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Purpose: Nonfunctioning pituitary adenomas (NFPAs) are benign tumors growing in the sellar region. Total surgical excision of the lesion is recommended as the preferred treatment choice with preservation of adjacent structures. The objective is to establish a radiological score to predict the feasibility of NFPA total surgical excision. Methods: Patients with treatment-naïve NFPA who underwent a transsphenoidal approach and sellar magnetic resonance imaging (MRI) in the preoperative period and 3 months after surgery were included. Data on age, sex, tumor diameter, extrasellar extension, postoperative cure rates, and hormone and transcription factor expression were collected. A combined score was proposed based on Knosp and SIPAP classifications. We proposed 3 classification groups depending on the tumoral extension to the suprasellar, infrasellar, anterior and posterior directions of the sellar region. Results: A total of 164 patients were included in the study, and 85 (52%) were female. Total excision was obtained in 46% (n= 75) of the patients. The majority of tumors were of gonadotrophic lineage (59%), followed by corticotrophic (17%) and other less common types. Largest tumor diameter was 6.8 cm [mean 3.8 cm (± 1.1 cm)]. From the established groups, 10 patients were classified in Group I, of whom 8 (80%) patients underwent total excision, 115 patients were classified in Group II, of whom 58 (50%) underwent complete excision and 39 patients in Group III, of whom 9 (23%) underwent complete excision (p value < 0.001). Conclusion: The newly proposed score helps to determine the feasibility of total NFPA excision, allowing for better surgical planning and predictions of postoperative outcomes.

Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype.

In neuroinflammation, astrocytes play multifaceted roles that regulate the neuronal environment. Astrocytes sense and respond to pro-inflammatory cytokines (CKs) and, by a repertoire of intracellular Ca2+signaling, contribute to disease progression. Therapeutic approaches wish to reduce the overactivation in Ca2+signaling in inflammatory-reactive astrocytes to restore dysregulated cellular changes. Cell-targeting therapeutics might take advantage by the use of nanomaterial-multifunctional platforms such as graphene oxide (GO). GO biomedical applications in the nervous system involve therapeutic delivery and sensing, and GO flakes were shown to enable interfacing of neuronal and glial membrane dynamics. We exploit organotypic spinal cord cultures and optical imaging to explore Ca2+changes in astrocytes, and we report, when spinal tissue is exposed to CKs, neuroinflammatory-associated modulation of resident glia. We show the efficacy of GO to revert these dynamic changes in astrocytic reactivity to CKs, and we translate this potential in an animal model of immune-mediated neuroinflammatory disease.

ABSTRACTIs Covid-19 undermining European democracies? Recent scholarship overlooks the fact that most pandemic-related erosions of democracy can be attributed to illiberal inertia long in place before 2019. Did the democratic decay occur during the pandemic or due to the pandemic? We analyse the extent to which pandemic power grabs succeeded and failed in Europe with special attention to the Czech Republic, Hungary, Poland, and Slovakia. The executive power of the purse was an opportunity to abuse state resources. Governments that engage in the “pandemic heist” with impunity can be directly linked to a power grab due to the pandemic.

ABSTRACTWe take the demand-side perspective of Sputnik V, trying to answer why facing vaccine scarcity, some countries opt for Sputnik V, and others do not. To show how the pandemic tests the institutional safeguards and soft guardrails of liberal democracy, we compiled a unique dataset and combined statistical analysis and case studies. While our quantitative analysis shows that the illiberalism of the party in power is the main explanatory factor in the import of Sputnik V, our qualitative case studies illustrate under what conditions institutional guardrails withstand the pressure of populist and illiberal leaders.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.Graphical Abstract

Frailty is a health condition leading to many adverse clinical outcomes. The relationship between frailty and advanced age, multimorbidity and disability has a significant impact on healthcare systems. Frailty increases cardiovascular (CV) morbidity and mortality both in patients with or without known CV disease. Though the recognition of this additional risk factor has become increasingly clinically relevant in CV diseases, uncertainty remains about operative definitions, screening, assessment, and management of frailty. Since the burdens of frailty components and domains may vary in the various CV diseases and clinical settings, the relevance of specific frailty-related aspects may be different. Understanding these issues may allow general cardiologists a clearer focus on frailty in CV diseases and thereby make more tailored clinical decisions and therapeutic choices in outpatients. Guidance on identification and management of frailty are sparse and an international consensus document on frailty in general cardiology is lacking. Moreover, new options linked with eHealth are going to better define and manage frailty. This consensus document on definition, assessment, clinical implications, and management of frailty provides an input to integrate strategies pre- and post-acute CV events with a comprehensive view including out of hospital, office-based diagnostic and therapeutic choices, and based on a multidisciplinary team approach (general cardiologists, nurses, and general practitioners).

