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Background and Aims: Deep repetitive Transcranial Magnetic Stimulation (deep rTMS) over the bilateral insula and prefrontal cortex (PFC) can promote weight-loss in obesity, preventing cardiometabolic complications as Type 2 Diabetes (T2D). To investigate the changes in the functional brain integration after dTMS, we conducted a resting-state functional connectivity (rsFC) study in obesity., Methods and Results: This preliminary study was designed as a randomized, double-blind, sham-controlled study: 9 participants were treated with high-frequency stimulation (realTMS group), 8 were sham-treated (shamTMS group). Out of the 17 enrolled patients, 6 were affected by T2D. Resting-state fMRI scans were acquired at baseline (T0) and after the 5-week intervention (T1). Body weight was measured at three time points [T0, T1, 1-month follow-up visit (FU1)]. A mixed-model analysis showed a significant group-by-time interaction for body weight (p = .04), with a significant decrease (p < .001) in the realTMS group. The rsFC data revealed a significant increase of degree centrality for the realTMS group in the medial orbitofrontal cortex (mOFC) and a significant decrease in the occipital pole., Conclusion: An increase of whole-brain functional connections of the mOFC, together with the decrease of whole-brain functional connections with the occipital pole, may reflect a brain mechanism behind weight-loss through a diminished reactivity to bottom-up visual-sensory processes in favor of increased reliance on top-down decision-making processes., Trial Registration Number: ClinicalTrials.gov NCT03009695., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The world population is facing a health challenge never seen since the Spanish influenza of one hundred years ago. During the last months, the scientific community has been debating on the potential harmful effect of angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin II receptor type 1 receptor blockers (AT1-receptor blockers, ARBs) during the COVID-19 pandemic. That is because the S spike protein of SARS-CoV viruses utilizes the angiotensin-converting enzyme 2 (ACE2) as a receptor to enter alveolar epithelial cells. Obesity, often associated to type 2 Diabetes, was shown to worsen the prognosis of SARS-CoV-2 infection. Herein we discuss the complex interaction between the renin-angiotensin-aldosterone system (RAAS), its receptors, and the interaction with the Kallikrein-Kinin-system (KKS) and the potential activation of the coagulation cascade. Alteration of the equilibrium between the RAAS system and the KKS cascade may explain the frequent thromboembolic complications of COVID-19 mainly seen in obese and diabetic-obese patients. In contrast, angiotensin (1-7) contributes to maintaining a correct balance between RAAS and KKS system. Our conclusion is that the higher mortality rate in patients with obesity is linked to the alteration of RAS and RAS-KKS interaction consequent to SARS-CoV-2-cell entrance. At present, no data support the necessity of modifying ACEi or ARBs treatment in hypertensive patients.

Purpose: Repetitive Transcranial Magnetic Stimulation (rTMS) has been demonstrated to be effective in body weight control in individuals with obesity. Most clinical trials on rTMS provided a reassuring safety profile. In the present work, we present an extensive analysis on both severe and mild Adverse Events (AEs) in obese individuals treated with rTMS., Methods: We examined the intensity, duration, correlation with the treatment, up to 1 year after the end of rTMS treatment., Results: Descriptive analysis included a total of 63 subjects undergoing a 5-week deep rTMS experimental treatment for obesity (age 48.3 ± 10.4 years; BMI 36.3 ± 4.4 kg/m 2 ): 31 patients were treated with high-frequency rTMS (HF), 13 with low-frequency rTMS (LF), and 19 were sham treated (Sham). Thirty-two subjects (50.8%) reported a total of 52 AEs, including mainly moderate (51.9%) events. The most frequently reported side effects were headaches of moderate intensity (40.4%) and local pain/discomfort (19.2%) and resulted significantly more frequent in HF group compared to other groups (p < 0.05). No significant differences among groups were found for the other reported AEs: drowsiness, insomnia, paresthesia, vasovagal reactions, hypertensive crisis. No AEs potentially related to the rTMS arised up to 1 year from the end of the treatment., Conclusions: This is the first comprehensive safety analysis in obese patients treated with rTMS. The analysis did not reveal any unexpected safety concerns. Only headaches and local pain/discomfort have been significantly more frequent in the HF group, confirming the good tolerability of rTMS even in the obese population potentially more susceptible to side effects of brain stimulation.

There are reported gender differences in brain connectivity associated with obesity. In the elderlies, the neural endophenotypes of obesity are yet to be elucidated. We aim at exploring the brain metabolic and connectivity correlates to different BMI levels in elderly individuals, taking into account gender as variable of interest.We evaluated the association between BMI, brain metabolism and connectivity, in elderly females and males, by retrospectively collecting a large cohort of healthy elderly subjects (N=222; age=74.03±5.88 [61.2-85.9] years; M/F=115/107; BMI=27.00±4.02 [19.21-38.79] kg/m 2 ). Subjects underwent positron emission tomography with [18F]FDG. We found that, in females, high BMI was associated with increased brain metabolism in the orbitofrontal cortex (R=0.44; p<0.001). A significant BMI-by-gender interaction was present (F=7.024, p=0.009). We also revealed an altered connectivity seeding from these orbitofrontal regions, namely expressing as a decreased connectivity in crucial control/decision making circuits, and as an abnormally elevated connectivity in reward circuits, only in females. Our findings support a link between high BMI and altered brain metabolism and neural connectivity, only in elderly females. These findings indicate a strong gender effect of high BMI and obesity that brings to considerations for medical practice and health policy.

Aim: To test the hypothesis that deep transcranial magnetic stimulation (dTMS) reduces food craving and causes weight loss via neuromodulation., Materials and Methods: This pilot study was designed as a randomized, double-blind, sham-controlled study. A total of 33 obese people (nine men, 24 women, mean age 48.1 ± 10.6 years, body mass index [BMI] 36.9 ± 4.7 kg/m 2 ) were randomized and completed the study: 13 participants underwent a 5-week treatment with high-frequency (HF) dTMS (18 Hz; HF group), 10 were treated with low-frequency (LF) dTMS (1 Hz; LF group), and 10 were sham-treated (sham group). Food craving, and metabolic and neuro-endocrine variables were evaluated at baseline, after the 5-week treatment, and at follow-up visits (1 month, 6 months, 1 year after the end of treatment)., Results: The mixed-model analysis for repeated measures showed a significant interaction of time and groups for body weight (P = 0.001) and BMI (P = 0.001), with a significant body weight (-7.83 ± 2.28 kg; P = 0.0009) and BMI (-2.83 ± 0.83, P = 0.0009) decrease in the HF versus the sham group. A decreasing trend in food craving in the HF versus the LF and sham groups (P = 0.073) was observed. A significant improvement of metabolic and physical activity variables was found (P < 0.05) in the HF group., Conclusions: We demonstrated the safety and efficacy of dTMS, in addition to physical exercise and a hypocaloric diet, in reducing body weight for up to 1 year in obese people. We hypothesize that a possible mechanism of HF dTMS treatment is modulation of the dopaminergic pathway and stimulation of physical activity., (© 2019 John Wiley & Sons Ltd.)

Purpose: In obesity, metabolic and voluntary factors regulate appetite, and a dysregulation of the reward pathway was demonstrated in all addiction disorders. Deep transcranial magnetic stimulation (dTMS) is already used to modulate cerebral dopamine activation in neuro-psychiatric diseases. We presently assess the acute effect of high frequency (HF) and low frequency (LF) dTMS on the modulation of the main neuropeptides and neurotransmitters involved in the reward pathway in obese subjects., Methods: This study was designed as a double-blind, sham-controlled, randomized clinical trial. Thirty-three obese patients (9 males, 24 females, age 48.1 ± 10.6, BMI 36.4 ± 4.7) were enrolled in the study. All patients were studied during a single dTMS session and blood aliquots were drawn before and after a single dTMS session. Metabolic and neuro-endocrine parameters were evaluated before and after: (1) 18 Hz dTMS (HF, 13 patients); (2) 1 Hz dTMS (LF, 10 patients); (3) Sham treatment (Sham, 10 patients)., Results: No statistically significant variations in metabolic parameters, systolic and diastolic blood pressure, and heart rate were shown acutely. HF showed a significant increase of β-endorphin compared to other groups (p = 0.048); a significant increase of ghrelin in LF (p = 0.041) was also demonstrated., Conclusions: A single session of HF dTMS treatment determines in obese subjects an acute increase of β-endorphin level, indicating an activation of the reward pathway. The present findings constitute proof of principle for a potential application of this methodology in obesity treatment.

Introduction: Alcohol Use Disorders (AUD) is a leading cause of mortality and morbidity worldwide. At present disulfiram, naltrexone and acamprosate are approved for the treatment of AUD in U.S. and Europe. Nalmefene is approved in Europe and sodium oxybate is approved in Italy and Austria only. Baclofen received a 'temporary recommendation for use' in France., Areas Covered: The safety of the above mentioned medications on liver, digestive system, kidney function, nervous system, pregnancy and lactation and their possible side effects are described and discussed., Expert Opinion: Mechanism of action and metabolism of these drugs as well as patients' clinical characteristics can affect the safety of treatment. All approved medications are valid tools for the treatment of AUD in patients without advanced liver disease. For some drugs, attention should be paid to patients with renal failure and medications may be used with caution, adjusting the dosage according to kidney function. In patients with AUD and advanced liver disease, at present only baclofen has been formally tested in randomized controlled trials showing its safety in this population.

