Questions and answers in the management of children with medulloblastoma over the time. How did we get here? A systematic review.

Introduction: Treatment of children with medulloblastoma (MB) includes surgery, radiation therapy (RT) and chemotherapy (CT). Several treatment protocols and clinical trials have been developed over the time to maximize survival and minimize side effects. Methods: We performed a systematic literature search in May 2023 using PubMed. We selected all clinical trials articles and multicenter studies focusing on MB. We excluded studies focusing exclusively on infants, adults, supratentorial PNETs or refractory/relapsed tumors, studies involving different tumors or different types of PNETs without differentiating survival, studies including <10 cases of MB, solely retrospective studies and those without reference to outcome and/or side effects after a defined treatment. Results: 1. The main poor-prognosis factors are: metastatic disease, anaplasia, MYC amplification, age younger than 36 months and some molecular subgroups. The postoperative residual tumor size is controversial. 2. MB is a collection of diseases. 3. MB is a curable disease at diagnosis, but survival is scarce upon relapse. 4. Children should be treated by experienced neurosurgeons and in advanced centers. 5. RT is an essential treatment for MB. It should be administered craniospinal, early and without interruptions. 6. Craniospinal RT dose could be lowered in some low-risk patients, but these reductions should be done with caution to avoid relapses. 7. Irradiation of the tumor area instead of the entire posterior fossa is safe enough. 8. Hyperfractionated RT is not superior to conventional RT 9. Both photon and proton RT are effective. 10. CT increases survival, especially in high-risk patients. 11. There are multiple drugs effective in MB. The combination of different drugs is appropriate management. 12. CT should be administered after RT. 13. The specific benefit of concomitant CT to RT is unknown. 14. Intensified CT with stem cell rescue has no benefit compared to standard CT regimens. 15. The efficacy of intraventricular/intrathecal CT is controversial. 16. We should start to think about incorporating targeted therapies in front-line treatment. 17. Survivors of MB still have significant side effects. Conclusion: Survival rates of MB improved greatly from 1940-1970, but since then the improvement has been smaller. We should consider introducing targeted therapy as front-line therapy. 1 Introductionpost-print5468 K

Length of the artificial incubation in red-legged partridge (Alectoris rufa)

La incubación artificial de los huevos es una fase del manejo clave para la viabilidad de las granjas cinegéticas de perdiz roja (Alectoris rufa). Sin embargo, la duración de la incubación artificial y la dispersión de las eclosiones no han sido previamente cuantificadas en esta especie. Con este objetivo se analizaron cuatro ensayos de incubación artificial de huevos de perdiz roja procedentes de tres granjas cinegéticas del sur de España realizados incluyendo variabilidad de factores de manejo de los reproductores y de la incubación. La duración media de la incubación fue de 23,4 días, difiriendo entre ensayos (P = 0,004), con un valor modal de 23 días y finalizando la mayoría de las eclosiones (percentil 95) el día 24,5 de incubación. La eclosión mostró una distribución asimétrica positiva y leptocúrtica, como corresponde al patrón de eclosión de las especies precociales. Las eclosiones, que pueden comenzar el día 21,5 y finalizar el día 26 de incubación, se extendieron en promedio durante cuatro días, periodo mayor que el descrito en la literatura divulgativa probablemente porque en el presente estudio los huevos no estuvieron en contacto entre sí, lo que pudo limitar la sincronía en la eclosión. Los resultados de este estudio son útiles para conocer la distribución de la eclosión en las granjas cinegéticas de perdiz roja, posibilitando la mejora del manejo de los lotes de huevos en la nacedoraThe artificial incubation of the eggs is a key management phase for the feasibility of the red-legged partridge (Alectoris rufa) game farms. However, the length of the artificial incubation and the spreading pattern of the hatching have not been previously quantified in this species. To this end, four trials of artificial incubation of eggs from three red-legged partridge game farms located in southern Spain were analised. The trials included a wide range of variability with regard to management of breeders and incubation process. The average length of the incubation period was 23.4 days, with differences among trials (P = 0,004), showing a modal value of 23 days. Most of the chicks (percentile 95) hatched before 24.5 days of incubation. The distribution of the hatch was leptokurtic and showed positive asymmetry, fitting with the hatching pattern of the precocial species. The hatching, that can start on day 21.5 and finish on day 26 of incubation, were spread over four days on average. This period was longer than that described in the informative literature, probably because in the present study the eggs were not in contact with each other, which could have limited the hatching synchrony. The results of the present study are useful to understand the distribution of hatching in the red-legged game farms, enabling improved management of the batches of eggs in the hatchery