Introduction: To evaluate retinal microvasculature modifications by means of optical coherence tomography angiography in human subjects diagnosed with arterial hypertension and to assess potential clinical relevance for early diagnosis.Methods: A cross-sectional study of 30 subjects affected by arterial hypertension compared to a matched cohort of healthy patients was conducted. Patients were evaluated by the Outpatient Clinic for Hypertension and the Retina Center, University of Insubria, Varese, Italy. Patients were divided into three groups: Group 1—healthy subjects, Group 2—patients first diagnosed with hypertension, and Group 3—patients with treated hypertension. Optical coherence tomography angiography was performed applying different analysis protocols for macula and optic disk, using an AngioVue OCTA System on an Optovue device. Morphological data were compared to and correlated with clinical vascular parameters, to evaluate preclinical microvascular damage.Results: A significant reduction in deep vascular layer density (Group 1: 59.2% ± 1.5% standard deviation; Group 2: 59.2% ± 2.2% standard deviation; Group 3: 57.8% ± 2.6% standard deviation; p < 0.05) as well as an enlargement of the deep foveal avascular zone area (Group 1: 0.34 ± 0.09 mm2; Group 2: 0.36 ± 0.07 mm2; Group 3: 0.39 ± 0.1 mm2; p < 0.05) was measured in patients with first diagnosed hypertension and in treated patients compared to healthy subjects. We also observed a significant decrease in mean foveal choroidal thickness in affected patients compared to controls (Group 1: 319.68 ± 61.72 µm standard deviation; Group 2: 251.04 ± 63.1 µm standard deviation; Group 3: 262.65 ± 51.08 µm standard deviation; p < 0.05). Our preliminary data did not show a significant correlation with microalbuminuria levels.Discussion: Retinal vascular density showed pathological modifications between healthy subjects and hypertensive patients. These preliminary findings suggest that optical coherence tomography angiography may identify pathological markers of an early hypertensive damage and help monitor disease progression with potential therapeutic advantages.

BackgroundDyspnoea is the most common sign of heart failure (HF). Patients accessing the ED for HF-related symptoms require fast diagnosis and early treatment. Transthoracic echocardiography has a crucial role in HF diagnosis, but requires qualified staff and adequate time for execution. The measurement of inferior vena cava (IVC) diameter has been recently proposed as a rapid, simple and reliable marker of volume overload. The aim of this systematic review was to assess the accuracy of IVC-ultrasound as a stand-alone test for HF diagnosis in patients presenting to the ED with acute dyspnoea.MethodsStudies evaluating the diagnostic accuracy of the inferior vena cava collapsibility index (IVC-CIx) for HF diagnosis were systematically searched in the EMBASE and MEDLINE databases (up to January 2018). Quality Assessment of Diagnostic Accuracy Studies 2 tool was used for the quality assessment of the primary studies. A bivariate random-effects regression approach was used for summary estimates of both sensitivity and specificity.ResultsSeven studies, for a total of 591 patients, were included. Three studies were at low-risk of bias. All studies used a proper reference test. Weighted mean prevalence of HF was 49.3% at random-effect model (I2index for heterogeneity=74.7%). IVC-CIx bivariate weighted mean sensitivity was 79.1% (95% CI 68.5% to 86.8%) and bivariate weighted mean specificity was 81.8% (95% CI 75.0% to 87.0%).ConclusionsOur findings suggest that the sensitivity and specificity of IVC-CIx are suboptimal to rule in or rule out HF diagnosis in patients with acute dyspnoea in the ED setting. Therefore, IVC-CIx is not advisable as a stand-alone test, but may be useful when integrated in a specific diagnostic algorithm for the differential diagnosis of acute dyspnoea.

Purpose: Collision sellar lesions represent the coexistence of distinct histopathological lesions found in the sella turcica. They are uncommon entities and have mainly been reported as pituitary adenoma (PA) associated to Rathke cleft cyst (RCC). Pre- and perioperative diagnosis is difficult, since most of the cases appear clinically, radiologically, and macroscopically as solitary cystic sellar lesion. Methods: A retrospective study of histological reports from patients operated for PA from 2013 to 2018 in a single neurosurgery reference center was performed. Patients who also exhibited RCC in the histological sections were included. Clinical and biochemical data were collected from medical files. MRI scans and histopathological slides were also reviewed. Results: Among 554 PA, five patients (0.9%) presented the association of PA and RCC. At diagnosis, patients had median age of 60 years (33–78) with, at least, one pituitary dysfunction, and visual field loss and/or headache. There was a female predominance (n= 3). All patients had nonfunctioning PA. MRI studies showed a predominantly cystic lesion and were unable to distinguish both lesions. The definitive diagnosis was made by histopathology. Conclusion: The association of PA and RCC is extremely rare. On MRI, they appear as a solid-cystic or cystic sellar tumors. RCC can rupture causing granulomatous reaction with cholesterol crystal formation, which can be mistaken for craniopharyngiomas during surgery. Therefore, collision sellar lesion must be included in the differential diagnosis of cystic sellar lesions. The definitive diagnosis is made by histological study.

