[Rural labor associated with lymphohematopoietic cancers in a public reference hospital: a case-control study, Ceará, Brazil, 2019-2021]. / Trabalho rural associado a cânceres linfohematopoiéticos em hospital público de referência: estudo caso-controle, Ceará, Brasil, 2019-2021.

This is a paired case-control study that sought to verify the association between professions and lymphohematopoietic cancers in a public reference hospital in the State of Ceará, Brazil, during 2019-2021. Case group consisted of hematological patients with multiple myeloma, leukemias or non-Hodgkin lymphomas, monitored by the social service of a bone marrow transplant hospital unit (n = 114), whereas comparable individuals from a different hospital unit made up the control group (n = 114), forming 1:1 pairs. Diagnosis was performed by a medical team and the variables were measured by accessing hospital records. Group comparison was conducted using bivariate conditional logistic regression and adjusted by region of residence. Results show that multiple myeloma (43.9%), leukemias (43%) and non-Hodgkin lymphomas (13.2%) were the cancer with the highest prevalence in the case group. Proportions of jobs, area of residence, water supply and Regional Superintendence of Health showed statistically significant difference between the case and control groups. Rural workers were more likely to present the cancers studied (ORraw = 5.00, 95%CI: 1.91; 13.06 and ORadjusted = 3.38, 95%CI: 1.20; 9.54), whereas trade workers had lower odds (ORraw = 0.26, 95%CI: 0.10; 0.70 and ORadjusted = 0.30, 95%CI: 0.10; 0.88). The findings allow us to reflect on the process of illness among rural workers and illustrate the potential of health services to contribute to investigations on occupational exposures.

Trata-se de um estudo do tipo caso-controle pareado com o objetivo de verificar a associação entre ocupações e cânceres linfohematopoiéticos em um hospital público de referência no Estado do Ceará, Brasil, durante 2019-2021. O grupo caso foi constituído por pacientes hematológicos que apresentavam mieloma múltiplo, leucemias ou linfomas não Hodgkin, acompanhados pelo serviço social de uma unidade hospitalar de transplante de medula óssea (n = 114), enquanto indivíduos comparáveis de unidade hospitalar distinta constituíram o grupo controle (n = 114), formando pares 1:1. O diagnóstico foi efetuado por equipe médica e as variáveis foram aferidas por acesso aos registros hospitalares. Comparamos os grupos em regressão logística condicional bivariada e ajustada por região de residência. Entre os resultados, destacamos que o câncer de maior prevalência no grupo caso foi o mieloma múltiplo (43,9%), seguido pelas leucemias (43%) e por linfomas não Hodgkin (13,2%). Proporções de ocupações, zona de residência, abastecimento de água e Superintendência Regional de Saúde de residência apresentaram diferença estatisticamente significante entre os grupos caso e controle. Verificamos que trabalhadores rurais possuíam maiores chances de apresentar os cânceres estudados (ORbruto = 5,00, IC95%: 1,91; 13,06 e ORajustado = 3,38, IC95%: 1,20; 9,54), enquanto trabalhadores do comércio apresentaram menores chances (ORbruto = 0,26, IC95%: 0,10; 0,70 e ORajustado = 0,30, IC95%: 0,10; 0,88). Os achados deste estudo possibilitam reflexões sobre o processo de adoecimento dos trabalhadores rurais e refletem o potencial dos serviços de saúde em contribuir com investigações sobre exposições ocupacionais.

Se trata de un estudio del tipo caso control apareado con el objetivo de verificar la asociación entre ocupaciones y cánceres linfohematopoyéticos en un hospital público de referencia en el estado de Ceará, Brasil, durante el período 2019-2021. El grupo caso estaba formado por pacientes hematológicos que presentaban mieloma múltiple, leucemias o linfomas no Hodgkin, bajo seguimiento por parte del servicio social de una unidad hospitalaria de trasplante de médula ósea (n = 114), mientras que individuos comparables de otra unidad hospitalaria constituyeron el grupo control (n = 114), formando pares 1:1. El diagnóstico fue realizado por un equipo médico, y las variables se midieron accediendo a los registros hospitalarios. Comparamos los grupos en regresión logística condicional bivariada y ajustada por región de residencia. Entre los resultados, destacamos que el cáncer de mayor prevalencia en el grupo caso fue el mieloma múltiple (43,9%), seguido de las leucemias (43%) y los linfomas no Hodgkin (13,2%). Las proporciones de ocupaciones, zona de residencia, abastecimiento de agua y Superintendencia Regional de Salud de residencia presentaron diferencia estadísticamente significativa entre los grupos caso y control. Constatamos que los trabajadores rurales tenían más probabilidades de padecer los cánceres estudiados (ORcrudo = 5,00, IC95%: 1,91; 13,06 y ORajustado = 3,38, IC95%: 1,20; 9,54), mientras que los trabajadores del comercio presentaron menos posibilidades (ORcrudo = 0,26, IC95%: 0,10; 0,70 y ORajustado = 0,30, IC95%: 0,10; 0,88). Los hallazgos de este estudio permiten reflexiones sobre el proceso de enfermedad de los trabajadores rurales y reflejan el potencial de los servicios de salud para contribuir a las investigaciones sobre exposiciones ocupacionales.

