GBS and ZIKV. Future genetic and immunologic studies are warranted to further investigate the cause of the outbreak in detail.


Assuntos
Surtos de Doenças , Síndrome de Guillain-Barré/epidemiologia , Infecção por Zika virus/epidemiologia , Adolescente , Adulto , Idoso , Colômbia/epidemiologia , Feminino , Síndrome de Guillain-Barré/terapia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Plasmaferese , RNA Viral/líquido cefalorraquidiano , Respiração Artificial , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Punção Espinal , Adulto Jovem , Zika virus/genética
11.
Nefrología (Madr.) ; 36(6): 660-666, nov.-dic. 2016. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-158756

RESUMO

Introducción: El impacto del rechazo agudo en la supervivencia del injerto renal es bien conocido; sin embargo, el pronóstico de otras entidades es incierto. Evaluamos la frecuencia y el impacto en la supervivencia del injerto de las diferentes categorías diagnósticas según la clasificación Banff 2013 en una cohorte de trasplantados renales y su impacto en la supervivencia del injerto. Material y métodos: Estudio retrospectivo de 495 biopsias renales por indicación, en 322 pacientes entre 1990 y 2014. Dos observadores independientes revisaron los diagnósticos histológicos y reclasificaron según Banff 2013. Resultados: De 495 biopsias, 28 (5,7%) fueron no diagnósticas. De las 467 restantes, 10,3% fueron «normales» (categoría 1), 19,6% fueron cambios mediados por anticuerpos (categoría 2), 5,9% fueron cambios borderline (categoría 3), el 8,7% fueron rechazo mediado por células T (categoría 4), el 23,4% fue fibrosis intersticial/atrofia tubular (FIAT) (categoría 5) y el 26,5% fueron otros diagnósticos (categoría 6). Al aumentar el tiempo postrasplante, disminuyen los diagnósticos de categorías 1, 3 y 4 y aumentan los de la 5 y la 2. Observamos peor supervivencia en injertos con diagnósticos de categoría 2 (45% a 7,5 años; HR pérdida del injerto 4,29 [IC 95%: 2,39-7,73]; p≤0,001, con respecto a categoría 1). Los injertos con «histología desfavorable» (rechazo crónico mediado por anticuerpos, IFTA moderada-severa) presentan peor supervivencia que los injertos con «histología favorable» (normal, necrosis tubular aguda, FIAT leve). Conclusiones: La clasificación de Banff 2013 permite el diagnóstico histológico en el 95% de las biopsias por indicación. La categoría 6 es la más frecuente, pero se observa una modificación en la histopatología predominante según el tiempo postrasplante. Los cambios mediados por anticuerpos se asocian con peor supervivencia del injerto (AU)


Introduction: The impact of acute rejection in kidney graft survival is well known, but the prognosis of other diagnoses is uncertain. We evaluated the frequency and impact on graft survival of different diagnostic categories according to the Banff 2013 classification in a cohort of renal transplant recipients. Material and methods: Retrospective study of 495 renal biopsies by indication in 322 patients from 1990-2014. Two independent observers reviewed the histological reports, reclassifying according to the Banff 2013 classification. Results: Of 495 biopsies, 28 (5.7%) were not diagnostic. Of the remaining 467, 10.3% were «normal» (category 1), 19.6% antibody-mediated changes (category 2), 5.9% «borderline» changes (category 3), 8.7% T-cell-mediated rejection (category 4), 23.4% interstitial fibrosis/tubular atrophy (IFTA) (category 5) and 26.5% with other diagnoses (category 6). As time after transplantation increases, diagnoses of categories 1, 3 and 4 decrease, while categories 5 and 2 increase. Worse graft survival with category 2 diagnosis was observed (45% at 7.5 years, HR 4.29 graft loss [95% CI, 2.39-7.73]; P≤.001, compared to category 1). Grafts with «unfavourable histology» (chronic antibody-mediated rejection, moderate-severe IFTA) presented worse survival that grafts with «favourable histology» (normal, acute tubular necrosis, mild IFTA). Conclusions: The Banff 2013 classification facilitates a histological diagnosis in 95% of indication biopsies. While diagnostic category 6 is the most common, a change in the predominant histopathology was observed according to time elapsed since transplantation. Antibody-mediated changes are associated with worse graft survival (AU)


Assuntos
Humanos , Sobrevivência de Enxerto , Transplante de Rim/estatística & dados numéricos , Biópsia/estatística & dados numéricos , Estudos Retrospectivos , Rejeição de Enxerto/epidemiologia
12.
Nefrologia ; 36(6): 660-666, 2016.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-27595515

