Impact of POR*28 Variant on Tacrolimus Pharmacokinetics in Kidney Transplant Patients with Different CYP3A5 Genotypes.

BACKGROUND: The introduction of tacrolimus (TAC) to clinical practice was essential to the establishment of transplantation as a therapy for patients with chronic renal disease. However, the higher interindividual variation of TAC metabolism has been an important limiting factor for its clinical use. Although the relationship between CYP3A5 polymorphisms and TAC pharmacokinetics (PK) is well established, the effects of other genetic variants on TAC metabolism, such as POR*28, still remain uncertain. OBJECTIVE: The study aimed to evaluate the impact of POR variants on TAC PK in renal transplant patients with different CYP3A5 genotypes (expressers and non-expressers). METHODS: A total of 115 patients were included in this study. Genomic DNA was isolated from peripheral blood, and the real-time PCR technique was used to analyze the polymorphism POR rs1057868; C>T. RESULTS: During the initial post-transplant period, variant allele carriers (*1/*28 and *28/*28) showed a lower TAC dose requirement than POR wild homozygotes (*1/*1). Regarding the influence of the different polymorphisms of POR within the CYP3A5 expresser and non-expresser groups, no differences were observed in any of the PK parameters analyzed during 12 months after transplantation. CONCLUSION: In the studied population, the variant allelic POR*28 was significantly associated with lower TAC dose requirements and higher Co/D ratio in the first-month post-transplant. However, the effects of this polymorphism on the CYP3A5 enzyme activity were not observed.

CYP3A5 and PPARA genetic variants are associated with low trough concentration to dose ratio of tacrolimus in kidney transplant recipients.

PURPOSE: Genetic polymorphisms have been associated with variation in the metabolism of tacrolimus (TAC) in kidney transplant patients. This study is aimed at assessing the impact of allelic variants of CYP3A5 and PPARA genes on the pharmacokinetics (PK) of TAC in Brazilian kidney transplant recipients in the first-year post-transplant. METHODS: A total of 127 patients were included for genetic evaluation. Genomic DNA was isolated from peripheral blood and real-time PCR was used to analyze the main polymorphisms described for the genes CYP3A5 (rs776746; C > G) and PPARA (rs4823613; A > G and rs4253728; G > A). RESULTS: CYP3A5 expressors showed a lower Co/dose ratio than non-expressors, with the median values of this parameter <1.01 ng/mL/mg in the first group at all evaluated times. Additionally, PPARA variant homozygotes had a lower Co/D ratio than wild allele carriers in the 12-month post-transplant period, with a median value of 0.65 ng/mL/mg. In the CYP3A5 expressers, the presence of the variant homozygous genotype PPARA was associated with a lower value of Co/D compared with the other genotypic groups at month 12. CONCLUSION: In the population under study, polymorphisms on CYP3A5 and PPARA were identified as determining and independent factors associated with the reduction of Co/D of TAC. Thus, the genotyping of these genetic variants may be a useful tool for the individualized prescription of TAC in kidney transplant patients.

Angiolymphatic invasion and absence of koilocytosis predict lymph node metastasis in penile cancer patients and might justify prophylactic lymphadenectomy.

To analyze possible clinical-pathological parameters and predictors of lymph node metastasis and evaluate the impact of lymphadenectomy in the survival of these patients.A retrospective study of patients diagnosed with penile cancer and submitted to regional lymphadenectomy at two reference hospitals in Maranhão, Northeast, Brazil, an area where the disease has a high incidence. We described here clinical and histopathological characteristics of patients diagnosed between January 2009 and September 2017.Fifty-five patients with an average age of 55.4 years (range: 25-84 years) were analyzed, with 24.4 months being the average time between the onset of symptoms and start of treatment. Among patients without palpable lymph nodes at the first examination, 51% were affected by inguinal metastasis. In the multivariate analysis, the presence of angiolymphatic invasion (P = .029) and absence of koilocytosis (P = .001) were found to be predictive factors for lymph node metastasis. Patients submitted to prophylactic lymphadenectomy presented with a disease-free period of 25.4 months (±5.81), whereas those who underwent therapeutic lymphadenectomy presented with a disease-free period of 19.9 months (±3.12).Angiolymphatic invasion and absence of koilocytosis appeared to be predictive factors for lymph node metastasis. Therefore, the submission of patients with metastatic risk to prophylactic lymphadenectomy may improve their survival. Thus, prophylactic lymphadenectomy in patients at risk for inguinal metastasis may create a positive impact in survival rates.

