iRGD tumor-penetrating peptide-modified oncolytic adenovirus shows enhanced tumor transduction, intratumoral dissemination and antitumor efficacy.

Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or tumor cells, exposure by proteolysis of a C-terminal motif that binds to neuropilin-1 (NRP-1) and cell internalization. We have genetically inserted the iRGD peptide in the fiber C terminus of ICOVIR15K, an oncolytic tumor-retargeted adenovirus to increase its tumor penetration. In vitro, NRP-1 interaction improved binding and internalization of the virus in different cancer cells overexpressing integrins and NRP-1. However, such NRP-1-mediated internalization did not affect transduction or cytotoxicity. In vivo, iRGD did not change the normal organ transduction pattern, with liver and spleen as main targeted organs. In tumors, however, iRGD enhanced transduction and early adenovirus dissemination through the tumor mass leading to an improved antitumor efficacy.

On the meaning of the diffusion layer thickness for slow electrode reactions.

A key concept underpinning electrochemical science is that of the diffusion layer - the zone of depletion around an electrode accompanying electrolysis. The size of this zone can be found either from the simulated or measured concentration profiles (yielding the 'true' diffusion layer thickness) or, in the case of the Nernst ('linear') diffusion layer by extrapolating the concentration gradient at the electrode surface to the distance at which the concentration takes its bulk value. The latter concept is very well developed in the case of fast (so-called reversible) electrode processes, however the study of the linear diffusion layer has received scant attention in the case of slow charge transfer processes, despite its study being of great interest in the analysis of the influence of different experimental variables which determine the electrochemical response. Analytical explicit solutions for the concentration profiles, surface concentrations and real and linear diffusion layers corresponding to the application of a potential step to a slow charge transfer process are presented. From these expressions the dependence of the diffusion layer thickness on the potential, pulse time, heterogeneous rate constant and ratio of bulk concentrations of electroactive species and of diffusion coefficients is quantified. A profound influence of the reversibility degree of the charge transfer on the diffusion layer thickness is clear, showing that for non-reversible processes the real and linear diffusion layers reveal a minimum thickness which coincides with the equilibrium potential of the redox couple in the former case and with the reversible half-wave potential in the latter one.

Effects of convergent diffusion and charge transfer kinetics on the diffusion layer thickness of spherical micro- and nanoelectrodes.

Nuances of the linear diffusion layer approximation are examined for slow charge transfer reactions at (hemi)spherical micro- and nanoelectrodes. This approximation is widely employed in Electrochemistry to evaluate the extent of electrolyte solution perturbed by the electrode process, which is essential to the understanding of the effects arising from thin-layer diffusion, convergent diffusion, convection, coupled chemical reactions and the double layer. The concept was well established for fast charge transfer processes at macroelectrodes, but remains unclear under other conditions such that a thorough assessment of its meaning was necessary. In a previous publication [A. Molina, J. González, E. Laborda and R. G. Compton, Phys. Chem. Chem. Phys., 2013, 15, 2381-2388] we shed some light on the influence of the reversibility degree. In the present work, the meaning of the diffusion layer thickness is investigated when very small electrodes are employed and so the contribution of convergent diffusion to the mass transport is very important. An analytical expression is given to calculate the linear diffusion layer thickness at (hemi)spherical electrodes and its behaviour is studied for a wide range of conditions of reversibility (from reversible to fully-irreversible processes) and electrode size (from macro- to nano-electrodes). Rigorous analytical solutions are deduced for true concentration profiles, surface concentrations, linear diffusion layer thickness and current densities when a potential pulse is applied at (hemi)spherical electrodes. The expressions for the magnitudes mentioned above are valid for electrodes of any size (including (hemi)spherical nanoelectrodes) and for any degree of reversibility, provided that mass transport occurs exclusively via diffusion. The variation of the above with the electrode size, applied potential and charge transfer kinetics is studied.

Square wave voltammetry at disc microelectrodes for characterization of two electron redox processes.

Analytical explicit solutions are presented for the use of square wave voltammetry (SWV) at disc microelectrodes to study two-electron reversible redox processes. This combines the advantages of SWV (minimization of capacitative effects, peak-shaped response and quick experiments) with those of microelectrodes (reduction of capacitative and ohmic drop effects, enhanced mass transport and measurements of small volumes). Further, the analytical expressions are very easy to implement in comparison with the numerical methods usually employed for simulation of electrochemical experiments at microdisc electrodes. From the theory, the effects of the technique parameters (frequency, pulse amplitude) are examined and procedures are given for the characterization of the redox system from the values of the peak current, peak potential and half-peak width. Finally, the theory is applied to the experimental study of the two-electron reduction of anthraquinone-2-sulfonate in aqueous media. For this system, the formal potentials of the redox centres in aqueous solutions can be tuned by means of the electrolyte cation.

