A Universal Antigen-Ranking Method to Design Personalized Vaccines Targeting Neoantigens against Melanoma.

Background: The main purpose of this article is to introduce a universal mathematics-aided vaccine design method against malignant melanoma based on neoantigens. The universal method can be adapted to the mutanome of each patient so that a specific candidate vaccine can be tailored for the corresponding patient. Methods: We extracted the 1134 most frequent mutations in melanoma, and we associated each of them to a vector with 10 components estimated with different bioinformatics tools, for which we found an aggregated value according to a set of weights, and then we ordered them in decreasing order of the scores. Results: We prepared a universal table of the most frequent mutations in melanoma ordered in decreasing order of viability to be used as candidate vaccines, so that the selection of a set of appropriate peptides for each particular patient can be easily and quickly implemented according to their specific mutanome and transcription profile. Conclusions: We have shown that the techniques that are commonly used for the design of personalized anti-tumor vaccines against malignant melanoma can be adapted for the design of universal rankings of neoantigens that originate personalized vaccines when the mutanome and transcription profile of specific patients is considered, with the consequent savings in time and money, shortening the design and production time.

Sex Modulates Cardiovascular Effects of Icodextrin-Based Peritoneal Dialysis Solutions.

Background/Aims: Some previous observations have noted that after six months of peritoneal dialysis (PD) treatment with icodextrin solutions, blood pressure (BP) and NT-proBNP tend to return to baseline values. This may be due to accumulation of icodextrin products that exert a colloid osmotic effect, which drives water into the bloodstream, causing the rise in blood pressure. Since icodextrin is metabolized by α-Amylase and its gene copies are lower in females than in males, we hypothesized icodextrin metabolites reach higher concentrations in females and that cardiovascular effects of icodextrin are influenced by sex. Methods: Secondary analysis of a RCT comparing factors influencing fluid balance control in diabetic PD patients with high or high average peritoneal transport receiving icodextrin (n = 30) or glucose (n = 29) PD solutions. Serum icodextrin metabolites, osmolality, body composition and Inferior Vena Cava (IVC) diameter were measured at baseline, and at 6 and 12 months of follow-up. Results: After six months of treatment, icodextrin metabolites showed higher levels in females than in males, particularly G5-7 and >G7, serum osmolality was lower in females. In spite of reduction in total and extracellular body water, ultrafiltration (UF) was lower and IVC diameter and BP increased in females, suggesting increment of blood volume. Conclusion: Females undergoing PD present with higher levels of icodextrin metabolites in serum that may exert an increased colloid-osmotic pressure followed by less UF volumes and increment in blood volume and blood pressure. Whether this could be due to the lesser number of α-Amylase gene copies described in diabetic females deserves further investigation.

Disfunción endotelial en niños con enfermedad renal crónica / Endothelial dysfunction in children with chronic kidney disease

Antecedentes y objetivo: La enfermedad cardiovascular es la principal causa de muerte en niños con enfermedad renal crónica. La inflamación y la disfunción endotelial se presenta en la mayoría de estos pacientes y son factores asociados a enfermedad cardiovascular. La dilatación mediada por flujo (DMF)<7% es un marcador subrogado validado en la evaluación de la disfunción endotelial. Nuestro objetivo fue identificar los factores de riesgo asociados a disfunción endotelial en niños con enfermedad renal crónica. Materiales y métodos: Se estudió a niños de 2-16 años de edad. Se recopiló su información clínica y variables bioquímicas, incluidos hormona paratiroidea intacta (iPTH), interleucinas 6 y 1β, proteína C reactiva de alta sensibilidad (hsCRP), glutatión reducido, óxido nítrico, malondialdehído y homocisteína. Se consideró DMF alterada<7%. Resultados: Se incluyó a 129 pacientes con edad de 13,1±2,6 años. Tuvieron DMF<7% 69 (52,7%). Los pacientes con DMF<7% tuvieron niveles más altos de triglicéridos y de hsCRP que aquellos con DMF≥7% (145,5 vs. 120,0mg/dl, p=0,042, y 1,24 vs. 0,55U/l, p=0,007, respectivamente), así como una mayor frecuencia de iPTH baja (19,1 vs. 4,9%, p=0,036). Los niveles de hsCRP se correlacionaron significativamente con la DMF (Rho=−0,28, p=0,003). Los pacientes con iPTH baja (OR 4,41, IC 95% 1,13-17,27, p=0,033) y con hsCRP incrementada (OR 2,89, IC 95% 1,16-7,17, p=0,022) tuvieron un riesgo ajustado mayor de DMF<7%. Conclusiones: La hipertrigliceridemia, la inflamación y una iPTH baja se asociaron significativamente a una DMF alterada. Son factores de riesgo de enfermedad cardiovascular frecuentes y tratables. (AU)

