Complications and mortality of Cushing’s disease: report on data collected over a 20-year period at a referral centre

Context: Cushing’s disease (CD) is rare condition burdened by several systemic complications correlated to higher mortality rates. The primary goal of clinicians is to achieve remission, but it is unclear if treatment can also increase life expectancy. Aim: To assess the prevalence of cortisol-related complications and mortality in a large cohort of CD patients attending a single referral centre. Materials and methods: The clinical charts of CD patients attending a referral hospital between 2001 and 2021 were reviewed. Results: 126 CD patients (median age at diagnosis 39 years) were included. At the last examination, 78/126 (61.9%) of the patients were in remission regardless of previous treatment strategies. Patients in remission showed a significant improvement in all the cardiovascular (CV) comorbidities (p < 0.05). The CV events were more frequent in older patients (p = 0.003), smokers and persistent CD groups (p < 0.05). Most of the thromboembolic (TE) and infective events occurred during active stages of the disease. The CV events were the most frequent cause of death. The standardized mortality ratio (SMR) resulted increased in persistent cases at the last follow-up (SMR 4.99, 95%CI [2.15; 9.83], p < 0.001) whilst it was not higher in those in remission (SMR 1.66, 95%CI [0.34; 4.85], p = 0.543) regardless of the timing or number of treatments carried out. A younger age at diagnosis (p = 0.005), a microadenoma (p = 0.002), and remission status at the last follow-up (p = 0.027) all increased survival. Furthermore, an elevated number of comorbidities, in particular arterial hypertension, increased mortality rates. Conclusions: Patients with active CD presented a poor survival outcome. Remission restored the patients’ life expectancy regardless of the timing or the types of treatments used to achieve it. Persistent CD-related comorbidities remained major risk factors

Tratamiento biológico de lixiviados de residuos sólidos urbanos con estiércol porcino

La fracción orgánica de los residuos sólidos urbanos como pecuarios son fuentes de contaminación, produciendo un impacto por significar un vector de enfermedades. En el presente trabajo se investiga el tratamiento anaeróbico de los residuos resultantes-de la actividad pecuaria mezclados con los lixiviados de la fracción orgánica provenientes de una feria de frutas y verduras municipal, con una relación DQO/N=17,75 y N/P=9. Se comparó este sustrato con medio sintético con una relación DQO/N=34,35 y N/P=7,99. La remoción de DQO obtenida al cabo de quince días para la mezcla de lixiviados fue de 23,78 %, con una producción de gas metano del 70 %. El método de tratamiento en estudio es factible de realizar. Para lograr un aumento de remoción de DQO es necesario mejorar la relación DQO/N aportando materia orgánica extra o disminuyendo la cantidad de nitrógeno con un post-tratamiento.Tema: Tratamiento de efluentes. Biomasa.Asociación Argentina de Energía Sola

Tratamiento biológico de lixiviados de residuos sólidos urbanos con estiércol porcino

La fracción orgánica de los residuos sólidos urbanos como pecuarios son fuentes de contaminación, produciendo un impacto por significar un vector de enfermedades. En el presente trabajo se investiga el tratamiento anaeróbico de los residuos resultantes-de la actividad pecuaria mezclados con los lixiviados de la fracción orgánica provenientes de una feria de frutas y verduras municipal, con una relación DQO/N=17,75 y N/P=9. Se comparó este sustrato con medio sintético con una relación DQO/N=34,35 y N/P=7,99. La remoción de DQO obtenida al cabo de quince días para la mezcla de lixiviados fue de 23,78 %, con una producción de gas metano del 70 %. El método de tratamiento en estudio es factible de realizar. Para lograr un aumento de remoción de DQO es necesario mejorar la relación DQO/N aportando materia orgánica extra o disminuyendo la cantidad de nitrógeno con un post-tratamiento.Tema: Tratamiento de efluentes. Biomasa.Asociación Argentina de Energía Sola

The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of gsp(-) somatotropinomas

Glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression has been recently described in a proportion of gsp(-) somatotropinomas and suggested to be associated with the paradoxical increase of GH (GH-PI) during an oral glucose load

The effects of iodine supplementation in pregnancy on iodine status, thyroglobulin levels and thyroid function parameters: Results from a randomized controlled clinical trial in a mild-to-moderate iodine deficiency area