RESUMO

INTRODUCTION: The impact of acute rejection in kidney graft survival is well known, but the prognosis of other diagnoses is uncertain. We evaluated the frequency and impact on graft survival of different diagnostic categories according to the Banff 2013 classification in a cohort of renal transplant recipients. MATERIAL AND METHODS: Retrospective study of 495 renal biopsies by indication in 322 patients from 1990-2014. Two independent observers reviewed the histological reports, reclassifying according to the Banff 2013 classification. RESULTS: Of 495 biopsies, 28 (5.7%) were not diagnostic. Of the remaining 467, 10.3% were «normal¼ (category 1), 19.6% antibody-mediated changes (category 2), 5.9% «borderline¼ changes (category 3), 8.7% T-cell-mediated rejection (category 4), 23.4% interstitial fibrosis/tubular atrophy (IFTA) (category 5) and 26.5% with other diagnoses (category 6). As time after transplantation increases, diagnoses of categories 1, 3 and 4 decrease, while categories 5 and 2 increase. Worse graft survival with category 2 diagnosis was observed (45% at 7.5 years, HR 4.29 graft loss [95% CI, 2.39-7.73]; P≤.001, compared to category 1). Grafts with «unfavourable histology¼ (chronic antibody-mediated rejection, moderate-severe IFTA) presented worse survival that grafts with «favourable histology¼ (normal, acute tubular necrosis, mild IFTA). CONCLUSIONS: The Banff 2013 classification facilitates a histological diagnosis in 95% of indication biopsies. While diagnostic category 6 is the most common, a change in the predominant histopathology was observed according to time elapsed since transplantation. Antibody-mediated changes are associated with worse graft survival.


Assuntos
Biópsia , Sobrevivência de Enxerto , Transplante de Rim , Rim/patologia , Adulto , Feminino , Rejeição de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Repert. med. cir ; 25(4): 247-251, 2016. ilus
Artigo em Espanhol | LILACS, COLNAL | ID: biblio-849326

RESUMO

La identidad de género es el sentido de masculinidad o feminidad que puede tener una persona o una combinación de ambas; desde 1940 Harry Benjamín plantea el término transexualidad o trastorno de identidad de género (TIG) cuando hay alteración de esta. Su manejo debe hacerse de manera multi e interdisciplinaria a través del proceso de easignación de género. A continuación se presenta el caso de una paciente de 50 anos con diagnóstico de disforia de género masculino a femenino (MTF), quien desde la infancia presentaba insatisfacción con su sexo asignado al acimiento, lo cual la hace candidata a terapia de reemplazo hormonal, tratamiento quirúrgico de feminización y asignación de sexo...(AU)


Gender identity is a person concept of self as being male or female, or ambivalent sex. Trans-sexuality or gender identity disorder was given that name by Harry Benjamin since 1940. The treatment should be multi and inter-disciplinary through a process of a gender reassignment. A case is presented of a 50 year-old patient with a diagnosis of male to female (MTF) gender dysphoria, who felt dissatisfied since childhood with her gender assigned at birth, thus being a candidate for hormone replacement therapy, surgical feminisation treatment, and gender assignment...(AU)


Assuntos
Humanos , Disforia de Gênero , Identidade de Gênero , Pessoas Transgênero
14.
Leuk Res ; 37(7): 769-76, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23639672

RESUMO

The prognosis of chromosome 17 (chr17) abnormalities in patients with primary myelodysplastic syndrome (MDS) remains unclear. The revised International Prognostic Scoring System (IPSS-R) includes these abnormalities within the intermediate cytogenetic risk group. This study assessed the impact on overall survival (OS) and risk of acute myeloid leukemia transformation (AMLt) of chr17 abnormalities in 88 patients with primary MDS. We have compared this group with 1346 patients with primary MDS and abnormal karyotype without chr17 involved. The alterations of chr17 should be considered within group of poor prognosis. The different types of alterations of chromosome 17 behave different prognosis. The study confirms the intermediate prognostic impact of the i(17q), as stated in IPSS-R. The results of the study, however, provide valuable new information on the prognostic impact of alterations of chromosome 17 in complex karyotypes.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 17/genética , Síndromes Mielodisplásicas/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Prognóstico , Taxa de Sobrevida , Adulto Jovem
15.
J Biol Chem ; 287(25): 21224-32, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22539351