Trabalho rural associado a cânceres linfohematopoiéticos em hospital público de referência: estudo caso-controle, Ceará, Brasil, 2019-2021 / Rural labor associated with lymphohematopoietic cancers in a public reference hospital: a case-control study, Ceará, Brazil, 2019-2021 / Trabajo rural asociado a cánceres linfohematopoyéticos en un hospital público de referencia: estudio de caso control, Ceará, Brasil, 2019-2021

Trata-se de um estudo do tipo caso-controle pareado com o objetivo de verificar a associação entre ocupações e cânceres linfohematopoiéticos em um hospital público de referência no Estado do Ceará, Brasil, durante 2019-2021. O grupo caso foi constituído por pacientes hematológicos que apresentavam mieloma múltiplo, leucemias ou linfomas não Hodgkin, acompanhados pelo serviço social de uma unidade hospitalar de transplante de medula óssea (n = 114), enquanto indivíduos comparáveis de unidade hospitalar distinta constituíram o grupo controle (n = 114), formando pares 1:1. O diagnóstico foi efetuado por equipe médica e as variáveis foram aferidas por acesso aos registros hospitalares. Comparamos os grupos em regressão logística condicional bivariada e ajustada por região de residência. Entre os resultados, destacamos que o câncer de maior prevalência no grupo caso foi o mieloma múltiplo (43,9%), seguido pelas leucemias (43%) e por linfomas não Hodgkin (13,2%). Proporções de ocupações, zona de residência, abastecimento de água e Superintendência Regional de Saúde de residência apresentaram diferença estatisticamente significante entre os grupos caso e controle. Verificamos que trabalhadores rurais possuíam maiores chances de apresentar os cânceres estudados (ORbruto = 5,00, IC95%: 1,91; 13,06 e ORajustado = 3,38, IC95%: 1,20; 9,54), enquanto trabalhadores do comércio apresentaram menores chances (ORbruto = 0,26, IC95%: 0,10; 0,70 e ORajustado = 0,30, IC95%: 0,10; 0,88). Os achados deste estudo possibilitam reflexões sobre o processo de adoecimento dos trabalhadores rurais e refletem o potencial dos serviços de saúde em contribuir com investigações sobre exposições ocupacionais.

This is a paired case-control study that sought to verify the association between professions and lymphohematopoietic cancers in a public reference hospital in the State of Ceará, Brazil, during 2019-2021. Case group consisted of hematological patients with multiple myeloma, leukemias or non-Hodgkin lymphomas, monitored by the social service of a bone marrow transplant hospital unit (n = 114), whereas comparable individuals from a different hospital unit made up the control group (n = 114), forming 1:1 pairs. Diagnosis was performed by a medical team and the variables were measured by accessing hospital records. Group comparison was conducted using bivariate conditional logistic regression and adjusted by region of residence. Results show that multiple myeloma (43.9%), leukemias (43%) and non-Hodgkin lymphomas (13.2%) were the cancer with the highest prevalence in the case group. Proportions of jobs, area of residence, water supply and Regional Superintendence of Health showed statistically significant difference between the case and control groups. Rural workers were more likely to present the cancers studied (ORraw = 5.00, 95%CI: 1.91; 13.06 and ORadjusted = 3.38, 95%CI: 1.20; 9.54), whereas trade workers had lower odds (ORraw = 0.26, 95%CI: 0.10; 0.70 and ORadjusted = 0.30, 95%CI: 0.10; 0.88). The findings allow us to reflect on the process of illness among rural workers and illustrate the potential of health services to contribute to investigations on occupational exposures.

Se trata de un estudio del tipo caso control apareado con el objetivo de verificar la asociación entre ocupaciones y cánceres linfohematopoyéticos en un hospital público de referencia en el estado de Ceará, Brasil, durante el período 2019-2021. El grupo caso estaba formado por pacientes hematológicos que presentaban mieloma múltiple, leucemias o linfomas no Hodgkin, bajo seguimiento por parte del servicio social de una unidad hospitalaria de trasplante de médula ósea (n = 114), mientras que individuos comparables de otra unidad hospitalaria constituyeron el grupo control (n = 114), formando pares 1:1. El diagnóstico fue realizado por un equipo médico, y las variables se midieron accediendo a los registros hospitalarios. Comparamos los grupos en regresión logística condicional bivariada y ajustada por región de residencia. Entre los resultados, destacamos que el cáncer de mayor prevalencia en el grupo caso fue el mieloma múltiple (43,9%), seguido de las leucemias (43%) y los linfomas no Hodgkin (13,2%). Las proporciones de ocupaciones, zona de residencia, abastecimiento de agua y Superintendencia Regional de Salud de residencia presentaron diferencia estadísticamente significativa entre los grupos caso y control. Constatamos que los trabajadores rurales tenían más probabilidades de padecer los cánceres estudiados (ORcrudo = 5,00, IC95%: 1,91; 13,06 y ORajustado = 3,38, IC95%: 1,20; 9,54), mientras que los trabajadores del comercio presentaron menos posibilidades (ORcrudo = 0,26, IC95%: 0,10; 0,70 y ORajustado = 0,30, IC95%: 0,10; 0,88). Los hallazgos de este estudio permiten reflexiones sobre el proceso de enfermedad de los trabajadores rurales y reflejan el potencial de los servicios de salud para contribuir a las investigaciones sobre exposiciones ocupacionales.

