Non-viral ocular gene therapy: potential ocular therapeutic avenues.

Non-viral vectors for potential gene replacement and therapy have been developed in order to overcome the drawbacks of viral vectors. The diversity of non-viral vectors allows for a wide range of various products, flexibility of application, ease of use, low-cost of production and enhanced "genomic" safety. Using non-viral strategies, oligonucleotides (ODNs) can be delivered naked (less efficient) or entrapped in cationic lipids, polymers or peptides forming slow release delivery systems, which can be adapted according to the organ targeted and the therapy purposes. Tissue and cell internalization can be further enhanced by changing by physical or chemical means. Moreover, a specific vector can be selected according to disease course and intensity of manifestations fulfilling specific requirements such as the duration of drug release and its level along with cells and tissues specific targeting. From accumulating knowledge and experience, it appears that combination of several non-viral techniques may increase the efficacy and ensure the safety of these evolving and interesting gene therapy strategies.

The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials?

Pharmacological treatment of hypertension represents a cost-effective way for preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment blood pressure (BP) should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Most of the time such targets cannot be reached using monotherapies. This is especially true in patients who exhibit a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases BP control. Such preparations are not only efficacious, but also well tolerated, and some fixed low-dose combinations have a tolerability profile similar to placebo. This is for instance the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has recently been shown in controlled interventional trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving macrovascular stiffness. Fixed-dose combinations are becoming more and more popular and are even proposed by current hypertension guidelines as a first-line option to treat hypertensive patients.

Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

Effectiveness of substituting cyclosporin A with tacrolimus in reducing gingival overgrowth in renal transplant patients

Objectives: This study aims to evaluate the effectiveness of periodontal therapy combined with tacrolimus in the suppression of gingival overgrowth (GO) and the effect on GO of changing from cyclosporin A to tacrolimus. Patients and Methods: Sixteen renal transplant patients, averaging 52 years of age, whose kidney function was stable and were receiving treatment with cyclosporin A, were randomly assigned to one of two groups. In the experimental group, patients were instructed in oral hygiene and underwent periodontal treatment, whereas in the control group, only oral hygiene instructions were given. After the first visit and the change of medication from cyclosporine to tacrolimus in both groups, periodic clinical revisions were carried out for 3 months in order to assess the evolution of GO. Results: All patients showed a progressive decrease in GO. There were no statistically significant differences between the two groups (p>0.05). A greater decrease in GO occurred within the first month after changing the medication. Conclusions: No improved effectiveness in reducing GO was observed for periodontal therapy in combination with tacrolimus. Tacrolimus is an alternative to cyclosporine when attempting to avoid GO in patients with kidney transplants

El ejercicio físico y el paciente renal crónico

Durante estos últimos años estamos asistiendo a un rápido y continuo desarrollo tecnológico en las terapias de hemodiálisis (HD). Este hecho produce el consecuente aumento en la esperanza de vida de los pacientes con enfermedad renal terminal, aumentando la supervivencia y mejorando el alivio de los síntomas urémicos. Sin embargo, la debilidad que sufren estos pacientes es bien conocida; siendo la causante de que haya una tendencia a llevar un estilo de vida sedentario, pese a que existen estudios que refieren que el ejercicio durante la HD es seguro incluso en pacientes de edad avanzada con múltiples comorbilidades1. Por este motivo, uno de los pilares de la atención que...

Fetal laser therapy: applications in the management of fetal pathologies.

Fetoscopic coagulation of placental anastomoses is the treatment of choice for severe twin-to-twin transfusion syndrome. In the present day, fetal laser therapy is also used to treat amniotic bands, chorioangiomas, sacrococcygeal teratomas, lower urinary tract obstructions and chest masses, all of which will be reviewed in this article. Amniotic band syndrome can cause limb amputation by impairing downstream blood flow. Large chorioangiomas (>4 cm), sacrococcygeal teratomas or fetal hyperechoic lung lesions can lead to fetal compromise and hydrops by vascular steal phenomenon or compression. Renal damage, bladder dysfunction and lastly death because of pulmonary hypolasia may be the result of megacystis caused by a posterior urethral valve. The prognosis of these pathologies can be dismal, and therapy options are limited, which has brought fetal laser therapy to the forefront. Management options discussed here are laser release of amniotic bands, laser coagulation of the placental or fetal tumor feeding vessels and laser therapy by fetal cystoscopy. This review, largely based on case reports, does not intend to provide a level of evidence supporting laser therapy over other treatment options. Centralized evaluation by specialists using strict selection criteria and long-term follow-up of these rare cases are now needed to prove the value of endoscopic or ultrasound-guided laser therapy.

Identification of Low-Risk Patients with Acute Symptomatic Pulmonary Embolism for Outpatient Therapy.