The exercise test that indicates a low risk of events. Differences in prognostic significance between patients with chronic stable angina and patients with unstable angina.

OBJECTIVES: The objective of this prospective study was to determine the differences in the prognostic significance of an exercise test (ET) that indicates a low risk of events (low-risk exercise test [LRET]) between patients with unstable angina (UA) and those with chronic stable angina (CSA). BACKGROUND: It is not known whether the prognostic significance of an LRET is influenced by the disease; that is the reason for performing exercise testing. METHODS: All patients not presenting with high-risk criteria were submitted to a prognostic ET. The ET was performed by patients with CSA and patients with primary UA stabilized with medical therapy. Medical therapy was planned for all patients. A combined end point was defined as cardiac death, nonfatal acute myocardial infarction or hospital admission for UA. Multivariate analysis was performed to determine the independent predictors of events. RESULTS: Low-risk criteria were fulfilled by 105 patients with UA and 86 patients with CSA. The mean follow-up time was 347 +/- 229 days. The event rate was higher in the UA group than in the CSA group (28% vs. 9%, p = 0.001). The CSA group showed worse ET results. Performance of ET by patients with UA was the principal predictor of events (odds ratio 4.2, p = 0.0005). CONCLUSIONS: Among patients who underwent an LRET, those with UA had a rate of events significantly higher than that of patients with CSA, despite the worse results of ET in patients with CSA.

Adequacy of dialysis in automated peritoneal dialysis: a clinical experience.

OBJECTIVES: To compare the peritoneal clearances of urea and creatinine in continuous ambulatory peritoneal dialysis (CAPD) with three types of automated peritoneal dialysis (APD): continuous cycling peritoneal dialysis (CCPD), 50% tidal peritoneal dialysis (TPD), and 25% TPD and to assess the usefulness of the peritoneal equilibration test (PET) in predicting peritoneal clearances in overnight APD. PATIENTS: Eleven uremic patients (mean age 44.5 +/- 15.45 years with a mean time on dialysis of 42.63 +/- 25.62 months) were included in the study. MEASUREMENTS: PET for urea and creatinine following Twardowski's method. Peritoneal clearances for urea and creatinine CAPD: samples of blood and dialysate within 24 hours. APD: blood mean levels of urea and creatinine before and after nighttime dialysis. Dialysate: urea and creatinine in nocturnal and daytime dialysate. RESULTS: Peritoneal clearance of creatinine was 38.14 +/- 9.99 L/week/1.73 m2 in CAPD, 44.28 +/- 12.4 L/week/1.73 m2 in CCPD, 50.07 +/- 17.86 L/week/1.73 m2 in 50% TPD (p < 0.05) and 40.18 +/- 6.65 L/week/1.73 m2 in 25% TPD. Peritoneal clearance of urea improved significantly in the three modalities of APD: 51.91 +/- 12.58 L/week/1.73 m2 in CAPD; 66.7 +/- 9.9 L/week/1.73 m2 in CCPD (p < 0.05); 76.3 +/- 14.5 L/week/1.73 m2 in 50% TPD (p < 0.001) and 64.4 +/- 11.4 L/week/1.73 m2 in 25% TPD (p < 0.05). The dialysate/ plasma (D/P) ratio of creatinine at 30, 60, 120, 180, and 240 minutes showed significant correlation with nighttime APD clearance. Nevertheless, only the D/P ratio of urea at 30, 60, and 120 minutes correlated with overnight APD clearance. CONCLUSIONS: A remarkable improvement was observed with APD regarding the clearance of urea mainly when 50% tidal peritoneal dialysis was used, whereas it was less noticeable in the clearance of creatinine. The PET is a helpful tool in predicting overnight peritoneal clearances of creatinine but it is less useful in predicting urea clearance.

[Urethral sonography in the diagnosis and preoperative evaluation of urethral stenosis]. / Sonouretrografía en el diagnóstico y evaluación preoperatoria de la estenosis de uretra.

An area of spongiofibrosis can be found proximal and distal to all stenosis of the urethra. The severity of such spongiofibrosis as well as its length are in many instances decisive when choosing an adequate surgical approach. Conventional radiological diagnosis of stenosis of the urethra only shows the area of urethral stricture but is unable to inform on the fibrosis of the spongy body. Sonourethrography or urethral echography affords a dynamic tridimensional examination of the anterior urethra which provides accurate data on the length of the stenosis, as well as the extend and severity of the spongiofribosis. Sixteen patients diagnosed with stenosis of the urethra through sonourethrography were evaluated. This easy-to-perform investigation, allowed the identification of 4 patients with peristenotic intense spongiofibrosis, hypercongenital urethra, who underwent open urethroplastia. The urethra of another 3 patients showed normal echogenicity, but diminished elasticity, and were diagnosed as of moderate spongiofibrosis requiring extensive internal urethrotomy. We believe sonourethrography should become a procedure to be included as part of the routine pre-surgical investigation of the stenosis of the urethra due to its non-invasive nature, easiness to perform, and because it provides highly useful information which would allow a decreased number of re-stenosis following surgery of the urethral stenosis.