RESUMO

The brain-specific isoform carnitine palmitoyltransferase 1C (CPT1C) has been implicated in the hypothalamic regulation of food intake and energy homeostasis. Nevertheless, its molecular function is not completely understood, and its role in other brain areas is unknown. We demonstrate that CPT1C is expressed in pyramidal neurons of the hippocampus and is located in the endoplasmic reticulum throughout the neuron, even inside dendritic spines. We used molecular, cellular, and behavioral approaches to determine CPT1C function. First, we analyzed the implication of CPT1C in ceramide metabolism. CPT1C overexpression in primary hippocampal cultured neurons increased ceramide levels, whereas in CPT1C-deficient neurons, ceramide levels were diminished. Correspondingly, CPT1C knock-out (KO) mice showed reduced ceramide levels in the hippocampus. At the cellular level, CPT1C deficiency altered dendritic spine morphology by increasing immature filopodia and reducing mature mushroom and stubby spines. Total protrusion density and spine head area in mature spines were unaffected. Treatment of cultured neurons with exogenous ceramide reverted the KO phenotype, as did ectopic overexpression of CPT1C, indicating that CPT1C regulation of spine maturation is mediated by ceramide. To study the repercussions of the KO phenotype on cognition, we performed the hippocampus-dependent Morris water maze test on mice. Results show that CPT1C deficiency strongly impairs spatial learning. All of these results demonstrate that CPT1C regulates the levels of ceramide in the endoplasmic reticulum of hippocampal neurons, and this is a relevant mechanism for the correct maturation of dendritic spines and for proper spatial learning.


Assuntos
Carnitina O-Palmitoiltransferase/biossíntese , Ceramidas/metabolismo , Dendritos/enzimologia , Metabolismo Energético/fisiologia , Regulação Enzimológica da Expressão Gênica/fisiologia , Metabolismo dos Lipídeos/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Células Piramidais/enzimologia , Animais , Comportamento Animal/fisiologia , Carnitina O-Palmitoiltransferase/genética , Células Cultivadas , Retículo Endoplasmático/enzimologia , Retículo Endoplasmático/genética , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Células Piramidais/citologia
16.
J Biol Chem ; 283(11): 6878-85, 2008 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-18192268

RESUMO

CPT1c is a carnitine palmitoyltransferase 1 (CPT1) isoform that is expressed only in the brain. The enzyme has recently been localized in neuron mitochondria. Although it has high sequence identity with the other two CPT1 isoenzymes (a and b), no CPT activity has been detected to date. Our results indicate that CPT1c is expressed in neurons but not in astrocytes of mouse brain sections. Overexpression of CPT1c fused to the green fluorescent protein in cultured cells demonstrates that CPT1c is localized in the endoplasmic reticulum rather than mitochondria and that the N-terminal region of CPT1c is responsible for endoplasmic reticulum protein localization. Western blot experiments with cell fractions from adult mouse brain corroborate these results. In addition, overexpression studies demonstrate that CPT1c does not participate in mitochondrial fatty acid oxidation, as would be expected from its subcellular localization. To identify the substrate of CPT1c enzyme, rat cDNA was overexpressed in neuronal PC-12 cells, and the levels of acylcarnitines were measured by high-performance liquid chromatography-mass spectrometry. Palmitoylcarnitine was the only acylcarnitine to increase in transfected cells, which indicates that palmitoyl-CoA is the enzyme substrate and that CPT1c has CPT1 activity. Microsomal fractions of PC-12 and HEK293T cells overexpressing CPT1c protein showed a significant increase in CPT1 activity of 0.57 and 0.13 nmol.mg(-1).min(-1), respectively, which is approximately 50% higher than endogenous CPT1 activity. Kinetic studies demonstrate that CPT1c has similar affinity to CPT1a for both substrates but 20-300 times lower catalytic efficiency.


Assuntos
Carnitina O-Palmitoiltransferase/química , Carnitina O-Palmitoiltransferase/metabolismo , Regulação da Expressão Gênica , Neurônios/metabolismo , Animais , Catálise , Linhagem Celular , Ácidos Graxos/metabolismo , Humanos , Cinética , Mitocôndrias/metabolismo , Modelos Biológicos , Oxigênio/metabolismo , Células PC12 , Isoformas de Proteínas , Ratos
17.
Anal Chim Acta ; 599(1): 1-6, 2007 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-17765057

RESUMO

The quantitative evaluation of long-chain acylcarnitines in lipid extracts from cultured cells or tissues is a prerequisite to study carnitine palmitoyltransferase (CPT) activity. There is thus a need for the accurate measurement of the concentration of long-chain acylcarnitines at the lowest concentration present in lipid extracts. Here we report a fast and reliable quantitative method based on the use of weak acid extraction and liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) to quantify acylcarnitines through hydrophilic interaction chromatography. The method was validated using isotopic dilution and the results allow the analysis of a large number of samples at low concentration levels (down to 0.35 nmol L(-1) for palmitoylcarnitine) with good inter- and intra-day precision. The method was used for the quantitative study of changes in concentration of palmitoylcarnitine and other acylcarnitines in PC-12 cells over-expressing CPT1a gene. It was also used to measure CPT1 activity in mitochondria isolated from transfected cells, giving similar results to the more common radiometric method, but with higher sensitivity.