Previous studies suggested that hypertensive patients with left ventricular (LV) hypertrophy display right ventricular (RV) remodelling. Few data are available about RV remodelling in naive hypertensives without severe cardiac organ damage. Our aim was to evaluate the relationship between RV and LV morpho-functional parameters in never-treated patients with grade 1 hypertension and whether central blood pressure (CBP), inflammatory and metabolic parameters are potentially associated with RV remodelling. 150 never-treated subjects without evidence of diabetes or other cardiovascular diseases were enrolled in our study. We recruited 100 patients with mild hypertension (twenty-four hours blood pressure (24 h BP) ≥ 130/80 mmHg) and 50 normotensive subjects matched for gender, age and body mass index. To estimate the LV/RV parameters, we performed echography as well as arterial tonometry to assess pulse wave analysis/velocity (PWA/PWV). We found 24 h BP, CBP and PWV were higher in hypertensive patients than in normotensives. In addition, LV mass index was higher in hypertensives, and greater RV free wall thickness was observed (5.3 ± 1.4 vs 4.6 ± 1.2 mm, P= 0.02). RV thickness correlated with interventricular septum (IVS), systolic CBP and RV E′ (r= 0.50, P= 0.0001, r= 0.30, P= 0.003, r= −0.24, P= 0.015); linear regression analysis showed a correlation with only IVS (β= 0.39, P= 0.001). RV E′ was correlated with IVS, LV E′ and systolic CBP (r= −0.35, P= 0.0001, r= 0.25, P= 0.012, r= −0.24, P= 0.019); the correlation with IVS and LV E′ (β= −0.310, P= 0.001; β= 0.27, P= 0.004) was confirmed by linear regression analysis. Our study shows RV remodelling is mostly correlated with IVS thickness, supporting the ventricular interdependence hypothesis.

ABSTRACTThis article explores the mechanisms of accommodation and backlash against a new identity group in the Czech Republic and Slovakia—LGBT. Minority demands spark political backlash because societal consensus lags behind the actual accommodation of sexual minorities. The legal framework of the European Union and international pressure groups further accelerate the process of accommodation and polarisation. Yesterday’s accommodation in Western Europe is today’s demand in Eastern Europe. The common European framework erodes the grip of domestic elites on minority rights and contributes to backlash by social conservative forces.

The increasing number of primary students with varying degrees of exposure to a family minority language requires a reflection on whether specific aspects of their daily language experience influence their learning. Indeed, Minority Language Children (MLC) often report difficulties in reading that must be better investigated to exclude neurodevelopmental conditions such as dyslexia.

The patient is a 34–year–old man who comes to the emergency room with mild hemoptysis, asthenia, low–grade fever, night sweats and weight loss. Cardiac auscultation reveals a diastolic murmur at the cardiac apex. Transthoracic and transesophageal echocardiograms are performed and show an isoechoic thickening encompassing the posterior leaflet, cranially involving the atrial septum and the lateral wall up to the inlet of the left atrial appendage and inferiorly involveing the subvalvular apparatus with diffuse thickening and chordal fusion. Functionally it determines a moderate mitral stenosis with an average gradient of 10 mmHg and a valve area of ​​1.1 cm2 and a mild–moderate regurgitation with an anteriorly directed eccentric jet. At this point we needed to make the differential diagnosis considering as possible etiologies infective endocardic vegetation, thrombosis, primary and secondary neoplasms, aseptic vegetation and inflammatory or rheumatic valvulitis. We therefore begin our diagnostic work–up by performing a scintigraphy with labeled leukocytes, which does not show the presence of hyperuptake areas referable to infective endocarditis, and a PET scan which shows, in addition to the increased uptake at the cardiac level, an area of ​​greater concentration of the metabolic tracer in the gastric area (between the body and the fundus). Given the confirmation of metabolically active tissue, the patient performed cardiac magnetic resonance with contrast medium which confirmed the presence of pathological tissue with inhomogeneous late post–contrast enhancement. After collegial discussion, due to the high risk of biopsy of the mitral lesion, which was poorly separable from the cardiac structures, given the other localization of the disease at the gastric level, it was decided to perform an EGDS with relief of an ulcerated lesion on the gastric fundus which is subjected to biopsy and histological typing. We then arrive at the diagnosis of “undifferentiated pleomorphic sarcoma”. Sarcoma is the most frequent histological type of primary malignant cardiac tumors. The clinic is characterized by constitutional symptoms, obstruction of the valve inflow or outflow tract, thromboembolism, and arrhythmias. It has a poor prognosis: 6–12 months from diagnosis. In conclusion, we reiterate the importance of integrated imaging to arrive at the final diagnosis, each method with a specific objective.

