Gender-Related Differences in the Presentation and Course of Cushing's Disease

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NEMO: A flexible and highly scalable network EMulatOr

Evaluating novel applications and protocols in realistic scenarios has always been a very important task for all stakeholders working in the networking field. Network emulation, being a trade-off between actual deployment and simulations, represents a very powerful solution to this issue, providing a working network platform without requiring the actual deployment of all network components. We present NEMO, a flexible and scalable Java-based network emulator, which can be used to emulate either only a single link, a portion of a network, or an entire network. NEMO is able to work in both real and virtual time, depending on the tested scenarios and goals, and it can be run as either a stand-alone instance on a single machine, or distributed among different network-connected machines, leading to distributed and highly scalable emulation infrastructures. Among different features, NEMO is also capable of virtualizing the execution of third-party Java applications by running them on top of virtual nodes, possibly attached to an emulated or external network. Keywords: Network emulation, Protocol stack, Jav

Expansion of Ash Dieback towards the scattered Fraxinus excelsior range of the Italian peninsula

AbstractHymenoscyphus fraxineus, causal agent of Ash Dieback, has posed a threat to Fraxinus excelsior (common ash) in Europe since the 1990s. In south-western Europe, optimal climatic conditions for H. fraxineus become scattered and host density decreases, reducing disease spread rates. To date, the Ash Dieback agent has not been reported from southern and most of central Italy, where native F. excelsior is present as small fragmented populations. This study examines the expansion of Ash Dieback into central Italy, and it considers the consequences of further local spread with regards to the loss of F. excelsior genetic resource. Symptomatic F. excelsior were sampled from sixteen sites in northern and central Italy during 2020. Specimens were analyzed with a culturomics and a quantitative PCR approach. A bibliographic search of F. excelsior floristic reports was conducted for the creation of a detailed range map. The combined use of both techniques confirmed the presence of H. fraxineus in all the sites of central Italy where host plants were symptomatic. These new records represent the southern limit of the current known distribution of this pathogen in Italy, and together with Montenegro, in Europe. The characterization of the F. excelsior scattered range suggests that further spread of Ash Dieback across southern Italy is a realistic scenario. This presents a threat not just to the southern European proveniences of F. excelsior, but to the species as a whole, should Ash Dieback lead to the loss of warm climate adapted genetic material, which may become increasingly valuable under climate change

Effect of retinoic acid on human adrenal corticosteroid synthesis.

AbstractAimsRetinoic acid has recently yielded promising results in the treatment of Cushing's disease, i.e., excess cortisol secretion due to a pituitary corticotropin (ACTH)-secreting adenoma. In addition to its effect on the tumoral corticotrope cell, clinical results suggest an additional adrenal site of action. Aim of this study was to evaluate whether retinoic acid modulates cortisol synthesis and secretion by human adrenals in vitro.Main methodsPrimary cultures from 10 human adrenals specimens were incubated with 10nM, 100nM and 1μM retinoic acid with and without 10nM ACTH for 24h. Cortisol levels were measured by radioimmunoassay and CYP11A1, STAR and MC2R gene expression analyzed by real-time PCR.Key findingsRetinoic acid increased cortisol secretion (149.5±33.01%, 151.3±49.45% and 129.3±8.32% control secretion for 10nM, 100nM and 1μM respectively, p<0.05) and potentiated STAR expression (1.51±0.22, 1.56±0.15 and 1.59±0.14 fold change over baseline, for 10nM, 100nM and 1μM respectively, p<0.05). Concurrently, retinoic acid markedly blunted constitutional and ACTH-induced MC2R expression (0.66±0.11, 0.62±0.08 and 0.53±0.07 fold change over baseline, for 10nM, 100nM and 1μM respectively, p<0.05; 0.71±0.10, 0.51±0.07 and 0.51±0.08 fold change over ACTH alone, for 10nM, 100nM and 1μM respectively, p<0.05). No effect on CYP11A1 was observed.SignificanceRetinoic acid stimulates cortisol synthesis and secretion in human adrenals and at the same time markedly blunts ACTH receptor transcription. These results reveal a novel, adrenal effect of retinoic acid which may contribute to its efficacy in patients with Cushing's disease

