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Il capitolo si occupa di analizzare le fattispecie di reato regolate all’interno dell’art. 73 del D.P.R. 309/1990, anche noto come il testo unico in materia di stupefacenti, prendendo le mosse da una prima ricostruzione storica, che ripercorre le tappe fondamentali dallo sviluppo e della modificazione della relativa disciplina, a partire dalla sua introduzione con la legge Iervolino-Vassalli, fino ad individuare un quadro il più possibile dettagliato della regolazione attuale. Si parte dunque da una breve ricognizione del sistema contenuto nell’art. 73, nella sua formulazione originaria, per poi analizzare le modifiche ad esso apportate dalla celebre legge 21 febbraio 2006, n. 49, c.d. Fini-Giovanardi, di conversione del d.l. 30 dicembre 2005, n. 272, che, tra le più importanti novità, eliminava il precedente sistema sanzionatorio a «doppio binario», che distingueva tra condotte illecite aventi ad oggetto droghe leggere ovvero droghe pesanti, e lo sostituiva con un sistema a «binario unico». Segue, poi, una approfondita analisi della sentenza 25 febbraio 2014, n. 32, con cui la Corte Costituzionale ha dichiarato illegittimi gli artt. 4-bis e 4-vices ter della l. 49/2006, con l’effetto di espungere dall’ordinamento le modifiche da essi apportate alla precedente disciplina sui reati in materia di stupefacenti. Si analizzano, dunque, le principali conseguenze scaturite dalla declaratoria di illegittimità, ponendo particolare attenzione alle questioni più complesse, legate ai problemi di diritto intertemporale, connesse alla individuazione del trattamento sanzionatorio applicabile al singolo caso; per questo tipo di indagine si procede prestando peculiare attenzione ai pronunciamenti della giurisprudenza di legittimità sul punto. Conclusa questa prima panoramica storica, il percorso di ricostruzione della disciplina si completa con l’analisi degli ultimi interventi normativi sul tema, tributando particolare enfasi alla l. 2 dicembre 2016, n. 242, in cui il legislatore ha disposto che le varietà di cannabis, c.d. sativa, iscritte nel Catalogo europeo delle varietà delle specie di piante agricole, non rientrano nell’ambito di applicazione del testo unico in materia di stupefacenti e che la coltivazione delle stesse è consentita senza necessità di autorizzazione. La trattazione si cala poi nello studio analitico delle singole fattispecie di reato, quali regolate all’interno dell’art. 73 D.P.R. 309/1990; analizza la disciplina dell’uso esclusivamente personale di sostanze stupefacenti e si preoccupa di precisare il tema dell’uso di gruppo. Si procede, di poi, ad indagare il tema dei fatti di lieve entità, anche in questo caso, prendendo le mosse da una prima ricognizione degli effetti prodotti sulla relativa regolazione dalla sentenza della Corte cost. 32/2014 e dalla successiva giurisprudenza costituzionale. A conclusione del capitolo segue la ricostruzione delle circostanze attenuanti e aggravanti.

Objectives Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired peripheral neuropathy of immunological origin with a clinical presentation and course that are extremely variable. The therapeutic approach generally includes corticosteroid drugs, intravenous immunoglobulins (IVIGs) or plasmapheresis alone or in combination as first line therapy, and immunosuppressants. In 2014 the Italian regulatory agency included subcutaneous immunoglobulins (SCIGs) in the list of off-label drugs reimbursed by the national health service. Our aim is to compare costs and outcomes of IVIG versus SCIG therapy. Methods Patients medical records and therapeutic plans were retrospectively analysed to collect data on IVIG treatments 1 year before the switch to SCIG, and after 1 year of treatment with SCIG. A budget impact analysis was conducted through resource identification and quantification, and healthcare and non-health care costs evaluation. Results 13 of 34 patients affected by CIDP who were referred to our neurophysiopathological unit and treated with IVIG were switched to home-based SCIG. After 1 year of receiving SCIG, 12 patients remained neurologically stable and reported good outcomes. Considering the cost of IVIG (€30.97/g) and adding to this the direct and indirect healthcare costs, the total cost of IVIG treatment for the 12 patients in a year was €371 417.06, compared with the cost of SCIG (€51.57/g) for a total annual cost of €631 745.16, not including indirect costs. Conclusions We observe a higher cost for SCIG treatment versus IVIG, which is not in line with data in the literature. However, SCIGs offer some important safety benefits and improvements in patient quality of life.

