The relationship between antioxidant supplements and oxidative stress in renal transplant recipients: A review

Renal transplant recipients (RTRs) have elevated oxidative stress and a high incidence of cardiovascular morbidity and mortality. Although recent studies do not support the use of antioxidant supplements as a cardioprotectant in the general population, evidence suggests that RTRs may represent individuals that would benefit from this therapy. RTRs have elevated oxidative stress probably caused by the immunosuppressive therapy, and although only a small number of studies have examined the effects of antioxidant supplementation in these patients, most have reported beneficial findings. This review discusses these studies along with the rationale for the use of antioxidant supplements in RTRs and a call for more research to investigate this important topic.

Expression of apoptotic regulatory molecules in renal cell carcinoma: Elevated expression of Fas ligand

Renal cell carcinoma (RCC) is the most common renal neoplasm. Despite being infiltrated by tumour infiltrating lymphocytes (TIL), these TIL are unable to control tumour growth in vivo, suggesting that the cytotoxic capacity of TIL against RCC is impaired, or that the tumour cells are resistant to killing and therefore escape detection by the immune system. It is postulated that the expression of apoptotic regulatory molecules in RCC favours tumour cell survival. The present study has therefore determined the expression of Fas (APO- 1/CD95), Fas ligand (Fas L) and bcl-2 in these tumours. The expression of Fas, Fas L and bcl-2 mRNA transcripts was determined in RCC, normal kidney and peripheral blood by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), following RNA extraction and cDNA synthesis from tissues and cell samples. Transcript levels were measured by densitometry after Southern blot hybridization of PCR products with internal radio-labelled oligonucleotide probes; a densitometry score was assigned to each hybridizing DNA band and expressed as a ratio of the glyceraldehyde-3-phosphate dehydrogenase content. In peripheral blood, the expression of Fas L and bcl-2 transcripts was similar between patients and normal healthy individuals; however, Fas transcript expression was significantly down-regulated in the patients' versus normal peripheral blood (P = 0.026). Most interestingly, significantly up-regulated Fas L expression was observed in RCC compared to normal kidney (P = 0.041). In contrast, bcl-2 transcripts were well represented in normal kidney but markedly decreased in RCC (P = 0.021). The expression of Fas transcripts in normal kidney and RCC was variable. These data demonstrate elevated expression of Fas L transcripts in RCC, but the functional relevance of this remains to be investigated.

Conhecimento da doença renal crônica entre médicos conforme as diretrizes práticas

INTRODUCTION: Chronic kidney disease (CKD) is a global health problem, with increasing prevalence in its terminal stage and one of the factors that can contribute is the failure to recognize the disease and its risk factors. OBJECTIVE: To evaluate the knowledge of medical residents (MR) and medical preceptors (MP) in hospitals in the Federal University of Rio Grande do Norte in Natal-RN - Brazil, on the DRC, based on the policy of the Kidney Disease Improving Global Outcomes (KDIGO ). METHODS: Cross-sectional study where 64 MR (R1 = 32; R2 = 15; R3 = 17) and 63 MP answered a questionnaire divided into seven sessions that addressed aspects of the DRC since the setting up referral to a nephrologist. RESULTS: Only 20 participants (15.7%) reported using any guidelines for the management of CKD. The scores obtained by session were: Definition and classification (46.1 ± 47.8); Risk factors (70.5 ± 27.9); Laboratory evaluation (58.2 ± 8.8); Clinical action plan (57.6 ± 19.9); Reduction in proteinuria (68.3 ± 15.0); Complications (64.8 ± 19.9); Referral to a nephrologist (73.0 ± 44.6). There was a statistically significant difference between the knowledge of MR and MP in the sessions: Laboratory evaluation (MR 61.5 ± 8.4 vs 54.8 ± 7.9 MP; p <0.001); Reduction in proteinuria (73.1 ± 11.4 vs MR MP 63.5 ± 16.7; p <0.001) and Referral to a nephrologist (MR 81.2 ± 39.3 vs 64.5 ± 48.2 MP; p = 0.035). Among the MR, the R2 obtained the best score (63.9 ± 22.6 vs R1 R2 R3 71.9 ± 17.2 vs 63.5 ± 22.5, p = 0.445). It identified a low percentage of success of the doctors on the definition of CKD (MP = 46%; R1 = 40.6%; R2 = 60%; R3 = 52.9%; p = 0.623) and classification (MP = 34.9%; R1 = 53.1%, R2 = 60%; R3 = 52.9%; p = 0.158). CONCLUSION: The study showed that most doctors do not use any guidelines for clinical management of CKD and that there are gaps in knowledge on the subject, even among physicians who work in the university environment. In this sense, we propose the realization of mini-workshops for participants and students from boarding UFRN, using Case-Based Learning Strategy (CBL), with small group discussion, to strengthen the incorporation of CKD guidelines in undergraduate teaching and in clinical medical practice in general.