[Rituximab for the treatment of generalised myasthenia gravis: experience in clinical practice]. / Rituximab para el tratamiento de la miastenia grave generalizada: experiencia en la práctica clínica.

INTRODUCTION AND AIMS: Rituximab (RTX) is an anti-CD20 monoclonal antibody that has been used in cases of refractory myasthenia gravis (MG). The aim of this work is to analyse the efficacy and safety of RTX in MG in real clinical practice in a tertiary hospital. PATIENTS AND METHODS: A retrospective study was conducted with patients with MG treated with RTX in our centre from March 2014 to September 2020. Demographic and serological data, together with information about previous immunomodulatory treatment, clinical response and adverse effects are collected. RESULTS: Twenty patients with MG - 100% generalised: 70% late-onset MG (LOMG) and 30% early-onset MG (EOMG) - were given RTX (mean age: 66.8 years; 70% male). A total of 90% are seropositive, 16 of them with positive anti-acetylcholine receptor antibodies and two with positive muscle-specific tyrosine kinase (anti-MuSK) antibodies. All had failed previous treatments: 100% with steroids, 100% with intravenous immunoglobulins and/or plasmapheresis, 55% with other immunosuppressants (25% with one previous immunosuppressant, 10% with two, 15% with three and 5% with four) and 35% with thymectomy. After RTX, 75% of patients showed a clinical response (12 patients with complete remission and the possibility of steroid withdrawal without recurrence; and three patients with partial remission and the possible reduction of steroid dosage) and 25% therapeutic failure; in all these cases RTX was withdrawn. All the anti-MuSK+ patients (100%) and 92.8% of the LOMG patients responded to RTX, while 66% of EOMG patients failed. Only three patients reported adverse effects, all of which were mild and did not require RTX withdrawal. CONCLUSION: In our experience, rituximab is a safe and effective treatment in aggressive generalised MG with anti-MuSK or late-onset MG (LOMG).

TITLE: Rituximab para el tratamiento de la miastenia grave generalizada: experiencia en la práctica clínica.Introducción y objetivos. El rituximab (RTX) es un anticuerpo monoclonal anti-CD20 que se ha utilizado en casos de miastenia grave (MG) refractaria. El objetivo de este trabajo es analizar la eficacia y la seguridad del RTX en la MG en la práctica clínica real en un hospital terciario. Pacientes y métodos. Se realiza un estudio retrospectivo de pacientes con MG tratados con RTX en nuestro centro de marzo de 2014 a septiembre de 2020. Se recogen datos demográficos, serológicos, tratamiento inmunomodulador previo, respuesta clínica y efectos adversos. Resultados. Veinte pacientes con MG ­el 100%, generalizada: el 70%, MG de inicio tardío (LOMG), y el 30%, MG de inicio temprano (EOMG)­ han recibido RTX (edad media: 66,8 años; 70%, varones). El 90% son seropositivos ­16 con anticuerpos antirreceptor de la acetilcolina positivos y dos con anticuerpos antitirosincinasa muscular específica (anti-MuSK) positivos­. Todos habían fracasado con tratamientos previos: el 100% con esteroides, el 100% con inmunoglobulinas intravenosas y/o con plasmaféresis, el 55% con otros inmunosupresores (25%, un inmunosupresor previo; 10%, dos; 15%, tres; y 5%, cuatro) y el 35% con timectomía. Tras el RTX, presentó respuesta clínica el 75% de los pacientes (12 pacientes, remisión completa con posibilidad de la retirada de los esteroides sin recurrencia; y tres parcial, con posibilidad de la reducción de la dosis de esteroides) y fracaso terapéutico el 25%; en todos estos casos se retiró el RTX. El 100% de los pacientes anti-MuSK+ y el 92,8% de los de LOMG presentaron respuesta al RTX, mientras que el 66% de los pacientes con EOMG fracasaron. Sólo tres pacientes presentaron efectos adversos, todos leves, que no requirieron la retirada del RTX. Conclusión. En nuestra experiencia, el rituximab es un tratamiento seguro y eficaz en la MG generalizada agresiva con anticuerpos anti-MuSK o de inicio tardío (LOMG).

Rituximab para el tratamiento de la miastenia grave generalizada: experiencia en la práctica clínica / Rituximab for the treatment of generalised myasthenia gravis: experience in clinical practice

Introducción y objetivos: El rituximab (RTX) es un anticuerpo monoclonal anti-CD20 que se ha utilizado en casos de miastenia grave (MG) refractaria. El objetivo de este trabajo es analizar la eficacia y la seguridad del RTX en la MG en la práctica clínica real en un hospital terciario. Pacientes y métodos:Se realiza un estudio retrospectivo de pacientes con MG tratados con RTX en nuestro centro de marzo de 2014 a septiembre de 2020. Se recogen datos demográficos, serológicos, tratamiento inmunomodulador previo, respuesta clínica y efectos adversos. Resultados: Veinte pacientes con MG –el 100%, generalizada: el 70%, MG de inicio tardío (LOMG), y el 30%, MG de inicio temprano (EOMG)– han recibido RTX (edad media: 66,8 años; 70%, varones). El 90% son seropositivos –16 con anticuerpos antirreceptor de la acetilcolina positivos y dos con anticuerpos antitirosincinasa muscular específica (anti-MuSK) positivos–. Todos habían fracasado con tratamientos previos: el 100% con esteroides, el 100% con inmunoglobulinas intravenosas y/o con plasmaféresis, el 55% con otros inmunosupresores (25%, un inmunosupresor previo; 10%, dos; 15%, tres; y 5%, cuatro) y el 35% con timectomía. Tras el RTX, presentó respuesta clínica el 75% de los pacientes (12 pacientes, remisión completa con posibilidad de la retirada de los esteroides sin recurrencia; y tres parcial, con posibilidad de la reducción de la dosis de esteroides) y fracaso terapéutico el 25%; en todos estos casos se retiró el RTX. El 100% de los pacientes anti-MuSK+ y el 92,8% de los de LOMG presentaron respuesta al RTX, mientras que el 66% de los pacientes con EOMG fracasaron. Sólo tres pacientes presentaron efectos adversos, todos leves, que no requirieron la retirada del RTX. Conclusión: En nuestra experiencia, el rituximab es un tratamiento seguro y eficaz en la MG generalizada agresiva con anticuerpos anti-MuSK o de inicio tardío (LOMG).(AU)

Introduction and aims: Rituximab (RTX) is an anti-CD20 monoclonal antibody that has been used in cases of refractory myasthenia gravis (MG). The aim of this work is to analyse the efficacy and safety of RTX in MG in real clinical practice in a tertiary hospital. Patients and methods: A retrospective study was conducted with patients with MG treated with RTX in our centre from March 2014 to September 2020. Demographic and serological data, together with information about previous immunomodulatory treatment, clinical response and adverse effects are collected. Results: Twenty patients with MG – 100% generalised: 70% late-onset MG (LOMG) and 30% early-onset MG (EOMG) – were given RTX (mean age: 66.8 years; 70% male). A total of 90% are seropositive, 16 of them with positive anti-acetylcholine receptor antibodies and two with positive muscle-specific tyrosine kinase (anti-MuSK) antibodies. All had failed previous treatments: 100% with steroids, 100% with intravenous immunoglobulins and/or plasmapheresis, 55% with other immunosuppressants (25% with one previous immunosuppressant, 10% with two, 15% with three and 5% with four) and 35% with thymectomy. After RTX, 75% of patients showed a clinical response (12 patients with complete remission and the possibility of steroid withdrawal without recurrence; and three patients with partial remission and the possible reduction of steroid dosage) and 25% therapeutic failure; in all these cases RTX was withdrawn. All the anti-MuSK+ patients (100%) and 92.8% of the LOMG patients responded to RTX, while 66% of EOMG patients failed. Only three patients reported adverse effects, all of which were mild and did not require RTX withdrawal. Conclusion: In our experience, rituximab is a safe and effective treatment in aggressive generalised MG with anti-MuSK or late-onset MG (LOMG).(AU)

Bayesian pharmacokinetic-guided prophylaxis with recombinant factor VIII in severe or moderate haemophilia A.

INTRODUCTION: Personalised pharmacokinetics (PK) using Bayesian analysis with limited sampling is assumed to help to optimise prophylaxis in haemophilia A (HA) patients. MATERIALS AND METHODS: Our prospective, observational study analysed the influence of PK parameters on clinical variables (bleeding rates, joint status, adherence, and consumption) using myPKFiT® in a cohort of twenty-one severe and moderate HA patients on prophylaxis with recombinant FVIII (Advate®) in two periods of one year, the first before PK-based tailoring and the second after PK-guided prophylaxis. Intra-individual and inter-individual coefficients of variation (CV) of half-life (t1/2) were calculated. RESULTS: A total of 73 PK estimations were performed in both periods, resulting in 17.2% inter-individual CV in mean t1/2, and 4.9% intra-individual CV. Before PK-based tailoring a significant association between joint bleeds and t1/2 was found (P = 0.010), especially in patients with short t1/2. This finding was reproduced (P = 0.013) after withdrawal of two patients with bleeding phenotype related to their advanced arthropathy but normal t1/2 and trough levels. Patients with joint bleeds weighed less (P = 0.039) and required higher doses (P = 0.032) than patients with zero joint bleeds. These associations were not observed in the second period after the adoption of PK-guided prophylaxis. There were no differences between the two periods, although a tendency to fewer spontaneous bleeds was suggested after PK-based tailoring. CONCLUSIONS: PK-guided prophylaxis facilitates an adequate level of bleeding control in patients with HA, maintaining clinical variables and patient convenience in an integrative manner, without increasing FVIII consumption.

