RNA Interference and Neuromuscular Diseases: A Focus on Hereditary Transthyretin Amyloidosis

: Neuromuscular diseases are severe disorders affecting the peripheral nervous system, usually driving to death in a limited time. Many new drugs, through RNA-interference technology, are revolutionizing the prognosis and quality of life for these patients. Nevertheless, given the increased life expectancy, some new issues and phenotypes are expected to be revealed. In the transthyretin-mediated hereditary amyloidosis (ATTR-v, "v" for "variant"), the RNA interference was demonstrated to effectively reduce the hepatic synthesis of transthyretin, with a significant increase in disease progression in terms of polyneuropathy and cardiomyopathy. The increased life expectancy could promote the involvement of organs where the extra-hepatic transthyretin is deposited, such as the brain and eye, which are probably not targeted by the available treatments. All these issues are discussed in this editorial

Central Sensitization in the Bladder Pain Syndrome

Introduction: Nociceptive hyper-excitability and Central Sensitization (CS), have been identified as responsible for maintaining pain in several chronic neuropathic pain conditions, among which Bladder pain syndrome (BPS). Aim of the present study was to evaluate in patients with BPS the correlation between CS and the following items pain duration, the number of other CS related diseases, the number of tried treatments for pain and of diagnostic investigations before the proper diagnosis and to identify the cut-off value of the pain delays for predicting the worsening of sensitization. Method: Fifty-eight consecutively BPS outpatients were recruited from 2014 to 2016. They were submitted to Central Sensitization Inventory (CSI), Overactive Bladder Questionnaire (OAB-8v) and visual analogic scale (VAS) for pain. We used a descriptive analysis (mean, standard deviation, range) and Spearman and Kendall test coefficient as correlation index. One-way ANOVA test was used for the comparison between groups. P-value less than 0.05 were required for statistical significance. We used receiver operating characteristic (ROC) curve analysis to retrospectively analyze the association between the years of the disease and pathological values o of CSI. Results: The patients were observed after 13.1 + 11.0 years by the onset of The CSI score was 69.7+15.8. Resulting significantly lower in patients with BPS onset in the last year the correlation between CSI and the disease duration was significant. The number of previous investigations was 3.7 + 2.8while the number of previous treatments for chronic pain was 5.9 + 3.1, resulting significantly related to CSI score. The OAB-8v was 21 + 7.5 (range 2-34). The worsening of the symptoms related to the overactive bladder at OAB-8v was related to a greater CS. After 1,5 years of the onset of the pain the CS show a progressive worsening. The mean number of other diseases (fibromyalgia, irritable bowel syndrome, anxiety or depression, migraine, neck injury, Panic Disorder Attack, chronic fatigue syndrome, temporomandibular joint syndrome, restless leg syndrome, multiple chemical sensitivities) associated to CS was 2.8+1.9. The correlation between the number of diseases associated to CS and the years of disease resulted significant. Conclusion: Patients with long lasting pelvic pain show high levels of CS, and other central sensitivity syndromes (CSS) together to worsening of overactive bladder symptoms, and increasing number of used drugs. The delay of diagnosis is related to a greater sensitization process

Dysphagia in amyotrophic lateral sclerosis: impact on patient behavior, diet adaptation, and riluzole management

This retrospective study aimed to investigate the clinical features associated with deteriorated swallow in amyotrophic lateral sclerosis (ALS) patients with spinal and bulbar onset, describe the modification of diet and liquid intake, and assess the impact of dysphagia on the use of riluzole. One hundred forty-five patients were observed periodically every 3-6 months. They underwent routinely fiberoptic endoscopic evaluation of swallowing (FEES) and spirometry; dysphagia severity was classified according to the Penetration Aspiration Scale and the Pooling score (P-score) integrated with other parameters such as sensation, collaboration, and age (P-SCA score). During a mean follow-up period of about 2 years, the percentage of ALS patients suffering from dysphagia increased to 85 (rising from 35 to 73% in patients with spinal onset and from 95 to 98% in those with bulbar onset). Also, 8% of patients with dysphagia by FEES did not perceive the disorder. The frequency of normal and semi-solid diets decreased over time, while that of pureed diets and percutaneous endoscopic gastrostomy (PEG) prescription increased. Forty-four percent of dysphagic patients refused thickeners or PEG. A significant difference was observed in the mortality rate between patients untreated with riluzole and patients treated with riluzole oral suspension (p < 0.05). Disease duration mainly impacted on the frequency of dysphagia in spinal onset patients, appearing very early in those with bulbar onset. Riluzole oral suspension would allow the safe administration in dysphagic ALS patients to avoid tablet crushing and consequent dispersion in food, common practices that are inconsistent with the safe and effective use of the drug