85 years counteracting an invasion: chestnut ecosystems and landscapes survival against ink disease

A retrospective examination of early pest and disease outbreaks, such as ink disease, offers new insights into their impact on ecosystems and landscapes. Ink disease, caused by Phytophthora spp., is one of the most destructive diseases affecting Castanea sativa Mill. It first appeared in Europe in the early 18th century, with the initial recorded case in Italy (Piedmont) dating back to 1845. However, its spread instilled significant concerns in several chestnut-growing regions primarily devoted to fruit production. In 1938, a comprehensive assessment of Phytophthora xcambivora outbreaks was conducted in the Bolognese Apennines (Italy), providing a detailed overview of chestnut cultivation status. Thirty-six disease foci were documented, and laboratory tests confirmed the presence of ink disease. To understand the disease’s impact on chestnut ecosystem and landscape over the past 85 years, the 1938 sites were revisited to assess chestnut persistence and phytosanitary status, with Phytophthora species detected using isolation and molecular techniques. Monitoring data revealed that C. sativa still thrives in all but one site, with its wood seemingly able to coexist in dynamic equilibrium with the disease. While P. xcambivora was still detected in several foci, the extent of damage appeared limited. The potential for natural control, likely influenced by the complexity of soil biota, along with the natural spread of hypovirulence in chestnut blight and biological control of the Asian chestnut gall wasp, could explain the continued presence of chestnut in the investigated area and potentially throughout the Italian chestnut range, despite nearly two centuries of ink disease prevalence. Nevertheless, ongoing monitoring is essential to dynamically comprehend the factors at play and their efficacy, particularly in the context of climate change and the possible spread of other Phytophthora species. The survival of chestnut ecosystems amidst ink disease underscores the preservation of the economic, ecological, and landscape values associated with these woodland

No Untoward Effect of Long-Term Ketoconazole Administration on Electrocardiographic QT Interval in Patients with Cushing's Disease.

Ketoconazole is listed among drugs that prolong QT interval and may increase the risk of torsade de pointes, a severe ventricular arrhythmia. This compound has recently been approved for treatment of Cushing's syndrome, a severe endocrine disorder. These patients harbour several risk factors for prolonged QT interval, for example hypokalaemia and left ventricular hypertrophy, but no study has evaluated whether administration of ketoconazole affects their QT interval. The aim of this study was to assess the QT interval in patients with Cushing's disease during long-term administration of ketoconazole. Electrocardiograms from 15 patients with Cushing's disease (12 women, 3 men, age: 37.8 ± 2.66 years) on ketoconazole treatment (100 mg-800 mg qd) for 1 month to 12 years were reviewed retrospectively. QT interval was measured and corrected for heart rate (QTc). Measurements before and during ketoconazole treatment were compared and any abnormal QTc value recorded. Concurrent medical therapies were also documented. On average, QTc was superimposable before and during ketoconazole treatment (393.2 ± 7.17 versus 403.3 ± 6.05 msec. in women; 424.3 ± 23.54 versus 398.0 ± 14.93 msec. in men, N.S.). QTc normalized on ketoconazole in one man with prolonged QTc prior to treatment; no abnormal QTc was observed in any other patient during the entire observation period, even during concurrent treatment with other QT-prolonging drugs. In conclusion, long-term ketoconazole administration does not appear to be associated with significant prolongation of QT interval in patients with Cushing's disease. ECG monitoring can follow recommendations drawn for other low-risk QT-prolonging drugs with attention to specific risk factors, for example hypokalaemia and drug interactions

Specificity and Sensitivity of a Rapid LAMP Assay for Early Detection of Emerald Ash Borer (Agrilus planipennis) in Europe

