Localization of Mineralocorticoid Receptors at Mammalian Synapses

In the brain, membrane associated nongenomic steroid receptors can induce fast-acting responses to ion conductance and second messenger systems of neurons. Emerging data suggest that membrane associated glucocorticoid and mineralocorticoid receptors may directly regulate synaptic excitability during times of stress when adrenal hormones are elevated. As the key neuron signaling interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. The lateral amygdala is a key site for synaptic plasticity underlying conditioned fear, which can both trigger and be coincident with the stress response. A large body of electrophysiological data shows rapid regulation of neuronal excitability by steroid hormone receptors. Despite the importance of these receptors, to date, only the glucocorticoid receptor has been anatomically localized to the membrane. We investigated the subcellular sites of mineralocorticoid receptors in the lateral amygdala of the Sprague-Dawley rat. Immunoblot analysis revealed the presence of mineralocorticoid receptors in the amygdala. Using electron microscopy, we found mineralocorticoid receptors expressed at both nuclear including: glutamatergic and GABAergic neurons and extra nuclear sites including: presynaptic terminals, neuronal dendrites, and dendritic spines. Importantly we also observed mineralocorticoid receptors at postsynaptic membrane densities of excitatory synapses. These data provide direct anatomical evidence supporting the concept that, at some synapses, synaptic transmission is regulated by mineralocorticoid receptors. Thus part of the stress signaling response in the brain is a direct modulation of the synapse itself by adrenal steroids

Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial

Purpose: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Methods: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. Results: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P < 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade ≥3 toxicity (50 vs. 70%). Conclusions: The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway (ClinicalTrials.gov NCT02915744)

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons

Incidence, predictive factors, and prognosis for winged scapula in breast cancer patients after axillary dissection

Axillary lymph node dissection is part of breast cancer surgery, and winged scapula is a possible sequela. Data regarding its incidence, predictive factors, and patient prognosis remains inconsistent. Ignorance of its diagnosis may lead to undertreatment with physical morbidity. Breast cancer patients with axillary lymph node dissection were prospectively recruited. Postoperative examinations by the physiotherapy staff were performed. One hundred eighty-seven patients were recruited during July-October 2012; 51 patients had a positive diagnosis (27.2 %), with 38 patients (86 %) who recovered completely from the winged scapula, while 6 patients (13 %) still had winged scapula at 6 months after surgery. One hundred thirty patients underwent mastectomy and 100 cases had immediate reconstruction. Age, BMI, previous shoulder joint morbidity, and breast surgery were not associated with winged scapula. Neoadjuvant treatment, mastectomy or conservative surgery, immediate reconstruction, tumor size, and nodal involvement also did not show any correlation. Breast reconstruction with prosthesis, even with serratus muscle dissection, does not increase the incidence of winged scapula. Winged scapula is not an uncommon incidence after breast cancer surgery. Physiotherapy is related to the complete recovery. The severity or grading of the winged scapula and the recovery time after physiotherapy should be investigated in the future studies.22616111617Umberto Veronesi Foundatio

Further studies on the mechanism of the mineralocorticoid action of licorice in humans.

The pathogenesis of pseudohyperaldosteronism from licorice has been evaluated in 6 male volunteers taking daily 7 g of a commercial preparation of licorice for 7 days, corresponding to an intake of 500 mg/day of glycyrrhizic acid. Pseudohyperaldosteronism was evident during the treatment (increase of body weight, suppression of plasma renin activity and plasma aldosterone, reduction of serum potassium). The ratio (tetrahydrocortisol + allo tetrahydrocortisol)/tetrahydrocortisone in urine increased in 5 cases after 3 days of treatment, without an increase of plasma mineralocorticoid activity (PMA). In the 6th case the urinary ratio was unchanged and PMA increased from the pretreatment value. After 7 days of therapy the ratio remained high and PMA was not measurable in 3 cases, while in the other 3 cases the ratio returned to pretreatment and PMA was higher than pretreatment value. We conclude that the pseudohyperaldosteronism from licorice is initially related to decreased activity of 11 beta-hydroxysteroid-dehydrogenase and afterwards also a direct effect of licorice derivatives on mineralocorticoid receptors becomes evident in some cases. In other cases however the effect on the enzyme is prevailing probably due to individual factors

Strategie di educazione a confronto. Progetto di miglioramento dell'aderenza al percorso riabilitativo rivolto a pazienti sottoposte a dissezione linfonodale ascellare

Introduzione: Le complicanze conseguenti al trattamento chirurgico del carcinoma mammario con dissezione ascellare possono, se non precocemente trattate, cronicizzare causando disabilità dell’arto superiore. Il percorso riabilitativo prevede: esecuzione autonoma di esercizi finalizzati al recupero dell’abilità motoria, attenersi a regole che riducono l’insorgenza del linfedema e saper riconoscere precocemente le complicanze, ovvero che la paziente partecipi attivamente al processo. Si ipotizza che modificando la strategia educativa che precede l’inizio di questo percorso autogestito, utilizzando tecniche di apprendimento attivo in gruppi educativi interattivi con proiezione di immagini, si possa influire sugli aspetti psicologico-motivazionali che influenzano la compliance. Metodo: Sono previste in questo studio randomizzato e controllato 200 pazienti sottoposte per la prima volta a dissezione ascellare assegnate a: educazione individuale/verbale standard (controllo) vs educazione in gruppo/immagini (intervento). Enpoint primario: incremento dell’aderenza della paziente al percorso riabilitativo autonomo. Endpoint secondari: funzionalità del braccio; costo/efficacia misurata come tempo educativo impiegato/disabilità residua (DASH); recupero articolare; comparsa linfedema; QoL; soddisfazione; dolore. Le variabili soggettive sono valutate con questionari. Sono previste 2 misurazioni degli endpoint: -basale; -a 3 mesi. Risultati preliminari: ad oggi 19 pazienti (10 gruppo/immagini; 9 individuale/verbale) hanno concluso lo studio. Non si e’ evidenziata alcuna differenza in termini di compliance. Tuttavia le pazienti del gruppo/immagini riportano: un tempo di educazione inferiore (15’ gruppo/immagini vs 20’ individuale/verbale; p=0.02), una minor assunzione di FANS/Analgesici [2(20%) pazienti gruppo/immagini vs 6(66.7%) individuale/verbale; p=0.04], e un miglior recupero funzionale da ritenersi clinicamente rilevante [delta DASH mediana(3m – T0) gruppo/immagini –2.1(IC95%: –17.5, 19.2) vs individuale/verbale 7.5 (IC95%: –21.7, 37.5); p=0.10]. Conclusioni: I risultati sono promettenti e, nonostante il numero limitato di pazienti, questa analisi preliminare ha già permesso di verificare la fattibilità dell’intervento suggerendo l’adeguatezza del programma educativo in “gruppo/immagini” perché, senza diminuire l'efficacia su tutte le variabili misurate rispetto all'intervento “individuale/verbale”, prevede un risparmio di risorse