Olive polyphenol effects in a mouse model of chronic ethanol addiction

Objectives Alcohol addiction elicits oxidative imbalance and it is well known that polyphenols possess antioxidant properties. We investigated whether or not polyphenols could confer a protective potential against alcohol-induced oxidative stress. Methods We administered (per os) for two months 20 mg/kg of olive polyphenols containing mostly hydroxytyrosol in alcoholic adult male mice. Hydroxytyrosol metabolites as hydroxytyrosol sulfate 1 and hydroxytyrosol sulfate 2 were found in the serum of mice administered with polyphenols with the highest amount in animals treated with both polyphenols and alcohol. Oxidative stress was evaluated by FORT (free oxygen radical test) and FORD (free oxygen radical defense) tests. Results Alcoholic mice showed a worse oxidative status than nonalcoholic mice (higher FORT and lower FORD) but polyphenol supplementation partially counteracted the alcohol pro-oxidant effects, as evidenced by FORT. Conclusions A better understanding of the antioxidant protection provided by polyphenols might be of primary interest for drug discovery and dietary-based prevention of the damage associated with chronic alcohol abus

The Compound Muscle Action Potential as Neurophysiological Marker for Amyotrophic Lateral Sclerosis.

Objectives: To definite the peripheral nervous involvement in ALS through the repeated use of the compound motor action potential (CMAP) to test the progression of disease, to determine different change of phrenic CMAP and forced vital capacity (FVC) in spinal and bulbar onset, and to establish clinical and neurophysiological features of patients with poor prognosis. Material & Methods: CMAP from phrenic, ulnar, and medial plantar nerves, Medical Research Council (MRC) score, revised ALS functional rating scale (ALSFRS-R) and FVC were evaluated in 117 ALS patients every three months in one year-period. Results: Bulbar onset patients had lower FVC but similar amplitude of phrenic CMAP at baseline compared to spinal onset patients. The patients with poor prognosis had lower phrenic CMAP and FVC at baseline. CMAP values, when compared to the rate found in the previous visit, reduced significantly in both poor and good prognosis groups during the entire follow-up period, while the FVC reduced significantly only in the first three months. Conclusions: CMAP is a reproducible sensitive marker for motor neurons loss and collateral reinnervation in ALS also in a short period of time. The changes in CMAP, MRC, FVC and ALSFRS-R score resulted correlated, but CMAP is the only parameter with the advantage to demonstrate objectively the progression of disease in both patients with poor and good prognosis for the entire period of follow-up. It should be used as clinical outcome of ALS in clinical trials, taking advantage of its objectivity and selectivity for peripheral nervous system study

A Firenze messe le basi per una Piattaforma internazionale per una corretta gestione delle risorse idriche sotterranee

II 10 dicembre, in occasione della Giornata dei Diritti umani si è tenuto a Firenze, nella monumentale Sala dei Cinquecento di Palazzo Vecchio, il 1° Workshop su: "Uso delle risorse idriche sotterranee in periodi siccitosi. Esperienze dalla Toscana al resto del mondo", organizzato dalla Sezione Italiana dell'Associazione Internazionale degli Idrogeologi (IAH) con Aquifera onlus e patrocinato, oltre che dalla Regione Toscana e dal Comune di Firenze (che ha gentilmente concesso l'uso della sala), dalla Società Geologica Italiana (SGI), dal Consiglio Nazionale dei Geologi (CNG) e dal'IAH-Burdon Groundwater Network for International Development [...]

Investigating alcohol consumption during pregnancy for the prevention of Fetal Alcohol Spectrum Disorders (FASD)

The term FASD (Fetal Alcohol Spectrum Disorders) is used to describe the entire spectrum of pathologies and disorders caused by alcohol exposure in uterus. Alcohol assumed in pregnancy passes directly through the placental barrier causing a broad range of symptoms whose severity can greatly vary in degree. The alcohol teratogenic effect may result in physical damage and specific facial anomalies, growth delays, neurological defects along with intellectual disabilities and behavioral problems. Children affected show difficulties in verbal learning, memory, visual-spatial abilities, attention, logic and math abilities, information processing, executive functions as well as in many other domains and in general coping with daily life. Total abstention from alcohol during pregnancy is strongly recommended, as a safe threshold of consumption has not been established yet. Hence, the early identification of alcohol consumption in pregnancy is crucial. Specific methodologies to overcome difficulties related to the identification of alcohol behavior in pregnant women are needed and intervention protocols should be implemented to prevent damage in offsprings. This paper gives an overview on this pathology, from clinical delineation to epidemiology and risk factors with a special focus to promote alcohol-free pregnanc