The melanocortin-2-receptor (MC2R), also known as the ACTH receptor, is a critical component of the hypothalamic–pituitary–adrenal axis. The importance of MC2R in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency (FGD), a potentially fatal disease characterised by isolated cortisol deficiency. MC2R mutations cause ~25% of cases. The discovery of a MC2R accessory protein MRAP, mutations of which account for ~20% of FGD, has provided insight into MC2R trafficking and signalling. MRAP is a single transmembrane domain accessory protein highly expressed in the adrenal gland and essential for MC2R expression and function. Mouse models helped elucidate the action of ACTH. The Mc2r-knockout (Mc2r−/−) mice was the first mouse model developed to have adrenal insufficiency with deficiencies in glucocorticoid, mineralocorticoid and catecholamines. We recently reported the generation of the Mrap−/−mice which better mimics the human FGD phenotype with isolated glucocorticoid deficiency alone. The adrenal glands of adult Mrap−/−mice were grossly dysmorphic with a thickened capsule, deranged zonation and deranged WNT4/beta-catenin and sonic hedgehog (SHH) pathway signalling. Collectively, these mouse models of FGD highlight the importance of ACTH and MRAP in adrenal progenitor cell regulation, cortex maintenance and zonation.

In this paper I analyze the rhetorical function of compositional neologisms in Cercidas’ versification, in order to provide a new semantical and/or syntactical explanation for single words that have not been correctly interpreted before. In particular I analyze the fragments 1.41–50 Lom., 2.25–7 Lom. and 60 Lom., focusing especially on the correct interpretation of τεθνακοχαλκίδης, συοπλουτοσύνη and μεταμελλοδύνη. At the end of the paper, final considerations on the rhetorical function of neologism in Cercidas’ text are offered.

Adrenal insufficiency is a life-threatening condition resulting from the inability to produce adrenal hormones in a dose- and time-dependent manner. Establishing a cell-based therapy would provide a physiologically responsive approach for the treatment of this condition. We report the generation of large numbers of human-induced steroidogenic cells (hiSCs) from human pluripotent stem cells (hPSCs). Directed differentiation of hPSCs into hiSCs recapitulates the initial stages of human adrenal development. Following expression of steroidogenic factor 1, activation of protein kinase A signaling drives a steroidogenic gene expression profile most comparable to human fetal adrenal cells, and leads to dynamic secretion of steroid hormones, in vitro. Moreover, expression of the adrenocorticotrophic hormone (ACTH) receptor/co-receptor (MC2R/MRAP) results in dose-dependent ACTH responsiveness. This protocol recapitulates adrenal insufficiency resulting from loss-of-function mutations in AAAS, which cause the enigmatic triple A syndrome. Our differentiation protocol generates sufficient numbers of hiSCs for cell-based therapy and offers a platform to study disorders causing adrenal insufficiency.

Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified.

Transsphenoidal surgery (TSS) is the cornerstone of acromegaly treatment, however there are no robust predictors of surgical outcome and remission can only be defined three months after surgery. To analyze if biochemical, demographical, radiological, and immunohistochemical characteristics are predictors of surgical remission and investigate if immediate postoperative GH and IGF-I levels can help defining remission earlier. Consecutive acromegaly patients submitted to TSS between 2013-2016 were evaluated. Remission criteria was defined as normal IGF-I and GH <1 mcg/L three months after surgery. Data of age, sex, GH and IGF-I levels, tumor volume, cavernous sinus invasion, T2-weighted signal, Ki-67, and granulation pattern were correlated with remission status. GH and IGF-I levels at 24, 48 h, and one week postoperative were evaluated as early criteria of remission. Sixty-nine patients were included (84% macroadenomas) and surgical remission was achieved in 45%. No difference between cured and not cured patients concerning age, gender, preoperative GH or IGF-I levels, tumor volume, T2-weighted signal, Ki-67 and tumor granularity was observed. Remission was obtained in 20 of 36 (56%) of the non-invasive tumors, and in 3 of 16 (19%) of the invasive tumors (p= 0.017). A GH <1.57 mcg/L 48 h after surgery was able to predict remission with 93% sensitivity and 86% specificity and an IGF-I < 231% ULNR one week after surgery predicted remission with 86% sensitivity and 93% specificity. Cavernous sinus invasion is the only preoperative predictor of surgical remission. GH at 48 h and IGF-I one week after surgery can define earlier not cured patients.

Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance.

Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach to restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here, we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood-, and urine-derived cells through forced expression of steroidogenic factor-1 and activation of the PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes, and secreted steroid hormones in response to stimuli. hiSCs were viable when transplanted into the mouse kidney capsule and intra-adrenal. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies.