The combination of i-leader truncation and gemcitabine improves oncolytic adenovirus efficacy in an immunocompetent model.

Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.

Surveillance for infections and other adverse events in dialysis patients in southern Gran Canaria.

BACKGROUND: Bacterial infections pose a major challenge to risk management activities in the area of chronic haemodialysis, as vascular access-related infections are the main cause of mortality among these patients. METHODS: Prospective surveillance study lasting 7 months (March-September, 2008) at two haemodialysis units in a district health area Gran Canaria, Spain. We used the methodology proposed by CDC´s Dialysis Surveillance Network. RESULTS: 1545 patients/month were recorded, 60.5% with an arteriovenous fistula (AVF), 35.5% with a permanent catheter (PC), 3.0% with grafts and 1.0% with temporary catheters. The rate of adverse events was 8.6 cases per 100 patients/month, 9.1 for AVF patients, and 2.9 for PC. Nevertheless, the other types of infections (respiratory, urinary tract, skin and chronic ulcers) showed similar rates. Microbiological cultures were taken in 82.2%, but this rate increased to 91.0% when a vascular access-related infection was suspected. Empirical treatment was adjusted to antibiogram results in 90.0% of occasions. A low incidence of multi-resistant microbes was observed. Gram-positive and gram-negative bacteria appeared in similar proportions. CONCLUSIONS: Vascular access is the main risk factor for infectious events. Epidemiological surveillance has allowed us to detect areas of improvement in different settings, acting as a key element in risk management and patient safety.

[Pseudoangiomatous stromal hyperplasia: magnetic resonance findings in two cases]. / Hiperplasia pseudoangiomatosa estromal: hallazgos en resonancia magnética de dos casos.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast tumor of uncertain etiology, although marked hormonal influence clearly plays a role in this disease. The differential diagnosis is important because this is an uncommon lesion that can simulate malignant lesions both at clinical and radiological examination, and even the histological results can be confusing. Little has been published regarding the MRI findings of PASH. The aim of this report is to describe the most remarkable findings observed at MRI in two patients with PASH.

Vigilancia de infecciones y otros eventos adversos en pacientes en diálisis en el área sur de Gran Canaria / Surveillance for infections and other adverse events in dialysis patients in southern Gran Canaria

Introducción: Las infecciones bacterianas representan un gran desafío en las estrategias de gestión del riesgo, prevención y seguridad del paciente en hemodiálisis de las cuales las infecciones del acceso vascular (AV) representan la primera causa morbi-mortalidad en estos pacientes. Métodos: Estudio prospectivo de incidencia de eventos adversos e infecciones de 7 meses (marzo-septiembre 2008) en las unidades de Hemodiálisis del Área sanitaria Sur de Gran Canaria (Hospital y Centro periférico) utilizando la metodología del Dialysis Surveillance Network del CDC. Resultados: Se vigilaron 1545 pacientes/mes, 60,5% con fístula (FAV), 35,5% con catéter permanente (CP), 3,0% con prótesis y 1,0% con catéter temporal. La incidencia de eventos en ambos centros fue 8,7 casos por 100 pacientes-mes; la tasa de eventos infecciosos fue de 9,1 para FAV y 20,6 para CP en ámbito hospitalario, mientras las tasas de otras infecciones (respiratorias, herida, orina) fueron similares. Se realizó cultivo antes de empezar tratamiento antibiótico en el 91,0% frente a sospecha de bacteriemia y/o infección AV. El 90,0% de tratamientos se ajustaron con antibiograma. Destaca una baja incidencia de bacterias mutirresistentes mientras que las infecciones relacionadas con el AV fueron causadas en proporción similar por bacterias grampositivas y gramnegativas. Conclusiones: El acceso vascular es el principal factor de riesgo para el desarrollo de infecciones. La vigilancia epidemiológica he permitido detectar oportunidades de mejora en ámbitos asistenciales distintos, integrándose como elemento fundamental en el desarrollo de estrategias multidisciplinarias de seguridad del paciente (AU)