Laryngeal sensitivity in patients with amyotrophic lateral sclerosis

Recent studies have shown the involvement of the sensory nervous system in patients with amyotrophic lateral sclerosis (ALS). The aim of our study was to investigate the correlation between the laryngeal sensitivity deficit and the type of ALS onset (bulbar or spinal) in a large series of 114 consecutive ALS patients. Participants were subdivided into two groups, bulbar and spinal ALS, according to the clinical onset of disease and submitted to a clinical and instrumental evaluation of swallowing, including a fiber-optic endoscopic evaluation of swallowing with sensory testing. Dysphagia severity was scored using the Penetration–Aspiration Scale (PAS) and the Pooling score (P-score). In addition, three patients with laryngeal sensitivity deficit were submitted to a laryngeal biopsy to assess the status of the sensory innervation. All patients showed a normal glottal closure during phonation and volitional cough. Fifty-six subjects (49%), 14 spinal- and 42 bulbar-onset ALS, showed dysphagia at the first clinical observation (PAS score >1; P-score >5). Dysphagia resulted more frequently in bulbar-onset ALS (P < 0.01). Thirty-eight (33%) patients had a sensory deficit of the larynx. The sensory deficit of the larynx was significantly more frequent in bulbar-onset ALS (P < 0.01). The sensory deficit of the larynx among dysphagic patients was also significantly more frequent in bulbar-onset ALS (P = 0.02). Several abnormalities were found in all three subjects who underwent a laryngeal biopsy: in one patient, no intraepidermal fiber was found; in the other two, the fibers showed morphological changes. Our observations are important to consider for assessment and management of dysphagia in patients with AL

Interleukin-8 and laryngeal squamous cell carcinoma

Laryngeal squamous cell carcinoma (LSCC) is the second most common neoplasm of the upper aerodigestive tract after cancer of the oral cavity. Over the past two decades, even though patients have benefited greatly from the latest advances in surgical techniques, chemotherapy and radiation therapy, the survival rate of LSCC has not improved significantly. It is reported that changes in the expression of cytokines and growth factors have implications in the malignant transformation of many cancers including head and neck squamous cell carcinoma and, more recently, LSCC. It has been hypothesized that some of these cytokines may be used as additional diagnostic markers in the sera of patients because of their excessive production by the tumor cells. This could be of great value since there are currently no reliable markers to predict either tumor development or relapse. Interleukin-8 (IL-8), a chemokine (C-X-C motif) ligand 8 (CXCL8), is now reported to play an important role in cancer invasion, angiogenesis and metastasis. Recent studies have shown an increased concentration of IL-8 in patients with LSCC and a positive association with lymph node metastasis and T classification. Interleukin-8 levels were not significantly associated with shorter overall survival and cancer progression-free survival. The investigation of the mechanisms of origin, invasion, and metastasis of the cancer is one of the emergent and most promising scientific fields in head and neck cancer, especially in LSCC. Biomarkers such as IL-8 could have a role as a screening test and as a support of the clinical decisions for appropriate therapy and postoperative care in individual patients

Role of neuropeptide tyrosine (NPY) in ethanol addiction

Here, an overview of neurophysiological, pharmacological and genetic research on the role of neuropeptide tyrosine (NPY) in ethanol consumption and withdrawal is presented. NPY is abundantly expressed in the extended amygdala and is critically involved in the regulation of negative affective states in rats, also is involved with neurobiological responses to ethanol and other drug of abuse. Genetic, molecular and pharmacological evidences suggest that NPY is an important neurobiological substrate for the predisposition to alcoholism. Administration, as well as the withdrawal of ethanol, alters central NPY expression. Alcohol- preferring rats exhibit basal NPY deficits in central amygdala. In the latter, NPY may rescue dependence-induced increases in anxiety and alcohol drinking. Low NPY levels in some brain regions following ethanol withdrawal contribute to the increased sensitivity to seizure and the heightened levels of anxiety characteristic of withdrawal responses. Mice with deletion of NPY gene exhibit a high-anxiety, high-alcohol-drinking phenotype. Pharmacological and genetic manipulations suggest that central NPY signaling modulates ethanol consumption via Y1, Y2, and Y5 receptors. Analysis of chromosomal regions (QTLs) associated with alcohol consumption identified NPY as one of the genes that influence alcohol dependence and as a promising target for pharmacotherapeutics to combat alcohol associated disorders. Consequently, NPY is a potentially new pharmacological target for the treatment of alcohol diseases