226Ra, 228Ra and 40K as tracers of erosion and accumulation processes: A 3-year study on a beach with different sediment dynamics

The aim of this study is to analyse the role of natural radionuclides 226Ra, 228Ra, 40K and unsupported 210Pb (210Pbex), as erosion and accumulation process tracers. For this purpose, a complex system, including both the characteristic dynamics of a closed beach and those associated with a beach open to wave action, was studied. A 3-year study of monthly variation of 226Ra, 228Ra, 40K and 210Pbex was carried out at Las Canteras beach, on the Island of Gran Canaria (Spain), covering several erosion and accumulation periods. A correlation analysis, ANOVA test and Tukey’s Honestly Significant Difference (HSD) Test proved that the marine erosion and accumulation agents influenced the activity concentration values found for the different radionuclides. Moreover, the geochemical analysis of samples from maximum and minimum activity concentration values showed that the natural radionuclides studied could be suitable tracers for studying beach sediment dynamics in erosion and accumulation periods

Tight blood pressure control decreases apoptosis during renal damage

Tight blood pressure control decreases apoptosis during renal damage.BackgroundAn excess rate of apoptosis could lead to the gradual loss of renal mass. In this study, we investigated the role of apoptosis in the renal damage secondary to hypertension.MethodsSpontaneously hypertensive rats with 5/6 renal mass reduction (subtotal nephrectomy) were distributed to receive no-treatment, 200mg/L quinapril, 360mg/L losartan, or triple therapy (200mg/L hydralazine, 4mg/L reserpine, and 100mg/L hydrochlorothiazide) for 5weeks. Sham-operated spontaneously hypertensive rats served as controls. Age-matched Wistar-Kyoto (WKY) rats, with or without subtotal nephrectomy, were also studied.ResultsNontreated spontaneously hypertensive rats + subtotal nephrectomy developed proteinuria, glomerular sclerosis, and tubulointerstitial lesions. In comparison to spontaneously hypertensive rats, an increment in the number of [proliferating cell nuclear antigen (PCNA)]-positive and apoptotic [terminal deoxynucleotidyl transferase (Tdt)-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL)]-positive tubular and glomerular cells was observed. By contrast, WKY + subtotal nephrectomy rats showed less severe morphologic lesions, and only the number of proliferating cells increased. By Western blot, an up-regulation of renal Bax (apoptosis inducer) was noted both in spontaneously hypertensive rats + subtotal nephrectomy and WKY + subtotal nephrectomy rats. By contrast, Bcl-xL (apoptosis protector) was up-regulated in WKY + subtotal nephrectomy rats but not in spontaneously hypertensive rats + subtotal nephrectomy. The administration of appropriate doses of quinapril, losartan, or triple therapy to spontaneously hypertensive rats + subtotal nephrectomy normalized systolic blood pressure, partially prevented proteinuria, renal lesions and apoptosis, and decreased Bax, but no changes were noted in Bcl-xL. The Bax/Bcl-xL index was significantly increased in spontaneously hypertensive rats + subtotal nephrectomy compared to sham-operated spontaneously hypertensive rats and decreased in treated groups.ConclusionThe combination of renal mass reduction and hypertension caused severe renal lesions associated to an increment of apoptosis rate, mainly in tubular epithelial cells. Tight blood pressure control decreased the apoptosis rate and morphologic lesions. These studies suggest that changes in the expression of apoptosis-regulatory genes contribute to the progressive damage in hypertensive rats with renal mass reduction