Prophylactic and Therapeutic Use of Strontium Ranelate Reduces the Progression of Experimental Osteoarthritis.

Introduction: Strontium ranelate (SrRan) has the potential to interfere in the progression of osteoarthritis (OA), multifactorial disease associated with mechanical problems and articular inflammatory changes. Objectives: This study aimed to test the effects of prophylactic and therapeutic use of SrRan on clinical parameters of pain, the inflammatory process, and degradation of the articular cartilage. Methods: This was an experimental study, using a model of knee OA induced by intra-articular injection of monoiodoacetate. Thirty Wistar rats were divided into five groups and treated as indicated: control, without intervention; prophylactic, received SrRan at a daily oral dose of 250 mg/kg for 28 days before OA induction; SrRan treatments, administered 250 or 500 mg/kg/day for 28 days after the induction; and model control, received saline solution after the induction. Behavioral tests (joint incapacity, mechanical hyperalgesia, tactile sensitivity, and forced ambulation), histological evaluation of articular cartilage, and determination of inflammatory cytokines in the synovial fluid (interleukin [IL]-6, IL-10, tumor necrosis factor [TNF]-α, and interferon [INF]-γ) were performed. Results: Both prophylactic and therapeutic treatments improved the articular discomfort. A prophylactic dose of 500 mg/kg/day also improved mechanical hyperalgesia and the same dose was beneficial on tactile sensitivity. SrRan did not improve ambulation. Levels of IL-6, IL-10, TNF-α, and IFN-γ in SrRan-treated groups with OA were not significantly different compared with those in the normal control animals. The histopathological evaluation showed less articular damage in the SrRan-treated and control groups compared to the saline-treated group. Conclusion: The prophylactic and therapeutic administration of SrRan was associated with improved behavioral patterns of pain, especially joint discomfort. SrRan administration mitigated histological changes in the articular cartilage and reduced the inflammatory process, which beneficially reduced the progression of OA in the experimental model studied.

Prevalence of Glomerulopathies in Canine Mammary Carcinoma.

The incidence and prevalence of paraneoplastic glomerulopathy, especially associated with carcinoma, are a matter of debate and the causal link between cancer and glomerular diseases remains unclear. The aim of this study was to evaluate renal biopsies of selected bitches with spontaneous mammary gland carcinoma. We hypothesized that dogs with mammary carcinomas would show histologic evidence of glomerular pathology. A prospective study was performed in dogs with naturally occurring mammary carcinoma that were undergoing tumor resection and ovariohysterectomy. We evaluated renal biopsies of 32 bitches with spontaneous mammary gland carcinoma and 11 control dogs without mammary gland neoplasia. Samples were obtained from the left kidney and the biopsy material was divided for light microscopy (LM), immunofluorescence (IF) and transmission electron microscopy (TEM). Light microscopy abnormalities were identified in 78.1% of dogs with mammary carcinoma (n = 25) and in none of the dogs in the control group. Focal glomerular mesangial matrix expansion was the most common alteration (n = 15, 60.0%), but mesangial cell proliferation (n = 9, 36.0%) and focal segmental glomerulosclerosis (n = 9, 36.0%), synechiae (n = 7, 28.0%), and globally sclerotic glomeruli (n = 6, 24.0%) were also frequent in dogs with malignancy. Immunofluorescence microscopy revealed strong IgM staining was demonstrated in 64.3% (n = 18) of carcinoma dogs. Transmission electron microscopy from dogs with carcinoma revealed slight changes, the most frequent of which was faint sub-endothelial and mesangial deposits of electron-dense material (78%). Mesangial cell interpositioning and segmental effacement of podocyte foot processes were identified in some specimens (45%). Changes in the glomerulus and proteinuria are common in dogs with naturally occurring mammary carcinoma and this condition appears to provide an excellent large animal model for cancer-associated glomerulopathy in humans.