The phenotypic impact of the male-specific region of chromosome-Y in inbred mating: the role of genetic variants and gene duplications in multiple inbred rat strains.

BACKGOUND: The male-specific region of chromosome-Y (MSY) contributes to phenotypes outside of testis development and has a high rate of evolution between mammalian species. With a lack of genomic crossover, MSY is one of the few genomic areas under similar variation and evolutionary selection in inbred and outbred animal populations, allowing for an assessment of evolutionary mechanisms to translate between the populations. METHODS: Using next-generation sequencing, MSY consomic strains, molecular characterization, and large-scale phenotyping, we present here regions of MSY that contribute to inbred strain phenotypes. RESULTS: We have shown that (1) MSY of rat has nine autosomal gene transposition events with strain-specific selection; (2) sequence variants in MSY occur with a 1.98-fold higher number of variants than other chromosomes in seven sequenced rat strains; (3) Sry, the most studied MSY gene, has undergone extensive gene duplications, driving ubiquitous expression not seen in human or mouse; (4) the expression profile of Sry in the rat is driven by the insertion of the Sry2 copy into an intron of the ubiquitously expressed Kdm5d gene in antisense orientation, but due to several loss of function mutations in the Sry2 protein, nuclear localization and transcriptional control are decreased; (5) expression of Sry copies other than Sry2 in the rat overlaps with the expression profile for human SRY; (6) gene duplications and sequence variants (P76T) of Sry can be selected for phenotypes such as high blood pressure and androgen receptor signaling within inbred mating; and most importantly, (7) per chromosome size, MSY contributes to higher strain-specific phenotypic variation relative to all other chromosomes, with 53 phenotypes showing both a male to female and consomic cross significance. CONCLUSION: The data presented supports a high probability of MSY genetic variation altering a broad range of inbred rat phenotypes.

Trichodiene Production in a Trichoderma harzianum erg1-Silenced Strain Provides Evidence of the Importance of the Sterol Biosynthetic Pathway in Inducing Plant Defense-Related Gene Expression.

Trichoderma species are often used as biocontrol agents against plant-pathogenic fungi. A complex molecular interaction occurs among the biocontrol agent, the antagonistic fungus, and the plant. Terpenes and sterols produced by the biocontrol fungus have been found to affect gene expression in both the antagonistic fungus and the plant. The terpene trichodiene (TD) elicits the expression of genes related to tomato defense and to Botrytis virulence. We show here that TD itself is able to induce the expression of Botrytis genes involved in the synthesis of botrydial (BOT) and also induces terpene gene expression in Trichoderma spp. The terpene ergosterol, in addition to its role as a structural component of the fungal cell membranes, acts as an elicitor of defense response in plants. In the present work, using a transformant of T. harzianum, which is silenced in the erg1 gene and accumulates high levels of squalene, we show that this ergosterol precursor also acts as an important elicitor molecule of tomato defense-related genes and induces Botrytis genes involved in BOT biosynthesis, in both cases, in a concentration-dependent manner. Our data emphasize the importance of a balance of squalene and ergosterol in fungal interactions as well as in the biocontrol activity of Trichoderma spp.

Effects of Trichothecene Production on the Plant Defense Response and Fungal Physiology: Overexpression of the Trichoderma arundinaceum tri4 Gene in T. harzianum.

Trichothecenes are fungal sesquiterpenoid compounds, the majority of which have phytotoxic activity. They contaminate food and feed stocks, resulting in potential harm to animals and human beings. Trichoderma brevicompactum and T. arundinaceum produce trichodermin and harzianum A (HA), respectively, two trichothecenes that show different bioactive properties. Both compounds have remarkable antibiotic and cytotoxic activities, but in addition, trichodermin is highly phytotoxic, while HA lacks this activity when analyzed in vivo. Analysis of Fusarium trichothecene intermediates led to the conclusion that most of them, with the exception of the hydrocarbon precursor trichodiene (TD), have a detectable phytotoxic activity which is not directly related to the structural complexity of the intermediate. In the present work, the HA intermediate 12,13-epoxytrichothec-9-ene (EPT) was produced by expression of the T. arundinaceum tri4 gene in a transgenic T. harzianum strain that already produces TD after transformation with the T. arundinaceum tri5 gene. Purified EPT did not show antifungal or phytotoxic activity, while purified HA showed both antifungal and phytotoxic activities. However, the use of the transgenic T. harzianum tri4 strain induced a downregulation of defense-related genes in tomato plants and also downregulated plant genes involved in fungal root colonization. The production of EPT by the transgenic tri4 strain raised levels of erg1 expression and reduced squalene accumulation while not affecting levels of ergosterol. Together, these results indicate the complex interactions among trichothecene intermediates, fungal antagonists, and host plants.