Randomised clinical trial and meta-analysis: mesalazine treatment in irritable bowel syndrome—effects on gastrointestinal symptoms and rectal biomarkers of immune activity

Background Low-grade immune activation in the gut is a potential treatment target in irritable bowel syndrome (IBS). Aims To determine improvement in IBS symptoms after mesalazine treatment, and the utility of measures of immune activity in the rectal mucosa Methods This was a randomised, double-blind, placebo-controlled, parallel-arm, multicentre trial in subjects with IBS (Rome III criteria), with an eight-week treatment period of mesalazine 2400 mg or plcebo once-daily. The primary endpoint was the global assessment of satisfactory relief of IBS symptoms in ≥50% of weeks during intervention. IBS symptoms were also measured with the IBS severity scoring system; immune activity was measured by mucosal patch technology. A post hoc meta-analysis of randomised placebo-controlled trials of mesalazine in IBS was added. Results Of 181 included patients, 91 received mesalazine and 90 received placebo. The primary endpoint was met by 32 (36%) patients after mesalazine and 27 (30%) after placebo (p = 0.40). There were no differences in response rates related to IBS subtype or post-infection symptom onset. More reduction of abdominal bloating was noted in the mesalazine group (p = 0.02). The meta-analysis showed no effect of mesalazine on IBS symptoms. No mucosal patch technology measure could predict response to mesalazine, and found no differences in the effects of intervention on levels of immune markers. Conclusions Mesalazine is ineffective in reducing IBS symptoms. Rectal measures of immune activity by the mucosal patch technology cannot predict a higher chance of response to mesalazine.publishedVersio

On the use of numerical models to predict/mitigate indoor radon levels in highly contaminated areas

The publication of the EURATOM directive BSS 2013/59 [1] has increased considerably the interest on radon studies in all EU countries. Certainly each member state has to establish a national action plan addressing long-term risks from radon exposures in dwellings, buildings with public access and workplaces for any source of radon ingress, whether from soil, building materials or water. The complexity generated by the number of parameters and processes affecting radon generation in the source, transport in source media, entry into dwellings, and its accumulation in the different rooms of the dwelling, makes the development of numerical models a very challenging exercise that might take also into account that the detailed information of the building-soil interface in an existing dwelling is normally not available. A new project funded by the Spanish Nuclear Safety Board (CSN) started in 2020. Its main goal is to establish and validate a numerical tool to predict and mitigate indoor radon levels in new and existing buildings in general, but paying special attention to the case of areas contaminated due to NORM industrial activities. Such a numerical tool might be of interest for Radiation Protection authorities to manage highly contaminated areas. In particular, 2 different numerical modelling strategies will be adapted to real sites and compared. The RAGENA [2] code, which was developed in the late 90s, will be updated with the last findings from experimental studies. This code allows modelling all radon sources and processes affecting radon accumulation indoors from a dynamic point of view in a very simple way, but lacks from spatial resolution. On the other hand, a CFD (computational fluid dynamics) model recently developed in Spain [3] numerically solves radon transport equation by finite elements with a good spatial resolution. The project focuses also on the experimental characterization of real sites. In this talk we will introduce the project, discuss the main features of both modelling approaches and describe in more detail the current status of the RAGENA code updating

The effect of dietary fish oil on weight gain and insulin sensitivity is dependent on APOE genotype in humanized targeted replacement mice