RATIONALE: Patients with acute symptomatic pulmonary embolism (PE) deemed to be at low risk for early complications might be candidates for partial or complete outpatient treatment. OBJECTIVES: To develop and validate a clinical prediction rule that accurately identifies patients with PE and low risk of short-term complications and to compare its prognostic ability with two previously validated models (i.e., the Pulmonary Embolism Severity Index [PESI] and the Simplified PESI [sPESI]) METHODS: Multivariable logistic regression of a large international cohort of patients with PE prospectively enrolled in the RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) registry. MEASUREMENTS AND MAIN RESULTS: All-cause mortality, recurrent PE, and major bleeding up to 10 days after PE diagnosis were determined. Of 18,707 eligible patients with acute symptomatic PE, 46 (0.25%) developed recurrent PE, 203 (1.09%) bled, and 471 (2.51%) died. Predictors included in the final model were chronic heart failure, recent immobilization, recent major bleeding, cancer, hypotension, tachycardia, hypoxemia, renal insufficiency, and abnormal platelet count. The area under receiver-operating characteristic curve was 0.77 (95% confidence interval [CI], 0.75-0.78) for the RIETE score, 0.72 (95% CI, 0.70-0.73) for PESI (P < 0.05), and 0.71 (95% CI, 0.69-0.73) for sPESI (P < 0.05). Our RIETE score outperformed the prognostic value of PESI in terms of net reclassification improvement (P < 0.001), integrated discrimination improvement (P < 0.001), and sPESI (net reclassification improvement, P < 0.001; integrated discrimination improvement, P < 0.001). CONCLUSIONS: We built a new score, based on widely available variables, that can be used to identify patients with PE at low risk of short-term complications, assisting in triage and potentially shortening duration of hospital stay.

Long-Term Anticoagulant Therapy of Patients with Venous Thromboembolism. What Are the Practices?

Current guidelines of antithrombotic therapy suggest early initiation of vitamin K antagonists (VKA) in non-cancer patients with venous thromboembolism (VTE), and long-term therapy with low-molecular weight heparin (LMWH) for those with cancer. We used data from RIETE (international registry of patients with VTE) to report the use of long-term anticoagulant therapy over time and to identify predictors of anticoagulant choice (regarding international guidelines) in patients with- and without cancer. Among 35,280 patients without cancer, 82% received long-term VKA (but 17% started after the first week). Among 4,378 patients with cancer, 66% received long term LMWH as monotherapy. In patients without cancer, recent bleeding (odds ratio [OR] 2.70, 95% CI 2.26-3.23), age >70 years (OR 1.15, 95% CI 1.06-1.24), immobility (OR 2.06, 95% CI 1.93-2.19), renal insufficiency (OR 2.42, 95% CI 2.15-2.71) and anemia (OR 1.75, 95% CI 1.65-1.87) predicted poor adherence to guidelines. In those with cancer, anemia (OR 1.83, 95% CI 1.64-2.06), immobility (OR 1.51, 95% CI 1.30-1.76) and metastases (OR 3.22, 95% CI 2.87-3.61) predicted long-term LMWH therapy. In conclusion, we report practices of VTE therapy in real life and found that a significant proportion of patients did not receive the recommended treatment. The perceived increased risk for bleeding has an impact on anticoagulant treatment decision.

De novo undifferentiated pleomorphic sarcoma arising from a renal allograft: A case report

To the best of our knowledge, this is the first report of an undifferentiated pleomorphic sarcoma arising from a renal graft. Transplantectomy was performed in a 47-year old woman presenting to the emergency room because of general weakness. Preoperative workup revealed a 5.5 cm malignant mass of the graft which was not present on routine ultrasound performed 12 months earlier. Following transplantectomy, local recurrence developed despite complete tumor resection and interruption of immunosuppression. Despite radiation therapy, the outcome was ultimately fatal. Genetic analysis revealed that the tumor had arisen from donor tissue. Annual ultrasound surveillance might not be enough effective to screen for these rare high grade neoplasms.

Renal cell carcinoma: histological classification and correlation with imaging findings

AbstractRenal cell carcinoma (RCC) is the seventh most common histological type of cancer in the Western world and has shown a sustained increase in its prevalence. The histological classification of RCCs is of utmost importance, considering the significant prognostic and therapeutic implications of its histological subtypes. Imaging methods play an outstanding role in the diagnosis, staging and follow-up of RCC. Clear cell, papillary and chromophobe are the most common histological subtypes of RCC, and their preoperative radiological characterization, either followed or not by confirmatory percutaneous biopsy, may be particularly useful in cases of poor surgical condition, metastatic disease, central mass in a solitary kidney, and in patients eligible for molecular targeted therapy. New strategies recently developed for treating renal cancer, such as cryo and radiofrequency ablation, molecularly targeted therapy and active surveillance also require appropriate preoperative characterization of renal masses. Less common histological types, although sharing nonspecific imaging features, may be suspected on the basis of clinical and epidemiological data. The present study is aimed at reviewing the main clinical and imaging findings of histological RCC subtypes.