Background: Bacterial infections pose a great challenge to risk management activities in the area of chronic haemodialysis, as vascular access related infections are the main cause of mortality among these patients. Methods: Prospective surveillance study lasting 7 months (March-September, 2008) at the two haemodialysis units in a district health area in Gran Canaria, Spain. We have used methodology proposed by CDC´s Dialysis Surveillance Network. Results: 1545 patientsmonth were enrolled, 60,5% having an arterio-venous fistula (AVF), 35,5% permanent catheter (PC), 3,0% graft and 1,0% temporary catheters. Events incidence rate at both centers was 8,6 cases per 100 patients-month, 9,1 rate for FAV and 2,9 rates for CP, So, the greatest incidence of vascular access related infections was for permanent catheter as compared with AFV. Nevertheless the other type of infections (respiratory, urinary tract, skin and chronic ulcers) showed a similar rate. Microbiological cultures before antibiotic treatment were performed in 82,2 %, but increased up to 91,0% when a vascular related infection was suspected. Empiric treatment was adjusted to antibiogram results in 90,0% of occasions. A low incidence of multirresistant microbes was seen. Gram-positive and gram-negative bacteria appeared in a similar proportion. Conclusions: Vascular access is the main risk factor for infectious events. Epidemiological surveillance has allowed us to detect areas of improvement in different settings, appearing as a key element in the risk management and patient safety areas (AU)

Mutagenic activity in synthetic pyrethroids in Salmonella typhimurium.

Four pyrethroids, allethrin, resmethrin, permethrin and fenvalerate, were tested for mutagenicity in bacterial reversion assay systems with seven strains (TA1535, TA100, TA1538, TA98, TA1537, TA97 and TA104) of Salmonella typhimurium. Our results show that three pyrethroids, namely resmethrin, permethrin and fenvalerate, were not found to be mutagenic in S. typhimurium in the presence or absence of a rat liver activation system. Allethrin was found to be mutagenic with TA100, TA104 and TA97 strains and required metabolic activation (S9 mix) in order to show its activity, mainly with TA100 and TA104 strains.

[Predictive value of short-term assays of chemical carcinogenesis]. / Valor predictivo de los ensayos de corta duración sobre carcinogénesis química.

Many agents of our surroundings are mutagenic, and a significant number of the mutagenic agents are carcinogenic. It is then useful to evaluate the short-term screening test allowing to predict the carcinogenic effect of chemicals. The authors make a summary about the predictive value of the existing assays, and write about the need of the systematic use of a convenient battery of tests to detect carcinogenicity in every product to which the human being may be exposed.

Breast and pectoralis muscle hypoplasia. A mild degree of Poland's syndrome.

PURPOSE: Poland's syndrome is a congenital and unilateral aplasia of the pectoralis major muscle (PMM), with other anomalies of the ipsilateral upper extremity. We present 6 cases in which the only clinical expression was asymmetry of the breasts associated with partial absence of the PMM. MATERIAL AND METHODS: We reviewed 95000 mammograms (obtained 1985-1995) to find patients with asymmetrical breast size. Where the asymmetry could not be ascribed to any other cause, the patients were recalled for an examination of the PMM which was conducted at rest and with active contraction of the muscle. RESULTS: Unilateral volume reduction of the PMM was found in 5 women of whom 2 were studied with MR. A 6th case was a fortuitous finding in a male patient. CONCLUSION: Mild forms of Poland's syndrome are more frequent than severe forms, and may go undiagnosed. Hypoplasia of one breast or a horizontal anterior axillary fold may be the sole clinical manifestation of this syndrome.

[Mutagenic evaluation of the urine of rats treated with oils implicated in the toxic oil syndrome using bacterial tests]. / Evaluación mutagénica de orina de ratas tratadas con aceites implicados en el síndrome tóxico mediante ensayos bacterianos.

The mutagenic activity of the urine of pregnant rats treated with toxic oil syndrome-related rape seed oil or with edible oil was evaluated by means of the Ames and Green tests. It was found that the urine of the pregnant rats treated with "Jen" oil, that was related to the toxic oil syndrome, was mutagenic.

[Atypical chest pain with normal coronary vessels: clinical study and follow-up of 22 patients]. / Dolor torácico atípico con coronarias normales: estudio clínico y seguimiento de 22 pacientes.

22 patients with normal coronarography but with angina pectoris or angina-like chest pain without evidence of coronary spasms are reviewed. We studied clinical characteristics, basal and exercise electrocardiography and other tests used to obtain a diagnosis, although only in one patient were we able to find an esophageal pathology which caused the clinical picture. After 20.7 +/- 14.4 months follow-up no patients had myocardial infarction or acute coronary events. Most of them still experience chest pain, are physically limited and use antianginal drugs. The fact that their coronarograms were normal decreased significantly the number of admissions to hospital (2.4 +/- 3.3 vs 0.26 +/- 0.95, P less than 0.02) and the amount of drugs prescribed. The lack of improvement of most of them seems to justify the need for other studies looking for a positive diagnosis and other types of treatment.