Conhecimento da doença renal crônica entre médicos conforme as diretrizes práticas

INTRODUCTION: Chronic kidney disease (CKD) is a global health problem, with increasing prevalence in its terminal stage and one of the factors that can contribute is the failure to recognize the disease and its risk factors. OBJECTIVE: To evaluate the knowledge of medical residents (MR) and medical preceptors (MP) in hospitals in the Federal University of Rio Grande do Norte in Natal-RN - Brazil, on the DRC, based on the policy of the Kidney Disease Improving Global Outcomes (KDIGO ). METHODS: Cross-sectional study where 64 MR (R1 = 32; R2 = 15; R3 = 17) and 63 MP answered a questionnaire divided into seven sessions that addressed aspects of the DRC since the setting up referral to a nephrologist. RESULTS: Only 20 participants (15.7%) reported using any guidelines for the management of CKD. The scores obtained by session were: Definition and classification (46.1 ± 47.8); Risk factors (70.5 ± 27.9); Laboratory evaluation (58.2 ± 8.8); Clinical action plan (57.6 ± 19.9); Reduction in proteinuria (68.3 ± 15.0); Complications (64.8 ± 19.9); Referral to a nephrologist (73.0 ± 44.6). There was a statistically significant difference between the knowledge of MR and MP in the sessions: Laboratory evaluation (MR 61.5 ± 8.4 vs 54.8 ± 7.9 MP; p <0.001); Reduction in proteinuria (73.1 ± 11.4 vs MR MP 63.5 ± 16.7; p <0.001) and Referral to a nephrologist (MR 81.2 ± 39.3 vs 64.5 ± 48.2 MP; p = 0.035). Among the MR, the R2 obtained the best score (63.9 ± 22.6 vs R1 R2 R3 71.9 ± 17.2 vs 63.5 ± 22.5, p = 0.445). It identified a low percentage of success of the doctors on the definition of CKD (MP = 46%; R1 = 40.6%; R2 = 60%; R3 = 52.9%; p = 0.623) and classification (MP = 34.9%; R1 = 53.1%, R2 = 60%; R3 = 52.9%; p = 0.158). CONCLUSION: The study showed that most doctors do not use any guidelines for clinical management of CKD and that there are gaps in knowledge on the subject, even among physicians who work in the university environment. In this sense, we propose the realization of mini-workshops for participants and students from boarding UFRN, using Case-Based Learning Strategy (CBL), with small group discussion, to strengthen the incorporation of CKD guidelines in undergraduate teaching and in clinical medical practice in general.

Estudo das alterações hematológicas e urinárias em cães em diferentes estágios de disfunção renal e avaliação do biomarcador cistatina C

Chapter 2 - Cystatin C is a cationic protein is not glycosylated, produced a steady state for all nucleated and present in biological fluids cells being freely filtered by the glomeruli and almost completely catabolized in the proximal tubule, it is a promising early renal dysfunction marker. This study aimed to determine and compare the serum concentration of cystatin C biomarker in 86 dogs. The animals were divided into four groups according to serum creatinine levels: G1 - up. 1.4 mg / dL (23 animals), G2 - 1.5-2.0 mg / dL (16 animals), G3 - 2.1 to 5.0 mg / dL (24 animals) and G4 - above 5.1 mg / dL (23 animals). There was the measurement of the parameters used in the clinical routine of small animals such as urea, urinary gamma glutamyl transferase, proteinuria, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorus, calcium/phosphorus ratio and cystatin C. There was no statistical difference for urea, proteinuria, phosphorus, calcium/phosphorus, potassium and cystatin C, however, the other showed no statistical difference. Based on the results we can infer that cystatin C was not a good early indicator of kidney disease in dogs. Chapter 3 - This study aimed to determine the hematological and urinalysis elements such as density, proteinuria, cylinders and pH in 86 dogs The animals were divided into four stages according to serum creatinine levels: I - up to 1.4 mg/dL (23 animals), II - 1.5-2.0 mg/dL (16 animals), III from 2.1 to 5.0 mg/dL (24 animals) and IV - above 5.1 mg/dL (23 animals). In stage III, IV there was anemia normocytic normochromic type. Stage II had a leukocytosis frame by neutrophilia with a regenerative left shift and stage III and IV detour degenerative left. The density remained within the reference values all stages. Proteinuria showed statistical significance for the classification 2+ (1.0 g/L), between stage I and II, II and IV. Only the cylinder granular statistical difference in the classification 2+ between stage II and III, and 3+ between stage I and III. The prevailing pH was acid. The haematological values compared to serum creatinine stages showed the changes in hemoglobin and packed cell volume erythrocytes become more pronounced as serum creatinine values rise , this is also the behavior of neutrophils rods and proteinuria.