Multiparametric MRI of the prostate: diagnostic performance and interreader agreement of two scoring systems.

OBJECTIVE: To compare the diagnostic accuracies and interreader agreements of the Prostate Imaging Reporting and Data System (PI-RADS) v. 2 and University of California San Francisco (UCSF) multiparametric prostate MRI scale for diagnosing clinically significant prostate cancer. METHODS: This institutional review board-approved retrospective study included 49 males who had 1.5 T endorectal MRI and prostatectomy. Two radiologists scored suspicious lesions on MRI using PI-RADS v. 2 and the UCSF scale. Percent agreement, 2 × 2 tables and the area under the receiver operating characteristic curves (Az) were used to assess and compare the individual and overall scores of these scales. Interreader agreements were estimated with kappa statistics. RESULTS: Reader 1 (R1) detected 78 lesions, and Reader 2 (R2) detected 80 lesions. Both identified 52 of 65 significant cancers. The Az for PI-RADS v. 2 and UCSF scale for R1 were 0.68 and 0.69 [T2 weighted imaging (T2WI)], 0.75 and 0.68 [diffusion-weighted imaging (DWI)] and 0.64 and 0.72 (overall score), respectively, and were 0.72 and 0.75 (T2WI), 0.73 and 0.67 (DWI) and 0.66 and 0.75 (overall score) for R2. The dynamic contrast-enhanced percent agreements between scales were 100% (R1) and 95% (R2). PI-RADS v. 2 DWI of R1 performed better than UCSF DWI (Az = 0.75 vs Az = 0.68; p = 0.05); no other differences were found. The interreader agreements were higher for PI-RADS v. 2 (T2WI: 0.56 vs 0.42; DWI: 0.60 vs 0.46; overall: 0.61 vs 0.42). The UCSF approach to derive the overall PI-RADS v. 2 scores increased the Az for the identification of significant cancer (R1 to 0.76, p < 0.05; R2 to 0.71, p = 0.35). CONCLUSION: Although PI-RADS v. 2 DWI score may have a higher discriminatory performance than the UCSF scale counterpart to diagnose clinically significant cancer, the utilization of the UCSF scale weighing system for the integration of PI-RADS v. 2 individual parameter scores improved the accuracy its overall score. ADVANCES IN KNOWLEDGE: PI-RADS v. 2 is moderately accurate for the identification of clinically significant prostate cancer, but the utilization of alternative approaches to derive the overall PI-RADS v. 2 score, including the one used by the UCSF system, may improve its diagnostic accuracy.

O papel da placenta na transmissão vertical do HIV-1 / The role of the placenta in the vertical transmission of HIV-1

A transmissão vertical (TV) consiste na principal forma de infecção pelo HIV-1 em menores de 13 anos e estimativas apontam que em 25% dos casos a transmissão tenha ocorrido intraútero. Nessas circunstâncias, o vírus de alguma forma ultrapassa a membrana placentária e chega ao sangue fetal. Esta revisão tem como objetivo realizar uma breve descrição sobre os mecanismos presentes na placenta humana que são capazes de gerar susceptibilidade ou proteção à TV do HIV-1. As células placentárias produzem um enorme grupo de citocinas, quimiocinas, hormônios e receptores que podem contribuir com o desfecho da transmissão do vírus ao concepto. Além disso, a capacidade do vírus de infectar as células placentárias também pode contribuir com a sua transmissão. Entretanto, o mecanismo pelo qual o vírus é capaz de sobrepujar a membrana placentária e as consequências dessa infecção no tecido placentário não estão totalmente elucidados. Dessa forma, novas pesquisas nessa área poderão contribuir com o desenvolvimento de estratégias profiláticas eficazes para redução da TV do HIV-1.