Floquet’s theorem applied to Hill’s equation, is translated to its Ermakov pair, namely, the nonlinear amplitude differential equation with periodic parameter. The nonlinear version states that if $$\rho \left( z\right) $$ ρz is a solution within one period d, to the nonlinear differential equation $$d^{2}\rho /dz^{2}+\rho \varOmega ^{2}-Q^{2}\rho ^{-3}=0$$ d2ρ/dz2+ρΩ2-Q2ρ-3=0 , with periodic parameter $$\varOmega ^{2}\left( z+Nd\right) =\varOmega ^{2}\left( z\right) $$ Ω2z+Nd=Ω2z , the solution after Nperiods is given by $$\rho \left( z+Nd\right) =\rho \left( z\right) \rho _{d}^{-N}\left[ 1+\left( \rho _{d}^{4N}-1\right) \cos ^{2}\left( \int Q/\rho ^{2}\left( z\right) dz+N\phi _{d}\right) \right] ^{\frac{1}{2}}$$ ρz+Nd=ρzρd-N1+ρd4N-1cos2∫Q/ρ2zdz+Nϕd12 . This proposition is proved and a physical interpretation to the Floquet solution is given in terms of counter-propagating waves when the formalism describes one dimensional wave propagation.

The human fetal adrenal (HFA) is an integral component of the fetoplacental unit and important for the maintenance of pregnancy. Low kisspeptin levels during pregnancy are associated with miscarriage, and kisspeptin and its receptor are expressed in the HFA. However, the role of kisspeptin in fetal adrenal function remains unknown.

Rutin is a bioflavonoid found in medicinal plants used to reduce anxiety. Evidence is lacking of rutin’s anxiolytic-like activity, putative mechanism(s) of action, and neural sites of effects. The basolateral amygdala (BLA) is the main brain region that regulates anxiety, through GABAA/benzodiazepine (BDZ) receptors, which are modulated by flavonoids. Therefore, the main aim of this study was to investigate whether the anxiolytic-like effect of rutin involves GABAA/BDZ receptors in the BLA. Rutin was administered systemically (30–1000 mg/kg, intraperitoneal) or microinjected into the BLA (16 nmol/4 µl, intracerebral), and its effects were assessed in the elevated plus-maze and open-field tests. Diazepam (1 mg/kg, intraperitoneal, or 7 nmol/4 µl, respectively) was used as a positive control. The mechanism of action was studied using flumazenil (BDZ antagonist, 5 mg/kg, intraperitoneal, or 7 nmol/4 µl, intracerebral) or picrotoxin (chloride channel GABAAantagonist, 0.3 nmol/4 µl, intracerebral). Rutin, administered systemically or intra-amygdala, induced anxiolytic-like responses, similar to those of diazepam. The effect of diazepam was completely blocked by flumazenil, which also partly antagonized the effects of systemic rutin. By contrast, flumazenil exerted no effect and picrotoxin had only a partial action when rutin was infused in the BLA. These results suggest that the anxiolytic-like effect of rutin in the BLA involves GABAergic neurotransmission that is not associated with BDZ receptors.

To evaluate the effects of canrenone as add‐on therapy in patients already treated with angiotensin‐converting enzyme inhibitors (ACE‐I) or angiotensin IIreceptor blockers (ARBs) and hydrochlorothiazide at the maximum dosage (25 mg/d). In this randomized, open‐label, controlled trial, we enrolled 175 Caucasian patients with essential hypertension not well controlled by concomitant ACE‐I or ARBs and hydrochlorothiazide. At baseline, 87 patients (57 males and 30 females) were randomized to add canrenone 50 mg, and 88 (56 males and 32 females) patients to canrenone 100 mg, once a day, for 3 months. At baseline and after 3 months, we evaluated blood pressure (BP), pulse pressure (PP), heart rate (HR), fasting plasma glucose (FPG), homeostasis model assessment insulin (HOMAIndex), lipid profile, electrolytes, uric acid, estimated glomerular filtration rate (eGFR), plasma urea, aldosterone, B‐type natriuretic peptide (BNP), and galectin‐3. Blood pressure decreased with both dosages of canrenone, with a better effect with canrenone 100 mg (−20.26 vs −23.68 mm Hg for SBP, and −10.58 vs −12.38 mm Hg for DBP), without a clinically relevant increase in potassium levels. We did not observe any differences regarding FPGor HOMAIndex, nor of lipid profile, with the exception of triglycerides, which increased compared to baseline with canrenone 50 mg (+0.25 vs +0.34 mEq/L). Creatinine slightly increased with canrenone 100 mg (+0.02 vs +0.05 mg/dL), although no variations of eGFRwere observed in neither groups. There was an increase in aldosterone levels with canrenone 50 mg. No changes in BNPor galectin‐3 were recorded. Both canrenone dosages gave a decrease in blood pressure, with a better effect with the higher dose, with only a slight increase in potassium and creatinine levels, which were not clinically relevant. Clinical Trials RegistrationEudract number: 2010‐023606‐13; ClinicalTrials.gov NCT02687178.