Background: Iodine supplementation during pregnancy in areas with mild-to-moderate iodine deficiency is still debated. Methods: A single-center, randomized, single-blind and placebo-controlled (3:2) trial was conducted. We enrolled 90 women before 12 weeks of gestation. From enrollment up until 8 weeks after delivery, 52 women were given an iodine supplement (225 ug/day, potassium iodide tablets) and 38 were given placebo. At recruitment (T0), in the second (T1) and third trimesters (T2), and 8 weeks after delivery (T3), we measured participants\u2019 urinary iodine-to-creatinine ratio (UI/Creat), thyroid function parameters (thyroglobulin (Tg), TSH, FT3, and FT4), and thyroid volume (TV). The newborns\u2019 urinary iodine concentrations were evaluated in 16 cases. Results: Median UI/Creat at recruitment was 53.3 ug/g. UI/Creat was significantly higher in supplemented women at T1 and T2. Tg levels were lower at T1 and T2 in women with UI/Creat 65 150 ug/g, and in the Iodine group at T2 (p = 0.02). There was a negative correlation between Tg and UI/Creat throughout the study (p = 0.03, r = 120.1268). A lower TSH level was found in the Iodine group at T3 (p = 0.001). TV increased by + 067.43% in the Iodine group, and by + 0611.17% in the Placebo group. No differences were found between the newborns\u2019 TSH levels on screening the two groups. Conclusion: Tg proved a good parameter for measuring iodine intake in our placebo-controlled series. Iodine supplementation did not prove harmful to pregnancy in areas of mild-to-moderate iodine deficiency, with no appreciable harmful effect on thyroid function

Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure

Microglia are highly plastic immune cells which exist in a continuum of activation states. By shaping the function of oligodendrocyte precursor cells (OPCs), the brain cells which differentiate to myelin-forming cells, microglia participate in both myelin injury and remyelination during multiple sclerosis. However, the mode(s) of action of microglia in supporting or inhibiting myelin repair is still largely unclear. Here, we analysed the effects of extracellular vesicles (EVs) produced in vitro by either pro-inflammatory or pro-regenerative microglia on OPCs at demyelinated lesions caused by lysolecithin injection in the mouse corpus callosum. Immunolabelling for myelin proteins and electron microscopy showed that EVs released by pro-inflammatory microglia blocked remyelination, whereas EVs produced by microglia co-cultured with immunosuppressive mesenchymal stem cells promoted OPC recruitment and myelin repair. The molecular mechanisms responsible for the harmful and beneficial EV actions were dissected in primary OPC cultures. By exposing OPCs, cultured either alone or with astrocytes, to inflammatory EVs, we observed a blockade of OPC maturation only in the presence of astrocytes, implicating these cells in remyelination failure. Biochemical fractionation revealed that astrocytes may be converted into harmful cells by the inflammatory EV cargo, as indicated by immunohistochemical and qPCR analyses, whereas surface lipid components of EVs promote OPC migration and/or differentiation, linking EV lipids to myelin repair. Although the mechanisms through which the lipid species enhance OPC maturation still remain to be fully defined, we provide the first demonstration that vesicular sphingosine 1 phosphate stimulates OPC migration, the first fundamental step in myelin repair. From this study, microglial EVs emerge as multimodal and multitarget signalling mediators able to influence both OPCs and astrocytes around myelin lesions, which may be exploited to develop novel approaches for myelin repair not only in multiple sclerosis, but also in neurological and neuropsychiatric diseases characterized by demyelination

Mitotane concentrations influence outcome in patients with advanced adrenocortical carcinoma

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for 653 months, with 653 measurements of plasma mitotane reported in the Lysosafe Online\uae database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane

Four domains for concurrency

AbstractWe give four domains for concurrency in a uniform way by means of domain equations. The domains are intended for modelling the four possible combinations of linear time versus branching time, and of interleaving versus noninterleaving concurrency. We use the linear time, noninterleaved domain to give operational and denotational semantics for a simple concurrent language with recursion, and prove that O = D

Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension

Objective To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11β-hydroxylase inhibitor, for treating Cushing’s disease (CD). Design/methods A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) > 1.5 × upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received ≥ 72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline. Results Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1–245) and median average dose was 7.4 mg/day (range 0.8–46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained ≤ ULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC ≤ ULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension. Conclusions Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated