Gli istituti deflattivi del contenzioso tributario. Stato attuale e criticit\ue0

ll legislatore tributario, soprattutto a partire dal 1997, ha ritenuto di affermare in maniera sempre pi\uf9 esplicita la necessit\ue0 della collaborazione e del contraddittorio nel rapporto tra Fisco e contribuente, soprattutto in considerazione del fatto che la mancanza di un confronto tra le parti finisce per facilitare la creazione di situazioni conflittuali, che sfociano nella attivazione di posizioni di contenzioso. Sono stati cos\uec introdotti nel nostro ordinamento, gli istituti deflattivi del contenzioso tributario, in base ai quali il contribuente che, trovandosi in una situazione di lite potenziale con gli Uffici, rinuncia al contenzioso e versa l\u2019imposta, ha diritto a sanzioni ridotte nonch\ue9 ad altri vantaggi, compresa una piccola copertura verso possibili futuri accertamenti e la possibilit\ue0 di effettuare il pagamento dilazionato delle somme dovute. Sebbene oggetto di intervento nel corso degli anni, tali istituti presentano ancora numerosi profili critici e ampi margini di miglioramento

Positron emissiontomography imaging of neuroinflammation in Multiple Sclerosis with a second generation translocator protein PET radioligand

This thesis describes a new approach for molecular imaging of neuroinflammation in Multiple Sclerosis (MS). My aim was to use the 2nd generation TSPO radioligand 18F-PBR111 to explore the potential of Positron Emission Tomography (PET) targeting the 18-kDa Translocator Protein (TSPO), as an in vivo biomarker of activated microglia in MS patients. This thesis addresses three research objectives. First, I characterised 18F-PBR111 PET signal in healthy controls’ brains and tested how it is affected by the TSPO gene polymorphism at rs6971. Second, I measured 18F-PBR111 uptake across white matter volumes segmented using structural MRI measures related to MS neuropathology. Third, I explored how 18F-PBR111 uptake in the hippocampus correlated with depressive symptoms and to the brain functional connectivity of the hippocampus. Eleven patients with relapsing-remitting MS and 22 age-matched healthy controls underwent 18F-PBR111 PET and MRI scans. Structural and functional MRI sequences were used to define conventional MS neuropathological markers and for the assessment of functional connectivity, respectively. I discovered that white matter 18F-PBR111 PET signal in healthy volunteers varied with TSPO genotype and correlated positively with age. In patients with MS, signal intensity in MRI-defined lesions was higher than that in normal-appearing white matter and correlated with the historical rate of progression of their disability. Hippocampal 18F-PBR111 uptake was higher in the MS patient group than in healthy volunteers and correlated with both depressive symptoms and functional connectivity of the hippocampus with frontal, temporal and parietal cortex. I thus discovered that this 2nd generation TSPO PET radiotracer, used in humans for the first time in our study, is sensitive to MS neuropathology consistent with recognized patterns of microglial activation and that differences between subjects can be related to disability progression. I also have discovered a novel relationship between this measure of hippocampal microglial activation and affective symptoms of MS.Open Acces

Gli istituti deflattivi del contenzioso tributario e il principio d'indisponibilit\ue0 dell'obbligazione fiscale

Il concetto d'indisponibilit\ue0 dell'obbligazione tributaria: contenuti e limiti. L'accertamento con adesione nel quadro degli strumenti deflattivi del contenzioso tributario: il discusso inquadramento teorico dell'istituto tra indisponibilit\ue0 ed accordo. Le modalit\ue0 di definizione alternativa delle controversie tributarie: l'impatto della conciliazione e della mediazione sul principio d'indisponibilit\ue0

Gli istituti deflattivi del contenzioso tributario e il principio d'indisponibilità dell'obbligazione fiscale

Il concetto d'indisponibilità dell'obbligazione tributaria: contenuti e limiti. L'accertamento con adesione nel quadro degli strumenti deflattivi del contenzioso tributario: il discusso inquadramento teorico dell'istituto tra indisponibilità ed accordo. Le modalità di definizione alternativa delle controversie tributarie: l'impatto della conciliazione e della mediazione sul principio d'indisponibilità

Effects of brief remote high ventilation breathwork with retention on mental health and wellbeing: a randomised placebo-controlled trial.

High ventilation breathwork with retention (HVBR) has been growing in popularity over the past decade and might be beneficial for mental and physical health. However, little research has explored the potential therapeutic effects of brief, remotely delivered HVBR and the tolerability profile of this technique. Accordingly, we investigated the effects of a fully-automated HVBR protocol, along with its tolerability, when delivered remotely in a brief format. This study (NCT06064474) was the largest blinded randomised-controlled trial on HVBR to date in which 200 young, healthy adults balanced for gender were randomly allocated in blocks of 2 by remote software to 3 weeks of 20 min daily HVBR (fast breathing with long breath holds) or a placebo HVBR comparator (15 breaths/min with short breath holds). The trial was concealed as a fast breathwork study wherein both intervention and comparator were masked, and only ~ 40% guessed their group assignment with no difference in accuracy between groups. Both groups reported analogous credibility and expectancy of benefit, subjective adherence, positive sentiment, along with short- and long-term tolerability. At post-intervention (primary timepoint) for stress level (primary outcome), we found no significant group × time interaction, F(1,180) = 1.98, p = 0.16, ηp2 = 0.01, d = 0.21), nor main effect of group, (F = 0.35, p = 0.55, ηp2 < 0.01) but we did find a significant main effect of time, (F = 13.0, p < 0.01, ηp2 = 0.07). There was a significant improvement in stress pre-post-intervention in both groups, however there was no significant difference in such improvement between groups. In addition to stress at follow-up, we found no significant group x time interactions for secondary trait outcomes of anxiety, depression, mental wellbeing, and sleep-related impairment. This was also the case for state positive and negative affect after the first session of breathwork and at post-intervention. Brief remote HVBR therefore may not be more efficacious at improving mental health than a well-designed active comparator in otherwise healthy, young adults