Background and objective: Cardiovascular disease is the main cause of death in children with chronic kidney disease. Inflammation and endothelial dysfunction are found in the majority of these patients and are factors associated to cardiovascular disease. Flow mediated dilatation (FMD) is a surrogate marker validated for evaluating endothelial dysfunction. Our objective was to identify risk factors associated to endothelial dysfunction in children with chronic kidney disease. Materials and methods: Children 2-16 years of age were studied. Clinical information and biochemical variables were gathered, including intact parathyroid hormone (iPTH), interleukins 6 and 1β, high sensitivity C reactive protein (hsCRP), reduced glutathione, nitric oxide, malondialdehyde and homocysteine. FMD was measured, and considered altered if<7%. Results: Included were 129 patients aged 13.1±2.6 years. FMD<7% was found in 69 (52.7%). Patients with altered FMD had higher levels of triglycerides and hsCRP than those with normal FMD (145.5 vs. 120.0mg/dL, P=.042, and 1.24 vs. 0.55U/L, P=.007, respectively), as well as higher frequency of low iPTH (19.1 vs. 4.9%, P=.036). Levels of hsCRP correlated significantly with FMD (Rho=−0.28, P=.003). Patients with low iPTH (OR 4.41, 95% CI 1.13-17.27, P=.033) and increased hsCRP (OR 2.89, 95% CI 1.16-7.17, P=.022) had higher adjusted risk of having FMD<7%. Conclusions: Hypertriglyceridemia, inflammation and low iPTH associated significantly with altered FMD. They are frequent, treatable risk factors for cardiovascular disease. (AU)

Endothelial dysfunction in children with chronic kidney disease.

BACKGROUND AND OBJECTIVE: Cardiovascular disease (CVD) is the main cause of death in children with chronic kidney disease (CKD). Inflammation and endothelial dysfunction (ED) are found in the majority of these patients and are factors associated to CVD. Flow mediated dilatation (FMD) is a surrogate marker validated for evaluating ED. Our objective was to identify risk factors associated to ED in children with CKD. MATERIALS AND METHODS: Children 2-16 years of age were studied. Clinical information and biochemical variables were gathered, including intact parathyroid hormone (iPTH), interleukins 6 and 1b, high sensitivity C reactive protein (hsCRP), reduced glutathione, nitric oxide, malondialdehyde and homocysteine. FMD was measured, and considered altered if <7%. RESULTS: Included were 129 patients aged 13.1 ±â€¯2.6 years. FMD < 7% was found in 69 (52.7%). Patients with altered FMD had higher levels of triglycerides and hsCRP than those with normal FMD (145.5 mg/dl vs. 120.0 mg/dl, P = .042, y 1.24 U/L vs. 0.55 U/L, P = .007, respectively), as well as higher frequency of low iPTH (19.1% vs. 4.9%, P = .036). Levels of hsCRP correlated significantly with FMD (Rho = -0.28, P = .003). Patients with low iPTH (OR = 4.41, 95%CI 1.13-17.27, P = .033) and increased hsCRP (OR = 2.89, 95%CI 1.16-7.17, P = .022) had higher adjusted risk of having FMD < 7%. CONCLUSIONS: Hypertriglyceridemia, inflammation and low iPTH associated significantly with altered FMD. They are frequent, treatable risk factors for CVD.

Diabetes and obesity during pregnancy are associated with oxidative stress genotoxicity in newborns.

Objective To compare the level of oxidative deoxyribonucleic acid (DNA) damage (genotoxicity) between the offspring of mothers with and without diabetes diagnosed during pregnancy and its association with maternal body mass index (BMI). Methods We measured 8-hydroxy-deoxyguanosine (8-OH-dG), a marker of DNA oxidative damage, in venous umbilical cord plasma from newborns of mothers with (n=34) and without (n=56) diabetes diagnoses obtained during pregnancy. Two markers of oxidative stress - namely, nitric oxide degradation products (NOx) and total glutathione (GSH) - were quantified in both mothers and newborns. The effects of BMI, glycated hemoglobin (HbA1c), age and delivery mode were also analyzed. Results Newborns of mothers with diabetes during pregnancy exhibited higher levels of 8-OH-dG than those of mothers without diabetes (P<0.001). The other markers of oxidative stress were also higher in both mothers with diabetes and their newborns, with the exception of NOx in the mothers. The association of diabetes with 8-OH-dG was independent of other analyzed factors. Conclusion The offspring of mothers with diabetes during pregnancy are born with increased genotoxicity than the offspring of mothers without diabetes. BMI and HbA1c display an independent association with 8-OH-dG, particularly in the offspring of mothers not diagnosed with diabetes.