Vertical transmission (VT) is the main form of infection by HIV-1 in children under 13 years and estimates show that in 25% of cases intrauterine transmission has occurred. Under these circumstances, the virus somehow overcomes the placental membrane and reaches the fetal blood. This review aims to conduct a brief description of the mechanisms present in human placenta that are capable of generating susceptibility or resistance to VT of HIV-1. Placental cells produces a huge group of cytokines, chemokines, hormones and receptors that may contribute to the outcome of virus transmission to the fetus. Moreover, the ability of the virus to infect placental cells can also contribute to its transmission. However, the mechanism by which the virus is able to overcome the placental tissue is not fully elucidated. Thus, further research in this area may contribute to the development of effective preventive strategies to reduce the VT of HIV-1.

Membranous glomerulonephritis associated with splenic marginal zone lymphoma mimicking multiple myeloma.

Glomerulonephritis may complicate the course of a wide variety of malignant diseases. However, there are relatively few reports of membranous glomerulonephritis (MGN) in patients with non-Hodgkin lymphoma (NHL). We describe for the first time a case of MGN associated with splenic marginal zone lymphoma with extreme plasmacytic differentiation and bone marrow infiltration mimicking multiple myeloma. We also reviewed the literature and summarize the clinical-pathological findings and the mechanisms involved in NHL-induced MGN. Our current case highlights the importance of a quick and correct diagnosis of the underlying disease and the value of a thorough physical examination. Clinicians should be aware of the possibility of an underlying hematologic malignancy in such cases, particularly in elderly patients with renal biopsy that shows the presence of atypical histology.

What lies beneath: Fabry nephropathy in a female patient with severe cerebrovascular disease.

Fabry disease is an X-linked inborn error of metabolism, which is caused by the deficiency of α-galactosidase A, leading to progressive accumulation of neutral glycosphingolipids and a-galactosyl breakdown products in most body fluids and several tissues, resulting in the clinical manifestations. The onset of Fabry disease symptoms in females is not observed as early as in males. We report a novel presentation of Fabry disease in a female patient with medical history of relapsing strokes and brain magnetic resonance angiography showing signs of microangiopathy and multiple lacunar strokes that were first diagnosed as Moyamoya disease (a chronic progressive cerebrovascular disease). The patient subsequently displayed increased levels of serum creatinine and proteinuria. Diagnosis of Fabry disease was made by a renal biopsy and was confirmed by molecular studies showing a missense mutation: c1066C > T (het) [R356W]. The diagnosis was delayed by 21 years with respect to her first symptom (stroke), probably because her initial clinical presentation was neurological and diagnosed as Moyamoya disease. Other factors that contributed to the delay of the diagnosis were the lack of acute or chronic pain (neuropathic pain) and angiokeratomas. Some similarities in the pathogenic aspects of the patient's vascular lesions lead us to speculate that this patient has Fabry disease, with a phenotype that had not yet been described. It is necessary to be aware of this possibility to avoid misdiagnosis of Fabry disease as Moyamoya disease.

The melatonin action on stromal stem cells within pericryptal area in colon cancer model under constant light.

Constant light (LL) is associated with high incidence of colon cancer. MLT supplementation was related to the significant control of preneoplastic patterns. We sought to analyze preneoplastic patterns in colon tissue from animals exposed to LL environment (14 days; 300 lx), MLT-supplementation (10mg/kg/day) and DMH-treatment (1,2 dimethylhydrazine; 125 mg/kg). Rodents were sacrificed and MLT serum levels were measured by radioimmunoassay. Our results indicated that LL induced ACF development (p < 0.001) with a great potential to increase the number of CD133(+) and CD68(+) cells (p < 0.05 and p < 0.001). LL also increased the proliferative process (PCNA-Li; p < 0.001) as well as decreased caspase-3 protein (p < 0.001), related to higher COX-2 protein expression (p < 0.001) within pericryptal colonic stroma (PCCS). However, MLT-supplementation controlled the development of dysplastic ACF (p < 0.001) diminishing preneoplastic patterns into PCCS as CD133 and CD68 (p < 0.05 and p < 0.001). These events were relative to decreased PCNA-Li index and higher expression of caspase-3 protein. Thus, MLT showed a great potential to control the preneoplastic patterns induced by LL.