L’impatto della terapia chirurgica sulla riduzione della pressione arteriosa e sui parametri indicativi di danno d’organo nel Morbo di Conn.

Il morbo di Conn è una patologia eterogenea che pone problemi reali nella selezione dei pazienti che presentano indicazione chirurgica. Inoltre, sebbene sia l’opzione terapeutica chirurgica sia quella farmacologica curino o migliorino l’ipertensione arteriosa, esistono pochi dati in letteratura sugli effetti cardiovascolari a lungo termine. METODI: È stato effettuato uno studio osservazionale su tutti i pazienti sottoposti a surrenectomia dal 1992 al 2009, presso il Dipartimento di Chirurgia dell’Università di Pisa, con diagnosi di ammissione di morbo di Conn, per la valutazione dei dati clinici, biochimici e cardiovascolari (ecocardiografia, ecodoppler carotideo) al fine di valutare l’impatto dell’opzione chirurgica sul profilo pressorio, sul rischio cardiovascolare e di fornire un’interpretazione adeguata di tutte le tecniche di studio preoperatorie. Inoltre, sono stati confrontati i dati dei pazienti sottoposti a surrenectomia con quelli di 41 pazienti afferenti dal Centro Ipertensione dell’Università di Pisa trattati farmacologicamente, al fine di confrontare l’outcome nei due tipi di trattamento. RISULTATI: La corretta selezione dei pazienti con malattia monolaterale è estremamente importante in quanto la surrenectomia offre migliori risultati rispetto alla terapia medica in termini di controllo del profilo pressorio e dei danni d’organo, anche in considerazione delle minime complicanze di cui è gravato l’approccio laparoscopico. Inoltre, al fine di diagnosticare correttamente il sottotipo di iperaldosteronismo primario, è necessario affiancare sempre alle tecniche di imaging il cateterismo delle vene surrenali.

Massive upper gastrointestinal bleeding from a pancreatic pseudocyst rupture: a case report

INTRODUCTION: Bleeding from pancreatic pseudocyst's rupture into adjacent organs is a rare, but potentially fatal, complication of chronic pancreatitis requiring quick management. Timing of the rupture is unpredictable; early diagnosis and correct management is essential in preventing the bleeding. CASE PRESENTATION: We describe the case of a 53 years old male patient successfully treated with emergency surgery for massive hematemesis due to a rupture of a bleeding pseudocyst into the stomach. Patient underwent emergency laparotomy and suture of the bleeding vessel. At 5 years follow-up patient is in healthy condition. CONCLUSION: This case shows to surgeons that pancreatic pseudocyst cannot be managed strictly with one rule and prompt surgical treatment is mandatory in case of haemodinamic instability

"Black Ink" Sonographic Pattern as a Predictor for Invasive Papillary Thyroid Micro Carcinoma: A Case Report

Background: This study investigated the utility of the Sonographic pattern "Black Ink" with BRAF mutation testing of thyroid fine-needle aspiration cytology specimens for the risk papillary thyroid microcarcinoma (PTMC). Case Presentation: We describe a case of a 41-year-old Caucasian woman affected by a ultrasonography "Black Ink" papillary thyroid microcarcinoma (PTMC) of the left lobe of the thyroid gland with very tiny size (Ø 0.4 cm). The characteristics, with the Diagnostic Imaging using Ultrasonography (US), Superb Micro-Vascular Imaging (SMI), fine-needle-aspiration cytology (FNAC) and mutation analysis are here discussed. There are more rare subtypes of thyroid cancer as papillary microcarcinoma "Black Ink" that even if small, are invasive and there is why the need to early diagnosis to avoid their aggressive behavior is needed. Nowadays, focusing on the size, the cut-off for non-occult tiny tumors has dropped to 0.3 cm. This value is of great relevance. Conclusion: Ultrasonography, FNAC and BRAF molecular study have proven to be the most sensitive diagnostic combination for the early detection of thyroid cancer. Despite the size of this micro-lesion, the Black Ink ultrasonographic pattern associated with malignant cytology at FNAC represents an important biological risk factor and could still be a predictor of the PTMC and risk for neck lymph node metastases

Calcium-dependent networks in dopamine-glutamate interaction: the role of postsynaptic scaffolding proteins