Buprestids are an emerging threat to broadleaf forests across the world. Species such as emerald ash borer (EAB, Agrilus planipennis) seriously threaten ash (Fraxinus spp.) in North America and Europe. As it continues spreading west from European Russia, native European ash populations will suffer dramatic losses. Due to their cryptic lifestyle of the egg and larval stages on developing bark and vascular tissue, buprestids and other wood borers can be difficult to detect. Early detection tools are vital to implement fast eradication measures, and prevent the establishment of invasive species populations. Detection methods using polymerase chain reaction (PCR) assays to target specific taxa can be extremely timely to obtain results especially since samples need to be transported to the laboratory first. However, loop-mediated isothermal amplification (LAMP) eDNA assays are highly specific and sensitive providing results within 30 min after sample extraction. In this study, we investigated the specificity and sensitivity of an EAB LAMP assay as an early detection tool in Europe. The assay was specific to EAB when tested against 12 European Agrilus spp., five buprestids, two Scolytinae, and five cerambycids (n = 24). The LAMP assay sensitivity amplified DNA from a concentration as low as 0.02 pg/mu L. These results demonstrate that the LAMP assay is a highly specific, sensitive tool that can be used to detect and monitor EAB in European forests and urban settings

Volatile organic compounds (VOC) as biomarkers for detection of Ceratocystis platani

AbstractCeratocystis platani causes canker stain of plane trees, and it represents a serious disease of Platanus spp. both in the United States and Europe. Current chemical or biological controls do not effectively manage C. platani, so new preventive methods need to be developed in order to limit this pathogen spreading. In this work, we have characterized the main volatile organic compounds (VOC) emitted in vitro from pure cultures of C. platani and other common pathogenic fungal species of hosts plants growing in the same ecosystems as plane trees. We found that C. platani emitted a similar blend of VOC compared with phylogenetically similar species C. populicola. In particular, C. platani was characterized by emission of isoamyl acetate and isobutyl acetate while C. populicola by ethyl acetate and isobutyl acetate, which were not released by any of the other out‐group fungal species grown on the same medium. Moreover, following a targeted approach based on the main VOC found in vitro, we have successfully validated in vivo that VOC uniquely emitted by C. platani (i.e. isobutyl acetate along with isoamyl alcohol) were released from the bark of plane trees following C. platani inoculation. Our results highlight the possibility to exploit VOC emitted specifically by C. platani as biomarkers to recognize Platanus x acerifolia plants infected by this pathogen

A homogeneous treatment for non-DIPG diffuse midline glioma

Introduction: The H3K27M-mutant diffuse midline glioma (DMG) was first included in the World Health Organization (WHO) Classification of central nervous system (CNS) tumors in 2016, and confirmed in its fifth edition. The biological behavior and dismal prognosis of this tumor resemble diffuse intrinsic pontine gliomas (DIPG). Homogeneously-treated series are rarely reported. Methods: From 2016 onwards, we treated patients with DMG with radiotherapy and concomitant/adjuvant nimotuzumab/vinorelbine, plus re-irradiation at relapse, as already done for DIPG. Results: We treated nine patients, seven females, with a median age at diagnosis of 13 years. Tumor sites were: thalamic in five cases, pontocerebellar in two, pineal in one, and paratrigonal with nodular/leptomeningeal dissemination in one. Three patients were biopsied, and six had partial tumor resections. Central pathological review was always performed. The median time to local progression was 12.7 months, and the median overall survival was 17.8 months. Six patients died of tumor progression, one of cerebral bleeding at progression. Two were alive, one in continuous remission, the other after relapsing, at 38.6 and 46.3 months after diagnosis. Progression-free survival was 33.3% at one year. Overall survival was 88.9%, 33.3% and 22.2% at 1, 2 and 3 years, respectively. Conclusions: This is a small series of homogeneously-treated DMG patients. The results obtained are comparable with those of DIPG patients. Given the phenotypically- and molecularly-defined setting of DMG and severe outcome in this orphan population, they should be treated and included in registries and protocols of DIPG