A 60–year–old woman with no cardiological history came to our attention for exertional dyspnea since few months. The electrocardiogram and chest radiograph were normal. Trans–thoracic echocardiogram revealed the presence of a floating parenchymatous formation measuring 12 x 2 cm starting from the inferior vena cava (IVC) and jutting into the right chambers, without obstruction to inflow. Chest CT and cardiac MRI described a nonvascularized inhomogeneous formation suggestive of thrombotic apposition in VCI, so the patient was treated with unfractionated heparin. Total body CT/PET scan excluded hypercaptant lesions. After two weeks of anticoagulant therapy, on echocardiogram the mass appeared unchanged in morphology and size. On reevaluation of the CT images, a probable origin of the formation at the level of the right ovarian vein was identified. In light of the positive history of bilateral hysteroannessiectomy for uterine myomas and the lack of response to anticoagulant treatment, the suspicion of intravascular and intracardiac leiomyomatosis was raised. After collegial discussion, given the high risk of an eventual thoraco–abdominal surgery, it was decided to remove only the portion of the mass adherent to the VCI jutting into the right heart chambers. The patient underwent cardiac surgery: a polypoid, capsular, hard–elastic mass, 12 x 2 cm in size, jutting into the right chambers and with the base of implantation located in the anterior wall of the VCI, was removed. The final histologic diagnosis was sclero–jalin leiomyoma. The surgery and postoperative course proceeded without complications. At follow–up at 20 months, the patient is asymptomatic and no mass is detectable on echocardiogram. Intracardiac leiomyomatosis is a rare condition characterized by benign smooth muscle tumors of extracardiac origin reaching the right heart by direct extension into the venous canal, described predominantly in women with a history of uterine myomas. Although histologically benign, intracardiac leiomyomatosis can result in sudden death if there is total obstruction to the outflow tract. In our case, the multimodality imaging approach and serial monitoring by echocardiography were essential to guide treatment choices and for the follow up.

ABSTRACTCancer-secreted exosomes influence tumor microenvironment and support cancer growth and metastasis. MiR-210 is frequently up-regulated in colorectal cancer tissues and correlates with metastatic disease. We investigated whether exosomes are actively released by HCT-8 colon cancer cells, the role of exosomal miR-210 in the cross-talk between primary cancer cells and neighboring metastatic cells and its contribution in regulating epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET).After 7 d of culture, a subpopulation of viable HCT-8 cells detached the monolayer and started to grow in suspension, suggesting anoikis resistance and a metastatic potential. The expression of key proteins of EMT revealed that these cells were E-cadherin negative and vimentin positive further confirming their metastatic phenotype and the acquisition of anoikis resistance. Metastatic cells, in the presence of adherently growing HCT-8, continued to grow in suspension whereas only if seeded in cell-free wells, were able to adhere again and to form E-cadherin positive and vimentin negative new colonies, suggesting the occurrence of MET.The chemosensitivity to 5 fluorouracil and to FOLFOX-like treatment of metastatic cells was significantly diminished compared to adherent HCT-8 cells. Of note, adherent new colonies undergoing MET, were insensitive to both chemotherapeutic strategies. Electron microscopy analysis demonstrated that adherently growing HCT-8, actually secreted exosomes and that exosomes in turn were taken up by metastatic cells. When exosomes secreted by adherently growing HCT-8 were administered to metastatic cells, MET was significantly inhibited. miR-210 was significantly upregulated in exosomes compared to its intracellular levels in adherently growing HCT-8 cells and correlated to anoikis resistance and EMT markers.Exosomes containing miR-210 might be considered as EMT promoting signals that preserve the local cancer-growth permissive milieu and also guide metastatic cells to free, new sites of dissemination.

Experimental evidence has demonstrated that glutamate is an essential factor for neurogenesis, whereas another line of research postulates that excessive glutamatergic neurotransmission is associated with the pathogenesis of depression. The present review shows that such paradox can be explained within the framework of hormesis, defined as biphasic dose responses. Low glutamate levels activate adaptive stress responses that include proteins that protect neurons against more severe stress. Conversely, abnormally high levels of glutamate, resulting from increased release and/or decreased removal, cause neuronal atrophy and depression. The dysregulation of the glutamatergic transmission in depression could be underlined by several factors including a decreased inhibition (γ-aminobutyric acid or serotonin) or an increased excitation (primarily within the glutamatergic system). Experimental evidence shows that the activation of N-methyl-D-aspartate receptor (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) can exert two opposite effects on neurogenesis and neuron survival depending on the synaptic or extrasynaptic concentration. Chronic stress, which usually underlies experimental and clinical depression, enhances glutamate release. This overactivates NMDA receptors (NMDAR) and consequently impairs AMPAR activity. Various studies show that treatment with antidepressants decreases plasma glutamate levels in depressed individuals and regulates glutamate receptors by reducing NMDAR function by decreasing the expression of its subunits and by potentiating AMPAR-mediated transmission. Additionally, it has been shown that chronic treatment with antidepressants having divergent mechanisms of action (including tricyclics, selective serotonin reuptake inhibitors, and ketamine) markedly reduced depolarization-evoked glutamate release in the hippocampus. These data, taken together, suggest that the glutamatergic system could be a final common pathway for antidepressant treatments.