Assuntos
Carnitina/análogos & derivados , Acetonitrilos/química , Animais , Carnitina/análise , Carnitina/farmacologia , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Cromatografia Líquida de Alta Pressão , Formiatos/química , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/enzimologia , Células PC12 , Palmitoil Coenzima A/farmacologia , Ratos , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Transfecção
18.
Mol Genet Metab ; 91(2): 120-7, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17459752

RESUMO

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase adopts a (betaalpha)(8) TIM barrel structure with an additional beta9, alpha11 and alpha12 helices. Location of HMG part of the substrate has been suggested but the binding mode for the CoA moiety remains to be resolved. As mutation F305 fs(-2), which involves the last 21 residues of the protein, and mutation K48N caused 3-hydroxy-3-methylglutaric aciduria in two patients, we examined the role of the C-terminal end and Lys(48) in enzyme activity. Expression studies of various C-terminal-end-deleted and K48N-mutated proteins revealed that residues 311-313 (localized in the loop between alpha11 and alpha12 helices) and Lys(48) are essential for enzyme activity. An in silico docking model locating HMG-CoA on the surface of the enzyme implicates Asn(311) and Lys(313) in substrate binding by establishing multiple polar contacts with phosphate and ribose groups of adenosine, and Lys(48) by contacting the carboxyl group of the panthotenic acid moiety.


Assuntos
Acil Coenzima A/química , Oxo-Ácido-Liases/química , Oxo-Ácido-Liases/genética , Sequência de Aminoácidos , Sequência Conservada , Escherichia coli/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Oxo-Ácido-Liases/biossíntese , Oxo-Ácido-Liases/deficiência , Ligação Proteica , Estrutura Secundária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética
19.
Biochem Biophys Res Commun ; 331(4): 1178-84, 2005 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-15883000

RESUMO

Plasmodium vivax malaria is one of the most prevalent parasitic diseases in Asia and Latin-America. The difficulty of maintaining this parasite culture in vitro has hampered identifying and characterising proteins implied in merozoite invasion of red blood cells. We have been able to identify an open reading frame in P. vivax encoding the Plasmodium falciparum merozoite surface protein 10 homologous protein using the partial sequences from this parasite's genome reported during 2004. This new protein contains 479 amino-acids, two epidermal growth factor-like domains, hydrophobic regions at the N- and C-termini, being compatible with a signal peptide and a glycosylphosphatidylinositol anchor site, respectively. The protein is expressed during the parasite's asexual stage and is recognised by polyclonal sera in parasite lysate using Western blot. P. vivax-infected patients' sera highly recognised recombinant protein by ELISA.


Assuntos
Plasmodium falciparum/química , Plasmodium vivax/química , Proteínas de Protozoários/química , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Primers do DNA , Dados de Sequência Molecular , Conformação Proteica , Coelhos , Homologia de Sequência de Aminoácidos
20.
Vaccine ; 23(31): 4048-53, 2005 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15893858

RESUMO

Effector mechanisms responsible for providing protective immunity against Plasmodium vivax (Pv) infection were examined in Aotus monkeys vaccinated with two Pv Merozoite Surface Protein-1 (PvMSP-1) recombinant polypeptides that had previously been shown to protect vaccines against parasite challenge. Vaccine efficacy was reproducible in this trial, showing that one out of the five monkeys immunised with the recombinant protein mixture was partially protected while three others controlled parasitaemia. Antibodies reactive to the parasite's native proteins, the recombinant polypeptides and peptides spanning both recombinant fragments were detected in most vaccinees. Despite substantial Peripheral Blood Mononuclear Cell (PBMC) antigen-specific cellular proliferation not being detected, high rPvMSP-1(20) specific gamma interferon (IFN-gamma) production was found in the three animals that controlled parasitaemia. Altogether the results suggest that antibody titres and antigen-specific IFN-gamma production mediate protective immunity against P. vivax.


Assuntos
Vacinas Antimaláricas/imunologia , Malária Vivax/prevenção & controle , Proteína 1 de Superfície de Merozoito/imunologia , Proteínas Recombinantes/imunologia , Animais , Anticorpos Antiprotozoários/sangue , Aotidae , Modelos Animais de Doenças , Interferon gama/análise , Leucócitos Mononucleares/imunologia , Parasitemia , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/imunologia
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