Dopamine and glutamate systems are both involved in cognitive, behavioral, and motor processes. Dysfunction of dopamine-glutamate interplay has been suggested in several psychotic diseases, above all in schizophrenia, for which there exists a need for novel medications. Intracellular calcium-dependent transduction pathways are key determinants of dopamine-glutamate interactions, which take place mainly, albeit not exclusively, in the postsynaptic density (PSD), a highly specialized postsynaptic ultrastructure. Stimulation of dopamine and glutamate receptors modulates the gene expression and the function of specific PSD proteins, the "scaffolding" proteins (Homer, Shank, and PSD95), belonging to a complex Ca(2+)-regulated network that integrates and converges dopamine and glutamate signaling to appropriate nuclear targets. Dysfunction of scaffolding proteins leads to severe impairment of Ca(2+)-dependent signaling, which may underlie the dopamine-glutamate aberrations putatively implicated in the pathogenesis of psychotic disorders. Antipsychotic therapy has been demonstrated to directly and indirectly affect the neuronal Ca(2+)-dependent pathways through the modulation of PSD scaffolding proteins, such as Homer, therefore influencing both dopaminergic and glutamatergic functions and enforcing Ca(2+)-mediated long-term synaptic changes. In this review, we will discuss the role of PSD scaffolding proteins in routing Ca(2+)-dependent signals to the nucleus. In particular, we will address the implication of PSD scaffolding proteins in the intracellular connections between dopamine and glutamate pathways, which involve both Ca(2+)-dependent and Ca(2+)-independent mechanisms. Finally, we will discuss how new strategies for the treatment of psychosis aim at developing antipsychotics that may impact both glutamate and dopamine signaling, and what should be the possible role of PSD scaffolding proteins

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies beyond Dopamine Receptor Antagonism

Dopamine partial agonism and functional selectivity have been innovative strategies in the pharmacological treatment of schizophrenia and mood disorders and have shifted the concept of dopamine modulation beyond the established approach of dopamine D2 receptor (D2R) antagonism. Despite the fact that aripiprazole was introduced in therapy more than 12 years ago, many questions are still unresolved regarding the complexity of the effects of this agent on signal transduction and intracellular pathways, in part linked to its pleiotropic receptor profile. The complexity of the mechanism of action has progressively shifted the conceptualization of this agent from partial agonism to functional selectivity. From the induction of early genes to modulation of scaffolding proteins and activation of transcription factors, aripiprazole has been shown to affect multiple cellular pathways and several cortical and subcortical neurotransmitter circuitries. Growing evidence shows that, beyond the consequences of D2R occupancy, aripiprazole has a unique neurobiology among available antipsychotics. The effect of chronic administration of aripiprazole on D2R affinity state and number has been especially highlighted, with relevant translational implications for long-term treatment of psychosis. The hypothesized effects of aripiprazole on cell-protective mechanisms and neurite growth, as well as the differential effects on intracellular pathways [i.e. extracellular signal-regulated kinase (ERK)] compared with full D2R antagonists, suggest further exploration of these targets by novel and future biased ligand compounds. This review aims to recapitulate the main neurobiological effects of aripiprazole and discuss the potential implications for upcoming improvements in schizophrenia therapy based on dopamine modulation beyond D2R antagonism

Scaffolding Proteins of the Post-synaptic Density Contribute to Synaptic Plasticity by Regulating Receptor Localization and Distribution: Relevance for Neuropsychiatric Diseases

Synaptic plasticity represents the long lasting activity-related strengthening or weakening of synaptic transmission, whose well-characterized types are the long term potentiation and depression. Despite this classical definition, however, the molecular mechanisms by which synaptic plasticity may occur appear to be extremely complex and various. The post-synaptic density (PSD) of glutamatergic synapses is a major site for synaptic plasticity processes and alterations of PSD members have been recently implicated in neuropsychiatric diseases where an impairment of synaptic plasticity has also been reported. Among PSD members, scaffolding proteins have been demonstrated to bridge surface receptors with their intracellular effectors and to regulate receptors distribution and localization both at surface membranes and within the PSD. This review will focus on the molecular physiology and pathophysiology of synaptic plasticity processes, which are tuned by scaffolding PSD proteins and their close related partners, through the modulation of receptor localization and distribution at post-synaptic sites. We suggest that, by regulating both the compartmentalization of receptors along surface membrane and their degradation as well as by modulating receptor trafficking into the PSD, postsynaptic scaffolding proteins may contribute to form distinct signaling micro-domains, whose efficacy in transmitting synaptic signals depends on the dynamic stability of the scaffold, which in turn is provided by relative amounts and post-translational modifications of scaffolding members. The putative relevance for neuropsychiatric diseases and possible pathophysiological mechanisms are discussed in the last part of this wor

Glutamatergic Postsynaptic Density Protein Dysfunctions in Synaptic Plasticity and Dendritic Spines Morphology: Relevance to Schizophrenia and Other Behavioral Disorders Pathophysiology, and Implications for Novel Therapeutic Approaches.