The potential therapeutic applications of targeting brown adipose tissue open new clinical avenues in fighting against metabolic pathologies. However, due to the limited extension in adult humans of brown depots, which are dramatically reduced after birth, solid cell models to study human brown adipogenesis and its regulatory factors in pathophysiology are urgently needed. Here, we generated a novel human model of brown adipose stem cells, hfB‐ASC, derived for the first time from fetal interscapular brown fat depots. Besides the characterization of their stem and classical brown adipose properties, we demonstrated that these cells retain a specific intrinsic differentiation program to functional brown adipocytes, even spontaneously generating organoid structures with brown features. Moreover, for the first time, we investigated the thermogenic and electrophysiological activity of the in vitro‐derived fetal brown adipocytes compared to their undifferentiated precursors hfB‐ASC, in basal and norepinephrine‐induced conditions. In conclusion, from interscapular brown fat of the human fetus we developed and functionally characterized a novel physiological brown adipose stem cell model early programmed to brown differentiation, which may represent a unique opportunity for further studies on brown adipogenesis processes in humans as well as the most suitable target to study novel therapeutic approaches for stimulating brown activity in metabolic pathologies. StemCells2016;34:1679–1691 Electron microscopy of a mature brown adipocyte obtained by in vitro‐induced adipogenesis of hfB‐ASC, shows several mitochondria with the typical features found in brown adipocytes, such as rod‐shape and elevated number of transversal cristae, in close proximity with two electron dense intracellular lipid droplets and endoplasmic reticulum. Scale Bar: 500 nm.

The developing brain is particularly vulnerable to alcohol: Drinking during pregnancy can lead to a number of physical, learning, and behavioral disorders in the newborn. It has been demonstrated that immature and mature brain tissues display a differential sensitivity to ethanol (EtOH) toxicity and that cerebral structure and function are diversely impaired according to the stage of synaptic maturation. Rat organotypic hippocampal slice cultures were exposed for 7 days to EtOH (100 to 300 mM) after 2 days (immature) or 10 days (mature) of culture in vitro; EtOH was then removed from the medium, and 24 hours later, slices were analyzed by fluorescence microscopy, Western blotting, electrophysiology, and electron microscopy to explore the molecular mechanisms of EtOH toxicity in the developing hippocampus. EtOH withdrawal elicited a selective CA1 pyramidal cell injury in mature slices, but not in immature slices. A significant increase in the expression of pre‐ and postsynaptic proteins in mature slices revealed that slice maturation is presumably associated with the development of new synapses. Incubation with chronic EtOH for 7 days and its removal from the medium induced a significant decrease in GluA1 and GluA2 expression levels; a significant reduction in the expression of synaptophysin and GluN2A was observed only after EtOH withdrawal. Whole‐cell patch‐clamp recordings showed that incubation with EtOH for 7 days induced a significant decrease in spontaneous excitatory postsynaptic current (sEPSC)frequency in CA1 pyramidal cells of immature slices and a trend toward a decrease in sEPSCamplitude. Electron microscopy revealed a disorganization of neurotubuli in immature slices after chronic exposure to EtOH. These results indicate that prolonged incubation with EtOH and its subsequent withdrawal from the medium induce an impairment of excitatory synaptic transmission and possibly an incorrect formation of neuronal circuits in developing hippocampus in vitro, which is suggestive of mechanisms that may lead to mental retardation in fetal alcohol spectrum disorders. Prolonged incubation with ethanol and its subsequent removal from the medium produce, in developing brain tissue, alterations in the expression of pre‐ and post‐synaptic proteins, an impairment of excitatory synaptic transmission and a dramatic disorganization of dendritic microtubules and neuronal processes. An incorrect formation of neuronal circuits and a compromised synaptic transmission in the developing hippocampal neurons are suggestive of mechanisms that may lead to mental retardation, which may be of relevance for the alterations observed in newborns affected by FASD.