Lymphocyte subpopulations during cytomegalovirus disease in renal transplant recipients

We have determined the number of circulating T, B and natural killer cells in renal transplant recipients in order to detect changes during cytomegalovirus (CMV) infections. Serial blood samples were taken from 61 patients on standard triple immunosuppression therapy (cyclosporin A, azathioprine and prednisone). Using two-color flow cytometry analysis, the absolute number of CD3+, CD4+, CD8+, CD19+, CD3+HLA-DR+ and CD16+56+ cells was determined. Forty-eight patients (78.7%) developed active CMV infection, and all of them subsequently recovered. Twenty of the infected patients (32.8%) presented symptoms compatible with CMV disease during the infectious process. The number of lymphocytes and their main subpopulations were normal before the onset of CMV disease. During the disease there was a decrease followed by a significant increase (P<0.005) in the number of CD3+, CD4+, CD8+ and CD3+HLA-DR+ cells. No significant changes were observed in natural killer cells or B lymphocytes during the disease. We conclude, as observed in all viremic patients recovering from infection, that recovery is associated with an increase in the number of T cell subsets. The monitoring of different lymphocyte subsets along with antigenemia can be extremely useful in the detection of patients at high risk of developing CMV symptoms, allowing the early introduction of antiviral therapy or the reduction of immunosuppression therapy.

Prevalence of low trauma fractures in long-term kidney transplant patients with preserved renal function

We evaluated the prevalence of low bone mineral density (BMD) and osteoporotic fractures in kidney transplantation (KT) patients and determined risk factors associated with osteoporotic fractures. The study was conducted on 191 patients (94 men and 97 women) with first KT for 3 years or more presenting stable and preserved renal function (serum creatinine levels lower than 2.5 mg/dl). KT patients were on immunosuppressive therapy and the cumulative doses of these drugs were also evaluated. BMD was determined by dual-energy X-ray absorptiometry at multiple sites (spine, femur and total body). Quantitative ultrasound of the calcaneus (broadband ultrasound attenuation, speed of sound, and stiffness index, SI) was also performed. Twenty-four percent (46) of all patients had either vertebral (29/46) or appendicular (17/46) fractures. We found osteoporosis and osteopenia in 8.5-13.4 and 30.9-35.1% of KT patients, respectively. Women had more fractures than men. In women, prevalent fractures were associated with diabetes mellitus [OR = 11.5, 95% CI (2.4-55.7)], time since menopause [OR = 3.7, 95% CI (1.2-11.9)], femoral neck BMD [OR = 1.99, 95% CI (1.4-2.8)], cumulative dose of steroids [OR = 1.1, 95% CI (1.02-1.12)] and low SI [OR = 1.1, 95% CI (1.0-1.2)]. In men, fractures were associated with lower lumbar spine BMD [OR = 1.75, 95% CI (1.1-2.7)], lower SI [OR = 1.1, 95% CI (1.03-1.13)], duration of dialysis [OR = 1.3, 95% CI (1.13-2.7)], and lower body mass index [OR = 1.24, 95% CI (1.1-1.4). Our results demonstrate high prevalence of low BMD and osteoporotic fractures in patients receiving a successful kidney transplant and indicate the need for specific intervention to prevent osteoporosis in this population.

Urinary NO3 excretion and renal failure in indinavir-treated patients

Treatment with indinavir (IDV), a protease inhibitor, is frequently associated with renal abnormalities. We determined the incidence of renal failure (creatinine clearance <80 mL min-1 1.73 (m²)-1) in HIV patients treated with highly active antiretroviral therapy, including IDV, and investigated the possible mechanisms and risk factors of IDV nephrotoxicity. Thirty-six patients receiving IDV were followed for 3 years. All were assessed for age, body weight, duration of infection, duration of IDV treatment, sulfur-derivative use, total cholesterol, triglycerides, magnesium, sodium, potassium, creatinine, and urinalysis. We also determined renal function in terms of creatinine clearance, urine osmolality and fractional excretion of sodium, potassium, and water. Urinary nitrate (NO3) excretion was measured in 18 IDV-treated patients and compared with that of 8 patients treated with efavirenz, a drug without renal side effects. Sterile leukocyturia occurred in 80.5% of the IDV-treated patients. Creatinine clearance <80 mL min-1 1.73 (m²)-1 was observed in 22 patients (61%) and was associated with low body weight and the use of sulfur-derivatives. These patients also had lower osmolality, lower urine volume and a higher fractional excretion of water compared to the normal renal function group. Urinary NO3 excretion was significantly lower in IDV-treated patients (809 ± 181 µM NO3-/mg creatinine) than in efavirenz-treated patients (2247 ± 648 µM NO3-/mg creatinine, P < 0.01). The lower NO3 excretion suggests that IDV decreases nitric oxide production.