Establishing an EGFR mutation screening service for non-small cell lung cancer - sample quality criteria and candidate histological predictors.

INTRODUCTION: EGFR screening requires good quality tissue, sensitivity and turn-around time (TAT). We report our experience of routine screening, describing sample type, TAT, specimen quality (cellularity and DNA yield), histopathological description, mutation result and clinical outcome. METHODS: Non-small cell lung cancer (NSCLC) sections were screened for EGFR mutations (M+) in exons 18-21. Clinical, pathological and screening outcome data were collected for year 1 of testing. Screening outcome alone was collected for year 2. RESULTS: In year 1, 152 samples were tested, most (72%) were diagnostic. TAT was 4.9 days (95%confidence interval (CI)=4.5-5.5). EGFR-M+ prevalence was 11% and higher (20%) among never-smoking women with adenocarcinomas (ADCs), but 30% of mutations occurred in current/ex-smoking men. EGFR-M+ tumours were non-mucinous ADCs and 100% thyroid transcription factor (TTF1+). No mutations were detected in poorly differentiated NSCLC-not otherwise specified (NOS). There was a trend for improved overall survival (OS) among EGFR-M+ versus EGFR-M- patients (median OS=78 versus 17 months). In year 1, test failure rate was 19%, and associated with scant cellularity and low DNA concentrations. However 75% of samples with poor cellularity but representative of tumour were informative and mutation prevalence was 9%. In year 2, 755 samples were tested; mutation prevalence was 13% and test failure only 5.4%. Although samples with low DNA concentration (2.2 ng/μL), the mutation rate was 9.2%. CONCLUSION: Routine epidermal growth factor receptor (EGFR) screening using diagnostic samples is fast and feasible even on samples with poor cellularity and DNA content. Mutations tend to occur in better-differentiated non-mucinous TTF1+ ADCs. Whether these histological criteria may be useful to select patients for EGFR testing merits further investigation.

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.
Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules.
Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma.
Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.

Radiotherapy and Immunotherapy Combinations in Non-small Cell Lung Cancer: A Promising Future?

The goal of re-programming the host immune system to target malignancy with durable anti-tumour clinical responses has been speculated for decades. In the last decade such speculation has been transformed into reality with unprecedented and durable responses to immune checkpoint inhibitors seen in solid tumours. This mini-review considers the mechanism of action of immune modulating agents and the potential for combination with radiotherapy in the treatment of non-small cell lung cancer.

Renal Drug Transporters – Clinical Significance and Role in Drug-Drug Interactions

Thesis (Ph.D.)--University of Washington, 2016-07

Neuroendocrine tumours of the female genital tract: a case-based imaging review with pathological correlation

Background Both primary and secondary gynaecological neuroendocrine (NE) tumours are uncommon, and the literature is scarce concerning their imaging features. Methods This article reviews the epidemiological, clinical and imaging features with pathological correlation of gynaecological NE tumours. Results The clinical features of gynaecological NE tumours are non-specific and depend on the organ of origin and on the extension and aggressiveness of the disease. The imaging approach to these tumours is similar to that for other histological types and the Revised International Federation of Gynecology and Obstetrics (FIGO) Staging System also applies to NE tumours. Neuroendocrine tumours were recently divided into two groups: poorly differentiated neuroendocrine carcinomas (NECs) and well-differentiated neuroendocrine tumours (NETs). NECs include small cell carcinoma and large cell neuroendocrine carcinoma, while NETs account for typical and atypical carcinoids. Cervical small cell carcinoma and ovarian carcinoid are the most common gynaecological NE tumours. The former typically behaves aggressively; the latter usually behaves in a benign fashion and tends to be confined to the organ. Conclusion While dealing with ovarian carcinoids, extraovarian extension, bilaterality and multinodularity raise the suspicion of metastatic disease. NE tumours of the endometrium and other gynaecological locations are very rare. Teaching Points • Primary or secondary neurondocrine (NE) tumours of the female genital tract are rare. • Cervical small cell carcinoma and ovarian carcinoids are the most common gynaecological NE tumours. • Cervical small cell carcinomas usually behave aggressively. • Ovarian carcinoids tend to behave in a benign fashion. • The imaging approach to gynaecological NE tumours and other histological types is similar.