Helicobacter pylori in esplenectomized patients with immune primary trombocytopenia / Helicobacter pylori en pacientes esplenectomizados con trombocitopenia inmune primaria

Background: Primary Immune Thrombocytopenia (TIP) is an autoimmune disease that accelerates the peripheral destruction of platelets and alters megakaryocytopoiesis. Helicobacter pylori infection and eradication has been associated with an increase in the platelet count in patients with IPT. The aim of this article is to evaluate the platelet response after H. pylori eradication in patients with chronic splenectomized IPT Methods: Between 2008 and 2009, adult patients with a diagnosis of chronic IPT, splenectomized; They were given breath test with carbon 13-labeled urea (PAU13C). Patients who tested positive received eradication treatment with amoxicillin, omeprazole and clarithromycin for 14 days. After 6 weeks of treatment, a second PAU13C was performed. Baseline platelet counts were performed and every six months until the completion of two years. Results: 40 patients, 34 women and 6 men were included, PAU13C was positive in 17 patients (42.5%). H. pylori eradication was obtained in 16 patients (94%) confirmed by post-treatment PAU13C. In the follow-up of the patients it was observed that there was increase of platelets in 7 of the patients with eradication of H. pylori, while of the patients not infected in 9 also an increase of platelets was observed. Conclusions: There were no differences in the increase in platelet count among patients positive or negative to the H. pylori breath test at followup at 24 months.

Introducción: La trombocitopenia inmune primaria (TIP) es una enfermedad autoinmune que acelera la destrucción periférica de las plaquetas y altera la megacariocitopoyesis. La erradicación de la infección por Helicobacter pylori se ha asociado al incremento en la cuenta de plaquetas en los pacientes con TIP. El objetivo de este trabajo fue evaluar la respuesta de plaquetas después de la erradicación del H. pylori en pacientes con TIP crónica esplenectomizados. Métodos: Entre 2008-2009 fueron incluidos pacientes adultos con diagnóstico de TIP crónica, esplenectomizados; se les realizó prueba de aliento con urea marcada con carbono 13 (PAU13C). Los pacientes que resultaron positivos a la prueba recibieron tratamiento de erradicación con amoxicilina, omeprazol y claritromicina por 14 días. Después de 6 semanas de tratamiento, se realizó una segunda PAU13C. Se realizaron cuenta de Plaquetas basal y cada seis meses hasta completar dos años. Resultados: Se incluyeron 40 pacientes, 34 mujeres y 6 hombres, la PAU13C resultó positiva en 17 pacientes (42.5%). La erradicación del H. pylori se obtuvo en 16 pacientes (94%) confirmado por PAU13C postratamiento. En el seguimiento de los pacientes se observó que hubo incremento de las plaquetas en 7 de los pacientes con erradicación del H. pylori, mientras que de los pacientes no infectados en 9 también se observó aumento de plaquetas. Conclusiones: No hubo diferencias en el incremento en la cuenta de plaquetas entre los pacientes positivos o negativos a la prueba de aliento para H. pylori en el seguimiento a 24 meses.

Hemorrheologic effect of diuretics in the control of blood pressure in the hypertensive patient / Efecto hemorreológico de los diuréticos en el control de la presión arterial en el paciente hipertenso

Background: Diuretics are the first choice as an antihypertensive, because of its efficacy and cost, however its mechanism of action is not well understood. The aim of this work was to analyze the hemorrheological effect of the diuretics as vasodilators in patients with newly diagnosed arterial hypertension. Methods: Patients with hypertension were given diet and exercise recommendations and 25 mg of chlorthalidone per day were prescribed; Hemoglobin/hematocrit, viscosity, and basal nitric oxide (ON) were determined at 15 and 45 days and compared with healthy subjects. Results: We included 28 patients with average age of 48 years old; systolic blood pressure in the treated patients decreased from baseline at 15 days from 130 to 119 mm Hg and at 114 mmHg at 15 to 45 days; diastolic blood pressure decreased from baseline at 15 days from 103 to 97 mm Hg, and at 93 mmHg at 15 to 45 days. The hematocrit increased in both men and women with a statistical significance of the baseline period at 15 days, after that, it remained without significative changes. The viscosity increased similarly to the hematocrit, which conditioned the ON elevation. Conclusions: The increase in hematocrit due to diuretic caused an increase in blood viscosity, which led to an increase in nitric oxide, resulting in lower blood pressure.