Results of kidney transplantation from deceased donors with acute kidney injury.

BACKGROUND: Different strategies have been initiated to shorten the waiting list time to receive a kidney transplant. Donors with acute kidney injury (AKI) may be a new option. METHODS: Fifty-nine patients received a kidney transplant from an AKI donor defined as having serum creatinine >2 mg/dL at the time of organ procurement. They were compared with a transplant group with normal kidney function defined as creatinine <1.5 mg/dL organ procurement in the same time period, paired by donor and recipient age (control group). Initial evolution, at 1 year, and at the end of the follow-up were evaluated. RESULTS: The AKI donor group had greater delayed graft function (68% versus 36%, P < .01). Graft and recipient survival were similar in both groups at 1 year (92% versus 88%, P = NS; 97% versus 98%, P = NS) and at the end of follow-up (66% versus 66%, P = NS; 90% versus 88%, P = NS). Serum creatinine at 1 year and at the end of the follow-up did not show any differences (1.4 ± 0.5 versus 1.4 ± 0.7 mg/dL, P = NS; 1.4 ± 0.5 versus 1.6 ± 0.9 mg/dL, P = NS). CONCLUSIONS: The transplants from donors with AKI showed greater incidence of delayed graft function, but this did not affect the short- or long-term prognosis of the graft or recipient. This type of donor may be a source of acceptable kidneys.

Everolimus-based immunosuppression therapy for BK virus nephropathy.

BACKGROUND: Mammalian target of rapamycin inhibitors (mTOR-i) have been proposed as possible immunosuppressants of choice in BK virus nephropathy (BKN) because of their antiviral capacity. On this basis, in 2007, our Service proposed a conversion to everolimus (EVE)-based therapy from calcineurin inhibitors with an anti-calcineurin-free therapy protocol in those patients diagnosed of BKN. METHODS: A prospective, single-center case series study was performed. Fifteen cases of BKN were diagnosed from 2007 to the end of 2010. According to our protocol, immunosuppressant treatment was modified in 9 of these patients with suspension of mycophenolate and conversion from tacrolimus to EVE. RESULTS: The renal function achieved by our patients after the transplantation was excellent. Mean serum creatinine (sCr) achieved was 1.16 ± 0.2 mg/dL. Evolution of the renal function after BKN diagnosis and conversion to mTOR-i was positive in all the patients. sCr on diagnosis was 1.85 ± 0.22 mg/dL, sCr at the point in time of conversion to EVE was 2 ± 0.21 mg/dL, and final sCr of the follow-up was 1.6 ± 0.39 mg/dL (P = .05). BK viremia became negative in 5 of our patients and decreased more than 95% in the remaining 4. None of the patients had an acute rejection episode after the change of immunosuppressant. CONCLUSIONS: Conversion to mTOR-i-based therapy could provide an added benefit in BKN and could be an effective strategy for the decrease of the viremia and increase of graft survival in selected patients.

Impact of left ventricular dysfunction on renal transplant survival: study of paired kidneys from the same donor.

INTRODUCTION: A significant number of patients with chronic kidney disease (CKD) have cardiac abnormalities, and left ventricular systolic dysfunction (LVSD) is a common manifestation. Our hypothesis is that a decrease in the left ventricular ejection fraction (LVEF) at the time of kidney transplantation is a factor of poor prognosis associated with poor graft evolution. METHODS AND RESULTS: A total of 954 kidney transplantations were performed in our center between 2005 and 2012. Nineteen (2%) of these patients had been diagnosed with left ventricular dysfunction that was defined by the presence of LVEF <50% on echocardiography. This group of patients was compared with a control group of recipients without LVSD who had received the contralateral kidney from the same donor. During a mean follow-up of 52 ± 14 months, it was observed that the patients with LVSD had a higher incidence of delayed graft function (DGF) as well as a significantly longer renal function recovery period than in the control group until they became dialysis free (19.8 [range, 0-90] vs 12 [range, 0-36] days; P = .01). Furthermore, graft function achieved by the LVSD group was worse during the evolution (serum creatinine 2.3 ± 1.9 vs 1.4 ± 0.5 mg/dL; P = .01). Patients with LVSD showed worse kidney graft survival at the end of the follow-up when compared with the control group (79% vs 100%; P = .03). CONCLUSIONS: Systolic dysfunction of the renal transplant recipient is associated with greater delay in graft function and worse graft survival with poorer renal function.

Dual kidney transplantation involving organs from expanded criteria donors: a review of our series and an update on current indications.