The pelvic floor is a complex anatomical entity and its neuromuscular assessment is evaluated through debated neurophysiological tests. An innovative approach is the study of pelvic floor through dynamic transperineal ultrasound (DTU). The aim of this study is to evaluate DTU sensitivity in recognizing patients with fecal incontinence and to evaluate its concordance with the results of the motor latency studied via pudendal nerve terminal motor latency (PNTML). Female patients affected by FI addressed to our center of coloproctology were prospectively assessed. After a coloproctological evaluation, comprising the PNTML assessment to identify pudendal neuropathy, patients were addressed to DTU to determine anterior and posterior displacement of puborectalis muscle by a blinded coloproctologist. In order to compare the data, a cohort of female healthy volunteers was enrolled. Sixty-eight subjects (34 patients and 34 healthy volunteers) were enrolled. The sensitivities of anterior displacement, posterior displacement and either anterior or posterior displacement in determining the fecal incontinence were 82%, 67% and 91%, respectively. A further high correlation of either anterior or posterior displacement with PTNML was also noted (88%). DTU is an indirect, painless and reproducible method for the identification of the pelvic floor neuromuscular integrity. Its findings seem to highly correlate with FI symptoms and with PNTML results. In the near future, after larger comparative studies, DTU would be considered a potential reliable non-invasive and feasible indirect procedure in the identification of fecal incontinence by pudendal neuropathy. Trial registration number is NCT03933683.

Rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has demonstrated good efficacy as treatment in patients with resistant chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but it is highly immunogenic due to its structure. Ocrelizumab (OCR) is a humanized anti-CD20 antibody, with higher tolerability and a lower immunogenic profile compared to RTX. We present a case of refractory CIDP effectively treated with OCR, switched from RTX after the development of anti-drug antibodies. A 25-year-old man was admitted to our clinic for the onset of distal upper and lower limb weakness and numbness, with electrodiagnostic criteria of CIDP. After several attempted standard CIDP treatments, RTX was introduced due to poor control of clinical relapses. Unfortunately, the patient developed a high anti-drug antibody titer after RTX infusion, with no control of disease. OCR was started as an off-label treatment, resulting in partial recovery from the last recurrence and achieving good prevention of new relapses with no adverse events. We suggest that OCR should be considered as another therapeutic option in refractory CIDP. In the literature, this is the first case of CIDP treated with OCR, demonstrating good efficacy for its anti-CD20 effect and better tolerability because of its lower immunogenicity.

Autosomal recessive Pompe disease is a lysosomal disorder caused by mutations of the acid-?-glucosidase (GAA) gene. Deficiency of GAA enzyme leads to glycogen accumulation and autophagy impairment in cardiac and skeletal muscles, but also in lymphocytes. Since an effective therapy is available, a rapid, sensitive, and specific test is crucial to early identify affected subjects. Number of lymphocytes containing PAS-positive vacuoles was evaluated on blood films from 72 consecutive adult patients with hyperckemia and/or muscle weakness, 13 genetically confirmed late-onset-Pompe-disease (LOPD) and 13 of their offspring. GAA activity, measured on dried blood spot (DBS) in all patients inversely correlated with number of PAS-positive lymphocytes. More than 4 PAS-positive lymphocytes were found in 11 out of the 72 patients (6 new diagnosis of LOPD, 3 different glycogen storage myopathies, 1 glucose-6-phosphate dehydrogenase deficiency, 1 caveolinopathy), in all 13 LOPD patients and in the 13 LOPD offspring. These latter resulted to have all a single GAA mutation but low GAA levels. Immunostaining with the autophagy markers LC3 and p62 confirmed the autophagic nature of lymphocytes vacuoles. ROC curve assessment of PAS-positive lymphocytes disclosed 100% of sensitivity and 94% of specificity in recognizing both compound heterozygous and heterozygous GAA carriers. The other myopathies with more than 4 PAS-positive lymphocytes appeared to be all related to impaired autophagy, which seems to be responsible of PAS-positive vacuolated lymphocytes formation. Quantification of PAS-positive lymphocytes in blood films is useful to identify autophagic vacuolar myopathies and should be routinely used as first level test for Pompe disease.

Paramyotonia congenita (PC) is a neuromuscular disorder caused by point mutations of the sodium channel gene SCN4A that leads to gating defects in the sodium channel of the muscle membranes, thus resulting in a persistent sodium influx into the sarcoplasma. Classic PC phenotype is characterised by episodes of cold-induced stiffness, prominently in the facial and upper limb muscles, exacerbated by a sustained muscular activity (paramyotonia) and followed by a variable degree of weakness. Electromyography (EMG) at rest discloses myotonic bursts and reduced Compound Muscle Action Potential (CMAP) amplitudes, while short-term forearm exercise and cooling tests induce further decrease resulting in electrical silence in some patients. Muscle paralysis, after paramyotonic attacks, may last from a few dozen minutes to 24–48 hours, thus reducing considerable quality of life and autonomy in daily activities. Among voltage-gating sodium channel blockers, mexiletine is considered the drug of choice in PC and other sodium channel myopathies.1 However, mexiletine efficacy has been investigated only in a few heterogeneous small PC series during a month-lasting follow-up. In experimental studies, flecainide, a class IC antiarrhythmic drug, appeared to be more effective than mexiletine to counteract SCN4A dysfunction.2 However, we lack long-term follow-up studies on flecainide efficiency in patients with PC with homogeneous pheno/genotype. The aim of this study was to assess the responsiveness to flecainide in a large family with classic PC phenotype by electrophysiological and quality of life evaluations. The Italian PC family pedigree includes 60 …

Motor neuron disease (MND) is a neurodegenerative disease determining progressive and relentless motor deterioration involving both upper and lower motor neurons (UMN and LMN); several variants at onset are described. Here we describe a case of MND presenting as pure spastic monoparesis in which magnetic resonance imaging (MRI) gave a substantial contribution in confirming the diagnosis and assessing the severity of UMN involvement. An isolated pyramidal syndrome, with complete absence of LMN signs, is a rare phenotype in the context of MND (less than 4% of total cases), especially if restricted to only one limb. Several other elements made this case an unusual presentation of MND: the late age of onset (8 th decade), the subacute evolution of symptoms (raising the suspicion of an ischemic or inflammatory, rather than degenerative, etiology), the patient’s past medical history (achalasia, erythema nodosum), the increase of inflammatory indices. Conventional MRI showed no focal lesions that could explain the clinical features; therefore, we used advanced MR sequences. Diffusion tensor imaging (DTI) evaluation evidenced bilateral impairment of corticospinal tract (CST) diffusion metrics, with clear right-left asymmetry, pointing to a neurodegenerative etiology, which clinically appeared less likely at that time. Magnetic resonance spectroscopy (MRS) showed a significant reduction of NAA/Cho + Cr ratio in the motor cortex (MC), further supporting the hypothesis of UMN degeneration. In conclusion, in this particular case of MND, whose nosographic framing has not been fully defined, advanced MRI techniques with DTI and MRS proved to be of great usefulness in confirming a diffuse UMN involvement, possibly at a more advanced stage than its clinical expression.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy usually respond to immune therapies including steroids and plasma exchange for CIDP and high-dose intravenous immunoglobulins (IVIgs) for both diseases. Other immune therapies have been used to reduce the costs or the side-effects of these therapies, but their efficacy was only recently assessed in randomized controlled trials (RCTs).The prolonged efficacy of IVIg in CIDP has been confirmed in a 48-week RCT. Two other RCTs showed that oral methotrexate or intramuscular interferon beta were not more effective than placebo in improving the efficacy or reducing the dose of IVIg or steroids. In multifocal motor neuropathy, a RCT showed that oral mycophenolate mofetil was not more effective than placebo in increasing the efficacy or reducing the dose of IVIg. Other immune therapies were assessed in open trials in both diseases, but their efficacy remains unclear, even if in some patients a possible efficacy of rituximab was reported. Some preliminary studies suggest that subcutaneous immunoglobulin may be as effective as IVIg in the maintenance therapy of CIDP and multifocal motor neuropathy.After several years of anecdotal reports, a number of RCT have now appeared in CIDP and multifocal motor neuropathy, but their results are still insufficient to support the use of new therapies in these diseases.

Metabolic profiling is defined as the simultaneous assessment of substrate fluxes within and among the different pathways of metabolite synthesis and energy production under various physiological conditions. The use of stable-isotope tracers and the analysis of the distribution of labeled carbons in various intermediates, by both mass spectrometry and NMR spectroscopy, allow the role of several metabolic processes in cell growth and death to be defined. In the present paper we describe the metabolic profiling of Jurkat cells by isotopomer analysis using 13 C-NMR spectroscopy and [1,2- 13 C 2 ]glucose as the stable-isotope tracer. The isotopomer analysis of the lactate, alanine, glutamate, proline, serine, glycine, malate and ribose-5-phosphate moiety of nucleotides has allowed original integrated information regarding the pentose phosphate pathway, TCA cycle, and amino acid metabolism in proliferating human leukemia T cells to be obtained. In particular, the contribution of the glucose-6-phosphate dehydrogenase and transketolase activities to phosphoribosyl-pyrophosphate synthesis was evaluated directly by the determination of isotopomers of the [1′- 13 C], [4′,5′- 13 C 2 ]ribosyl moiety of nucleotides. Furthermore, the relative contribution of the glycolysis and pentose cycle to lactate production was estimated via analysis of lactate isotopomers. Interestingly, pyruvate carboxylase and pyruvate dehydrogenase flux ratios measured by glutamate isotopomers and the production of isotopomers of several metabolites showed that the metabolic processes described could not take place simultaneously in the same macrocompartments (cells). Results revealed a heterogeneous metabolism in an asynchronous cell population that may be interpreted on the basis of different metabolic phenotypes of subpopulations in relation to different cell cycle phases.

Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of beta-oxidation flux by labeled palmitate demonstrates that tBid inhibits beta-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on beta-oxidation. The unexpected role of tBid in the regulation of lipid beta-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.