Emerging researches point to a relevant role of postsynaptic density (PSD) proteins, such as PSD-95, Homer, Shank, and DISC-1, in the pathophysiology of schizophrenia and autism spectrum disorders. The PSD is a thickness, detectable at electronic microscopy, localized at the postsynaptic membrane of glutamatergic synapses, and made by scaffolding proteins, receptors, and effector proteins; it is considered a structural and functional crossroad where multiple neurotransmitter systems converge, including the dopaminergic, serotonergic, and glutamatergic ones, which are all implicated in the pathophysiology of psychosis. Decreased PSD-95 protein levels have been reported in postmortem brains of schizophrenia patients. Variants of Homer1, a key PSD protein for glutamate signaling, have been associated with schizophrenia symptoms severity and therapeutic response. Mutations in Shank gene have been recognized in autism spectrum disorder patients, as well as reported to be associated to behaviors reminiscent of schizophrenia symptoms when expressed in genetically engineered mice. Here, we provide a critical appraisal of PSD proteins role in the pathophysiology of schizophrenia and autism spectrum disorders. Then, we discuss how antipsychotics may affect PSD proteins in brain regions relevant to psychosis pathophysiology, possibly by controlling synaptic plasticity and dendritic spine rearrangements through the modulation of glutamate-related targets. We finally provide a framework that may explain how PSD proteins might be useful candidates to develop new therapeutic approaches for schizophrenia and related disorders in which there is a need for new biological treatments, especially against some symptom domains, such as negative symptoms, that are poorly affected by current antipsychotics

Homer splice variants modulation within cortico-subcortical regions by dopamine D2 antagonists, a partial agonist, and an indirect agonist: implication for glutamatergic postsynaptic density in antipsychotics action

Homer proteins are linked to both dopamine and glutamate neurotransmission and are putatively involved in the mechanisms of action of psychoactive drugs. In the present study, we evaluated the effects of compounds differently impacting dopaminergic neurotransmission on the transcripts of different Homer isoforms in rat forebrain by means of in situ hybridization histochemistry. Animals were treated with the typical antipsychotic haloperidol 0.8 mg/kg, the atypical antipsychotic clozapine 15 mg/kg, the dopamine partial agonist aripiprazole 12 mg/kg and 30 mg/kg and the dopamine transporter inhibitor GBR12909 30 mg/kg in acute and chronic paradigms. Homer 1a and ania-3 were induced in the caudate-putamen by acute administration of aripiprazole 12 mg/kg, while aripiprazole 30 mg/kg had no significant effects. Furthermore, acute haloperidol and GBR12909 induced both the splice variants of Homer 1 in the caudate-putamen. In the nucleus accumbens, aripiprazole 30 mg/kg and clozapine increased Homer 1a and ania-3 transcripts in the shell, whereas haloperidol induced expression of both isoforms in core and shell. Aripiprazole 30 mg/kg increased Homer 1a in the frontal cortex. Homer 1 splice variants were both up-regulated by GBR12909 in the frontal cortex, whereas GBR12909 induced only ania-3 in the parietal cortex. In the chronic paradigm, results showed a significant induction of Homer 1a and ania-3 in the striatum by haloperidol and aripiprazole. The constitutive Homer 2 isoform was overexpressed in the lateral septum by chronic administration of haloperidol and clozapine. In the cortex the expression of Homer 1a and ania-3 was down-regulated by chronic clozapine and aripiprazole. These results may indicate a differential modulation of Homer genes by compounds differently regulating dopaminergic neurotransmission in discrete regions of the rat forebrain and suggest that Homer could be a molecular marker of the involvement of the glutamatergic postsynaptic density in antipsychotic mechanisms of action