We investigated the independent and interactive impact of the common APOE genotype and marine n-3 polyunsaturated fatty acids (PUFA) on the development of obesity and associated cardiometabolic dysfunction in a murine model. Human APOE3 and APOE4 targeted replacement mice were fed either a high-fat control diet (HFD) or a HFD supplemented with 3% n-3 PUFA from fish oil (HFD + FO) for 8 wk. We established the impact of intervention on food intake, bodyweight, and visceral adipose tissue (VAT) mass; plasma, lipids (cholesterol and triglycerides), liver enzymes, and adipokines; glucose and insulin during an intraperitoneal glucose tolerance test; and Glut4 and ApoE expression in VAT. HFD feeding induced more weight gain and higher plasma lipids in APOE3 compared to APOE4 mice (P < 0.05), along with a 2-fold higher insulin and impaired glucose tolerance. Supplementing APOE3, but not APOE4, animals with dietary n-3 PUFA decreased bodyweight gain, plasma lipids, and insulin (P < 0.05) and improved glucose tolerance, which was associated with increased VAT Glut4 mRNA levels (P < 0.05). Our findings demonstrate that an APOE3 genotype predisposes mice to develop obesity and its metabolic complications, which was attenuated by n-3 PUFA supplementation.—Slim, K. E., Vauzour, D., Tejera, N., Voshol, P. J., Cassidy, A., Minihane, A. M. The effect of dietary fish oil on weight gain and insulin sensitivity is dependent on APOE genotype in humanized targeted replacement mice

La diversidad palinológica y los cambios climáticos en el Paleozoico Superior en Brasil y Uruguay

We have analysed the diversity of the late Paleozoic palynoflora of the Paraná (Brazil and Uruguay), Parnaíba and Amazon (Brazil) basins using already published data. In order to do this the total diversity and diversity with range-through approach curves were built up, as well as Foote’s appearance and disappearance rates at the generic level. These parameters were also obtained separately for each group of sporomorphs. An important increase in diversity in the Asselian and Sakmarian and a posterior decrease until the Lopingian were observed. The values of the appearance rates were higher than those of disappearance and they peaked in the Asselian, while the highest disappearances took place in the Capitanian and, to a lesser extent, in the Sakmarian. On the other hand, spores and pollen grains show some differences in the general diversity trend. However, there are differences in the patterns of appearance and disappearance. Despite possible biases, mainly related to the collecting effort, the diversity curves and appearance and disappearance rates obtained are congruent with the climatic phases proposed for this region in these periods. The increase in the number of palynomorph genera is associated to the early Permian climatic amelioration whilst a decrease in diversity is related to the beginning of an arid phase.Se analizó la diversidad de la palinoflora correspondiente a estratos del Paleozoico superior de las cuencas de Paraná (Brasil y Uruguay), Parnaíba y Amazonas (Brasil), utilizando datos previamente publicados. Se elaboraron curvas de diversidad total y diversidad calculadas mediante el método range-through y se calcularon los índices de aparición y desaparición de los diferentes géneros utilizando como herramienta el índice de Foote. También se analizaron esos parámetros en diferentes grupos de esporomorfos por separado. Se observó un aumento importante de la diversidad en el Asseliano y Sakmariano y una posterior disminución gradual hasta el Lopingiano. Los valores de los índices de aparición fueron más importantes que los de desaparición y se dieron en el Asseliano, mientras que las mayores desapariciones se observaron en el Capitaniano y en menor medida en el Sakmariano. Por otra parte, las esporas y los granos de polen presentan algunas diferencias en la tendencia general de diversidad. Sin embargo, se aprecian diferencias en los patrones de aparición y desaparición. A pesar de los posibles sesgos, fundamentalmente relacionados con el esfuerzo de colecta, existe cierta coherencia entre la diversidad, los índices de apariciones y desapariciones y las fases climáticas propuestas para esa edad en la región. El cambio hacia un clima más templado ocurrido en el Pérmico inferior estaría asociado a un aumento en el número de géneros de palinomorfos mientras que el comienzo de una fase más árida estaría relacionado a una disminución en la diversidad