BACKGROUND: Our purpose was to review our kidney transplantation program based on the use of expanded criteria donors, and to determine current indications for dual kidney transplantation (DKT). In 1996, a program was initiated to transplant kidneys from donors of over 60 years performing single or dual transplantation. METHODS: In 1996, a program was initiated to transplant kidneys from donors of over 60 years performing single or dual transplantation. DKT were performed with donors >75 and donors between 60 and 74 years of age and glomerulosclerosis of >15%. The kidneys of donors between 60 and 74 years of age and with glomerulosclerosis of <15% were used for single kidney transplantation (SKT). In 2005, we started to perform SKT despite glomerulosclerosis being >15%, taking into account donor and recipient characteristics. RESULTS: From 1996 to 2004, 222 SKTs and 88 DKTs were performed. Graft survival after 1 and 4 years was, respectively, 91% and 78% for SKT and 95% and 79% for DKT. In 2005, we started to perform SKT despite glomerulosclerosis being >15%, taking into account donor and recipient characteristics. From 2005 to 2011, 328 SKT and 32 DKT were performed. During this period most kidneys used for DKT were from female donors >75 years old, weighing <65 kg, with a creatinine of >1 mg/dL and glomerulosclerosis of >15%. The recipients for DKT were mostly male, <70 years old and whose weight was >75 kg. CONCLUSION: DKT from expanded criteria donors shows good outcomes. However, in many cases SKT may fulfill the need of the recipient. The archetype for DKT is an older female weighing <65 kg and the most common recipient is an overweight male who is <70 years old.

Analysis of Sry duplications on the Rattus norvegicus Y-chromosome.

BACKGROUND: Gene copy number variation plays a large role in the evolution of genomes. In Rattus norvegicus and other rodent species, the Y-chromosome has accumulated multiple copies of Sry loci. These copy number variations have been previously linked with changes in phenotype of animal models such as the spontaneously hypertensive rat (SHR). This study characterizes the Y-chromosome in the Sry region of Rattus norvegicus, while addressing functional variations seen in the Sry protein products. RESULTS: Eleven Sry loci have been identified in the SHR with one (nonHMG Sry) containing a frame shift mutation. The nonHMGSry is found and conserved in the related WKY and SD rat strains. Three new, previously unidentified, Sry loci were identified in this study (Sry3BII, Sry4 and Sry4A) in both SHR and WKY. Repetitive element analysis revealed numerous LINE-L1 elements at regions where conservation is lost among the Sry copies. In addition we have identified a retrotransposed copy of Med14 originating from spliced mRNA, two autosomal genes (Ccdc110 and HMGB1) and a normal mammalian Y-chromosome gene (Zfy) in the Sry region of the rat Y-chromosome. Translation of the sequences of each Sry gene reveals eight proteins with amino acid differences leading to changes in nuclear localization and promoter activation of a Sry-responsive gene. Sry-ß (coded by the Sry2 locus) has an increased cytoplasmic fraction due to alterations at amino acid 21. Sry-γ has altered gene regulation of the Sry1 promoter due to changes at amino acid 76. CONCLUSIONS: The duplication of Sry on the Rattus norvegicus Y-chromosome has led to proteins with altered functional ability that may have been selected for functions in addition to testis determination. Additionally, several other genes not normally found on the Y-chromosome have duplicated new copies into the region around the Sry genes. These suggest a role of active transposable elements in the evolution of the mammalian Y-chromosome in species such as Rattus norvegicus.

The Phoenix Physician: defining a pathway toward leadership in patient-centered care.

Health care delivery has evolved in reaction to scientific and technological discoveries, emergent patient needs, and market forces. A current focus on patient-centered care has pointed to the need for the reallocation of resources to improve access to and delivery of efficient, cost-effective, quality care. In response to this need, primary care physicians will find themselves in a new role as team leader. The American College of Osteopathic Internists has developed the Phoenix Physician, a training program that will prepare primary care residents and practicing physicians for the changes in health care delivery and provide them with skills such as understanding the contributions of all team members (including an empowered and educated patient), evaluating and treating patients, and applying performance metrics and information technology to measure and improve patient care and satisfaction. Through the program, physicians will also develop personal leadership and communication skills.

Involvement of Trichoderma trichothecenes in the biocontrol activity and induction of plant defense-related genes.

Trichoderma species produce trichothecenes, most notably trichodermin and harzianum A (HA), by a biosynthetic pathway in which several of the involved proteins have significant differences in functionality compared to their Fusarium orthologues. In addition, the genes encoding these proteins show a genomic organization differing from that of the Fusarium tri clusters. Here we describe the isolation of Trichoderma arundinaceum IBT 40837 transformants which have a disrupted or silenced tri4 gene, a gene encoding a cytochrome P450 monooxygenase that oxygenates trichodiene to give rise to isotrichodiol, and the effect of tri4 gene disruption and silencing on the expression of other tri genes. Our results indicate that the tri4 gene disruption resulted in a reduced antifungal activity against Botrytis cinerea and Rhizoctonia solani and also in a reduced ability to induce the expression of tomato plant defense-related genes belonging to the salicylic acid (SA) and jasmonate (JA) pathways against B. cinerea, in comparison to the wild-type strain, indicating that HA plays an important function in the sensitization of Trichoderma-pretreated plants against this fungal pathogen. Additionally, the effect of the interaction of T. arundinaceum with B. cinerea or R. solani and with tomato seedlings on the expressions of the tri genes was studied.

From rat to human: regulation of Renin-Angiotensin system genes by sry.