Introduction:Dual antiplatelet therapy is the standard of care for patients with acute coronary syndromes or with recent coronary stents implantation. P2Y12receptor antagonists have shown to reduce the risk of recurrent ischemic events among these patients, at the expense of an increased risk of bleeding. Cangreloris a novel, intravenous, short-acting, reversible platelet P2Y12inhibitor, which has been evaluated for the treatment of arterial thrombosis.Areas covered:Studies on the pharmacological characteristics of cangrelor and clinical trials were retrieved by a PubMed literature search.Expert opinion:Cangrelor has been tested in patients with coronary artery diseases undergoing percutaneous coronary intervention and as bridging therapy for patients undergoing coronary artery bypass graft. The rapid peak of action allows a fast and complete inhibition of platelet aggregation; the rapid offset is advantageous in case of bleeding complications; and finally, the intravenous administration also makes this drug suitable for patients unable to consume oral medications. Unfortunately, the large clinical trials evaluating cangrelor in percutaneous coronary intervention did not show superiority to the standard antiplatelet therapy, and its future use in this setting still needs to be better assessed. Conversely, when used as bridging therapy to coronary artery bypass graft, cangrelor showed promising results.

We describe the case of a newborn presenting with multicystic encephalomalacy, hydrocephalus and bilateral hemovitreous. An underlying coagulation disorder was suspected and laboratory tests revealed severe protein C deficiency. At 25 days of life, after the appearance of purpura fulminans, replacement therapy with intravenous protein C concentrate (Ceprotin; Baxter, Vienna, Austria) was started.

Paragangliomas (PGLs) are rare neuroendocrine tumours. About 30–40 % of these tumours are mutated in one of the different susceptibility genes, including those encoding the different subunits of the succinate dehydrogenase, a complex involved both in the tricarboxylic acid cycle and in the oxygen transport chain. The aim of this work was to investigate whether SDHBmutations may account for alterations in cell metabolism and functions. Since human PGL cell lines are not available, we used the neuroblastoma cell line (SK-N-AS) stably transfected with the wild-type human SDHBor different SDHB-mutated constructs carrying some significant mutations found in our patients affected by PGLs. Similarly to succinate dehydrogenase (SDH)-mutated tumour cells, mutated SK-N-AS clones showed reduced SDH enzyme activity. All clones showed normal citrate synthase activity, reduced oxygen consumption and reduced carbonic anhydride production, thus demonstrating a decreased in mitochondrial metabolism. In two of the three mutated SK-N-AS, we also found an increase in HIF1α expression. Surprisingly and unexpectedly, in all the SDHB-mutated clones, we found a significant decrease in glucose uptake and in lactate culture medium concentration, suggesting also a decrease of cytosolic metabolism. Finally, we found that these energetic changes were associated to an increase in cell proliferation and migration. Overall, these data demonstrate that although SDHBmutations significantly downregulate both mitochondrial and cytoplasmic cellular metabolism, these mutations are associated to an upregulation of some cellular functions, such as growth rate and invasiveness.

The Pulmonary Embolism (PE) Severity Index (PESI) is a clinical prognostic rule that accurately classifies PE patients into five risk classes with increasing mortality. PESI score has been validated in studies with a relatively short‐term follow‐up and its accuracy in predicting long‐term prognosis has never been established.

Computed tomographic pulmonary angiography (CTPA) has simplified the diagnostic approach to patients with suspected pulmonary embolism (PE). However, PE diagnosis is still probabilistic and CTPA should be used with caution in some patient groups, such as patients with severe renal insufficiency and pregnant women. Among alternative imaging tests, lung ultrasound is the most promising technique. We aimed to systematically assess the diagnostic accuracy of lung ultrasound for PE diagnosis.

Introduction:Several low-molecular-weight heparins are available for the prevention and treatment of venous thromboembolism and arterial thrombosis. Certoparinhas been extensively tested in different clinical settings for about 20 years.Areas covered:The authors provide a drug evaluation based on literature searches performed through Medline. Specifically, the authors review studies on the pharmacological characteristics of certoparin and the clinical trial and post-marketing studies in the field of venous thromboembolism. Furthermore, the authors also review the available smaller studies performed in clinical settings for indications such as stroke, atrial fibrillation, and hemodialysis.Expert opinion:Certoparin has proved to be effective and safe therapy for preventing venous thromboembolism in different surgical and medical settings. With regards to DVT treatment, certoparin shows the peculiar feature of being used at a fixed, weight-independent dose (subcutaneous 8000 IU twice daily). Unfortunately, certoparin has no specific data from clinical trials on treatment of pulmonary embolism. Furthermore, certoparin has not been specifically tested in unusual site thrombosis. Certoparin represents a valid option for venous thromboembolism prevention and DVT treatment. Further studies are also required to provide data on the use of certoparin to treat acute pulmonary embolisms and to further substantiate results on atrial fibrillation and bridging therapy.

Reflectivity of a random monolayer, consisting of transparent spherical particles, is estimated using a graded refractive index model, an effective medium approach, and two scattering models. Two cases, a self-standing film and one with a substrate, are considered. Neither the surrounding medium nor the substrate are absorbing materials. Results at normal incidence, with different particle sizes, covering ratios and refractive indexes, are compared. The purpose of this work is to find under which circumstances, for reflectivity at normal incidence, a particle monolayer behaves as a graded refractive index film.