Introducción: Los diuréticos son la primera elección como antihipertensivo por su eficacia y costo, sin embargo su mecanismo de acción no está bien esclarecido. El objetivo de este trabajo fue analizar el efecto hemorreológico del diurético como vasodilatador en pacientes con hipertensión arterial de reciente diagnóstico. Métodos: A los pacientes con hipertensión arterial se les dieron recomendaciones de dieta, ejercicio y se prescribió 25 mg de clortalidona al día; se determinaron hemoglobina/hematocrito, viscosidad y óxido nítrico (ON) basal, a los 15 y 45 días y se compararon con sujetos sanos. Resultados: Se incluyeron 28 pacientes, con edad promedio de 48 años; la presión arterial sistólica en los pacientes tratados descendió de la cifra basal a los 15 días de 130 a 119 mmHg, y a 114 mmHg de los 15 a los 45 días; la presión arterial diastólica descendió de la basal a los 15 días de 103 a 97 mmHg, y a 93 mmHg de los 15 a los 45 días . El hematocrito se incrementó en ambos géneros, con significancia estadística del período basal a los 15 días de tratamiento, posteriormente permaneció sin cambios. La viscosidad se incrementó de forma similar al hematocrito, lo que condicionó elevación del ON. Conclusiones: El incremento del hematocrito debido al diurético causó elevación de la viscosidad sanguínea, lo que condujo a incremento del óxido nítrico, repercutiendo en el descenso de la presión arterial.

A letter visual-similarity matrix for Latin-based alphabets.

Indicators of letter visual similarity have been used for controlling the design of empirical and neuropsychological studies and for rigorously determining the factors that underlie reading ability and literacy acquisition. Additionally, these letter similarity/confusability matrices have been useful for studies examining more general aspects of human cognition, such as perception. Despite many letter visual-similarity matrices being available, they all have two serious limitations if they are to be used by researchers in the reading domain: (1) They have been constructed using atypical reading data obtained from speeded reading-aloud tasks and/or under degraded presentation conditions; (2) they only include letters from the English alphabet. Although some letter visual-similarity matrices have been constructed using data gathered from normal reading conditions, these either are based on old fonts, which may not resemble the letters found in modern print, or were never published. For the first time, this article presents a comprehensive letter visual-similarity/confusability matrix that has been constructed based on untimed responses to clearly presented upper- and lowercase letters that are present in many languages that use Latin-based alphabets, including Catalan, Dutch, English, French, Galician, German, Italian, Portuguese, and Spanish. Such a matrix will be useful for researchers interested in the processes underpinning reading and literacy acquisition.

Diagnostics in assisted human reproduction.

The World Health Organization (WHO) estimates that 50-80 x 10(6) couples in the world are infertile, i.e. 7-15% of all couples of reproductive age (15-45 years old). The term infertility refers to couples who have been unable to conceive children for at least 1 year of regular unprotected intercourse. Although the frequency and origin of infertility varies, approximately 40-60% of the aetiology of infertility in the population studied is due to female causes. The introduction of assisted reproduction techniques, which offer couples the best opportunities for pregnancy, has opened a vast field of knowledge in reproductive biology. The medical history must be taken meticulously, with enough time to obtain the largest possible amount of relevant information. It is recommended that both partners be included in the initial work-up. In recent decades, technological progress has been favoured with the development of a great variety of diagnostic tests. Moreover, a very valuable tool helping to solve this problem has gained strength and is available to everybody - so-called 'evidence-based medicine'. There are three categories in infertility diagnostic tests. The first category includes tests showing a well-established correlation with pregnancy, e.g. semen analysis, tubal patency with hysterosalpingography or laparoscopy, and ovulation detection. The second category includes patients whose results are not consistently related to pregnancy. Here, these tests include sperm penetration assay in the zona-free hamster oocyte, post-coital tests, sperm penetration into cervical mucus, and tests to detect anti-sperm antibodies. The third group includes patients whose tests are not correlated with pregnancy. The relevant tests include endometrial biopsy, the presence of varicocele, and Chlamydia detection tests. Tests for infertility are often expensive. Since these patients are usually anxious and eager and will do almost anything to have a child, care must be taken to avoid exploitation of their hopes with unnecessary procedures. This text now reviews and updates the procedures used to investigate infertility.