CD4 T lymphocyte autophagy is upregulated in the salivary glands of primary Sjögren’s syndrome patients and correlates with focus score and disease activity

Background: Primary Sjögren’s syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and peripheral lymphocyte perturbation. In the current study, we aimed to investigate the possible pathogenic implication of autophagy in T lymphocytes in patients with pSS. Methods: Thirty consecutive pSS patients were recruited together with 20 patients affected by sicca syndrome a nd/or chronic sialoadenitis and 30 healthy controls. Disease activity and damage were evaluated according to SS disease activity index, EULAR SS disease activity index, and SS disease damage index. T lymphocytes were analyzed for the expression of autophagy-specific markers by biochemical, molecular, and histological assays in peripheral blood and labial gland biopsies. Serum interleukin (IL)-23 and IL-21 levels were quantified by enzyme-linked immunosorbent assay. Results: Our study provides evidence for the first time that autophagy is upregulated in CD4+ T lymphocyte salivary glands from pSS patients. Furthermore, a statistically significant correlation was detected between lymphocyte autophagy levels, disease activity, and damage indexes. We also found a positive correlation between autophagy enhancement and the increased salivary gland expression of IL-21 and IL-23, providing a further link between innate and adaptive immune responses in pSS. Conclusions: These findings suggest that CD4+ T lymphocyte autophagy could play a key role in pSS pathogenesis. Additionally, our data highlight the potential exploitation of T cell autophagy as a biomarker of disease activity and provide new ground to verify the therapeutic implications of autophagy as an innovative drug target in pSS

The neurometabolic basis of mood instability: the parvalbumin interneuron link — a systematic review and meta-analysis

The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the pathophysiology of mood and anxiety conditions associated with mood instability and hence are candidate mechanisms underlying its neurobiology. Fast-spiking parvalbumin GABAergic interneurons modulate the activity of principal excitatory neurons through their inhibitory action determining precise neuronal excitation balance. These interneurons are directly involved in generating neuronal networks activities responsible for sustaining higher cerebral functions and are especially vulnerable to metabolic stress associated with deficiency of energy substrates or mitochondrial dysfunction. Parvalbumin interneurons are therefore candidate key players involved in mechanisms underlying the pathogenesis of brain disorders associated with both neuronal networks’ dysfunction and brain metabolism dysregulation. To provide empirical support to this hypothesis, we hereby report meta-analytical evidence of parvalbumin interneurons loss or dysfunction in the brain of patients with Bipolar Affective Disorder (BPAD), a condition primarily characterized by mood instability for which the pathophysiological role of mitochondrial dysfunction has recently emerged as critically important. We then present a comprehensive review of evidence from the literature illustrating the bidirectional relationship between deficiency in mitochondrial-dependent energy production and parvalbumin interneuron abnormalities. We propose a mechanistic explanation of how alterations in neuronal excitability, resulting from parvalbumin interneurons loss or dysfunction, might manifest clinically as mood instability, a poorly understood clinical phenotype typical of the most severe forms of affective disorders. The evidence we report provides insights on the broader therapeutic potential of pharmacologically targeting parvalbumin interneurons in psychiatric and neurological conditions characterized by both neurometabolic and neuroexcitability abnormalities

Substance abuse in first-episode schizophrenic patients:A retrospective study

Several studies suggest a high comorbidity of substance abuse and schizophrenia, associated with higher frequency of relapse, more positive symptoms and depression, cognitive impairment, poorer outcome and treatment response. A high incidence of substance abuse is also observed in first-episode patients. Among patients with substance abuse, the onset precedes the onset of psychosis of several years in most cases. All the patients with a first episode of schizophrenia, at first admission to the Psychiatric Service of Diagnosis and Treatment of Ospedale Maggiore of Milan during the years 1990 to 2004, have been included in our study. The clinical evaluation has been obtained considering the following items of Brief Psychiatric Rating Scale (BPRS): conceptual disorganization, depressed mood, hostility, hallucinations, unusual content of thought. The results showed that 34.7% of first-episode schizophrenic patients had a lifetime history of substance abuse. The age of onset of schizophrenia is significantly lower for drug abusers than for patients without any type of abuse and for alcohol abusers (p &lt; 0.005). In multi drug abusers, cannabis resulted the most frequently used (49%), followed by alcohol (13%), and cocaine (4%). Substance abusers have obtained a significant higher score in "thought disturbance" item (p &lt; 0.005) and in "hostility" item (p &lt; 0.005) compared to non substance abusers. Non drug abusers showed lower mean scores of "hostility" item compared to cocaine abusers and multi drug abusers (p &lt; 0.005). Our findings seem to indicate that substance abuse in the early course of illness determines an earlier onset of schizophrenia and increases severity of some psychotic symptoms like "hallucination" and "unusual content of thought". Therefore persons incurring a risk of schizophrenia may be warned of the possible relation between substances and psychosis and have to be counselled against the use of them.</p

Online information on medical cannabis is not always aligned with scientific evidence and may raise unrealistic expectations

There is a growing literature on the potential medical uses of Cannabis sativa and cannabinoid compounds. Although these have only been approved by regulatory agencies for a few indications, there is a hype about their possible benefits in a variety of conditions and a large market in the wellness industry. As in many cases patients search for information on cannabis products online, we have analyzed the information on medical cannabis available on the Internet. Therefore, this study aims at assessing the quality of the information available online on medical cannabis