The testis determining protein, Sry, has functions outside of testis determination. Multiple Sry loci are found on the Y-chromosome. Proteins from these loci have differential activity on promoters of renin-angiotensin system genes, possibly contributing to elevation of blood pressure. Variation at amino acid 76 accounts for the majority of differential effects by rat proteins Sry1 and Sry3. Human SRY regulated rat promoters in the same manner as rat Sry, elevating Agt, Ren, and Ace promoter activity while downregulating Ace 2. Human SRY significantly regulated human promoters of AGT, REN, ACE2, AT2, and MAS compared to control levels, elevating AGT and REN promoter activity while decreasing ACE2, AT2, and MAS. While the effect of human SRY on individual genes is often modest, we show that many different genes participating in the renin-angiotensin system can be affected by SRY, apparently in coordinated fashion, to produce more Ang II and less Ang-(1-7).

Identification of loci and functional characterization of trichothecene biosynthesis genes in filamentous fungi of the genus Trichoderma.

Trichothecenes are mycotoxins produced by Trichoderma, Fusarium, and at least four other genera in the fungal order Hypocreales. Fusarium has a trichothecene biosynthetic gene (TRI) cluster that encodes transport and regulatory proteins as well as most enzymes required for the formation of the mycotoxins. However, little is known about trichothecene biosynthesis in the other genera. Here, we identify and characterize TRI gene orthologues (tri) in Trichoderma arundinaceum and Trichoderma brevicompactum. Our results indicate that both Trichoderma species have a tri cluster that consists of orthologues of seven genes present in the Fusarium TRI cluster. Organization of genes in the cluster is the same in the two Trichoderma species but differs from the organization in Fusarium. Sequence and functional analysis revealed that the gene (tri5) responsible for the first committed step in trichothecene biosynthesis is located outside the cluster in both Trichoderma species rather than inside the cluster as it is in Fusarium. Heterologous expression analysis revealed that two T. arundinaceum cluster genes (tri4 and tri11) differ in function from their Fusarium orthologues. The Tatri4-encoded enzyme catalyzes only three of the four oxygenation reactions catalyzed by the orthologous enzyme in Fusarium. The Tatri11-encoded enzyme catalyzes a completely different reaction (trichothecene C-4 hydroxylation) than the Fusarium orthologue (trichothecene C-15 hydroxylation). The results of this study indicate that although some characteristics of the tri/TRI cluster have been conserved during evolution of Trichoderma and Fusarium, the cluster has undergone marked changes, including gene loss and/or gain, gene rearrangement, and divergence of gene function.

Sry, more than testis determination?

The Sry locus on the mammalian Y chromosome is the developmental switch responsible for testis determination. Inconsistent with this important function, the Sry locus is transcribed in adult males at times and in tissues not involved with testis determination. Sry is expressed in multiple tissues of the peripheral and central nervous system. Sry is derived from Sox3 and is similar to other SOXB family loci. The SOXB loci are responsible for nervous system development. Sry has been demonstrated to modulate the catecholamine pathway, so it should have functional consequences in the central and peripheral nervous system. The nervous system expression and potential function are consistent with Sry as a SOXB family member. In mammals, Sox3 is X-linked and undergoes dosage compensation in females. The expression of Sry in adult males allows for a type of sexual differentiation independent of circulating gonadal hormones. A quantitative difference in Sox3 plus Sry expression in males vs. females could drive changes in the transcriptome of these cells, differentiating male and female cells. Sry expression and its transcriptional effects should be considered when investigating sexual dimorphic phenotypes.

Serum and CSF N-acetyl aspartate levels differ in multiple sclerosis and neuromyelitis optica.

BACKGROUND: The identification of biomarkers able to improve the differential diagnosis between multiple sclerosis (MS) and neuromyelitis optica (NMO) is challenging because of a different prognosis and response to treatment. Growing evidence indicates that brain and CSF N-acetyl aspartate (NAA) concentration is a useful marker for characterising different phases of axonal pathology in demyelinating diseases, and preliminary studies suggest that increased serum NAA levels may be a telltale sign of acute neuronal damage or defective NAA metabolism in oligodendrocytes. OBJECTIVE: To evaluate whether serum and CSF NAA concentration differs in patients with MS and NMO. DESIGN: Observational, multicentre, prospective, cross sectional study. METHODS: Serum samples were collected from 48 relapsing-remitting MS, 32 NMO and 76 age matched healthy controls. Coeval CSF samples were available for all MS and for 8/32 NMO patients. NAA was measured in serum and CSF by liquid chromatography-mass spectrometry. RESULTS: MS patients showed higher serum and CSF NAA levels than NMO patients, and higher serum NAA levels than healthy controls (p<0.001). High serum NAA values, exceeding the 95th percentile of serum NAA values in healthy controls, were found in 100% of patients with MS and in no patient with NMO. No differences in serum NAA levels were found between NMO and healthy controls. In MS, serum and CSF NAA levels correlated with disability score. CONCLUSIONS: Determination of serum and CSF NAA levels may represent a suitable tool in the diagnostic laboratory workup to differentiate MS and NMO.