Aims: Primary outcome of this observational study was to compare weight changes in two groups of overweight and obese individuals: subjects who had a diet prescribed on the base of resting energy expenditure (REE) measured by indirect calorimetry and subjects whose REE was estimated by a predictive equation. In addition, we analyzed differences in weight and metabolic parameter variation in subjects with and without an adequate to predicted REE., Methods: We retrospectively analyzed data of 355 overweight and obese patients: 215 on a diet based on REE measured by indirect calorimetry and 140 following a diet based on REE estimated by the Harris-Benedict equation. Anthropometric and metabolic parameters were evaluated for 18 months from baseline. Propensity score adjustment was used to adjust for known differences between the groups being compared., Results: A significant greater decrease in body weight was observed in the group that underwent indirect calorimetry compared to the group that did not undergo it (p < 0.001). No significant differences were observed between patients with not adequate to predicted REE compared to patients with adequate to predicted REE., Conclusions: A weight reduction program based on REE measurement appears more effective than a dietary program based on predictive formulas. This study suggests the routine use of indirect calorimetry in all weight reduction procedures.

Previous studies in humans with type 1 diabetes mellitus (T1D) and in nonobese diabetic mice have investigated the beneficial immunomodulatory potential of aerobic physical activity. Performing high volume of aerobic exercise may favorably regulate autoimmunity in diabetes. We tested whether increased physical activity is a self-sufficient positive factor in T1D subjects. During a 3-month observational period, active (six males; 40.5 ± 6.1 years; BMI: 24.5 ± 2.1) and sedentary (four males, three females; 35.9 ± 8.9 years; BMI: 25.7 ± 3.8) T1D individuals on insulin pump therapy were studied for metabolic, inflammatory, and autoimmune parameters. At baseline and at the end of a 3-month period, glycosylated hemoglobin (HbA1c), autoantibodies (anti-GAD, anti-ZnT8, anti-IA2, and ICA) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. During the third month of the period, physically active T1D patients showed a significant reduction in the average glucose levels (-9%, p = 0.025, by CGM) compared to the first month values, and even their hyperglycemic episodes (>180 mg/dl) diminished significantly (-24.2%, p = 0.032 vs. first month). Moreover, active T1D subjects exhibited an improved body composition with respect to sedentary controls. No significant changes were detected as to the autoimmune and inflammatory profiles. This study confirms the beneficial role of physical exercise associated with insulin pump therapy in order to improve metabolic control in individuals with T1D. These preliminary positive observations need to be challenged in a prolonged interventional follow-up.

Introduction: Sodium oxybate (SMO) has been shown to be safe and effective in the treatment of patients with alcohol use disorders (AUDs); it was approved in Italy and Austria for the treatment of alcohol withdrawal syndrome and for relapse prevention. The focus of this review is to discuss the clinical evidence on the therapeutic potential of SMO for AUDs., Areas Covered: This review covers the studies in patients with alcohol withdrawal syndrome who received SMO for the treatment of withdrawal symptoms and the studies in patients with AUDs who received SMO to achieve total alcohol abstinence, reduction of alcohol intake, and relapse prevention. Relevant medical literature on SMO was identified by searching databases including MEDLINE and EMBASE (searches last updated 20 September 2013), bibliographies from published literature, clinical trial registries/databases, and websites., Expert Opinion: SMO has proved safe and effective in the treatment of alcohol withdrawal syndrome and in the prevention of relapses. Craving for and abuse of SMO have been reported, in particular in some subtypes of alcoholic patients, e.g., those affected by co-addiction and/or psychiatric comorbidity. Future multicenter, multinational, randomized clinical trials should be useful to optimize the treatments in relation with patients' characteristics, for example, pharmacogenetic, neurobiological, and psychological.

Background: Persistent hiccup is a worrying symptom both for patients, because of reduced quality of life, and for physicians, because of frustration for unsuccessful treatments., Aim: To test baclofen administration for the treatment of persistent hiccup., Method: We report a series of seven patients affected by persistent hiccup successfully treated with baclofen., Results: Hiccup stopped in all patients after a single administration of the drug., Conclusions: Baclofen is a GABA(B) receptor agonist. It is conceivable that the reduction of dopamine release by GABA(B) receptor stimulation is able to interrupt hiccup's reflex arc., (© 2013 John Wiley & Sons Ltd.)

Hepatitis C virus (HCV) and alcoholic liver disease (ALD), either alone or in combination, count for more than two thirds of all liver diseases in the Western world. There is no safe level of drinking in HCV-infected patients and the most effective goal for these patients is total abstinence. Baclofen, a GABA(B) receptor agonist, represents a promising pharmacotherapy for alcohol dependence (AD). Previously, we performed a randomized clinical trial (RCT), which demonstrated the safety and efficacy of baclofen in patients affected by AD and cirrhosis. The goal of this post-hoc analysis was to explore baclofen's effect in a subgroup of alcohol-dependent HCV-infected cirrhotic patients. Any patient with HCV infection was selected for this analysis. Among the 84 subjects randomized in the main trial, 24 alcohol-dependent cirrhotic patients had a HCV infection; 12 received baclofen 10mg t.i.d. and 12 received placebo for 12-weeks. With respect to the placebo group (3/12, 25.0%), a significantly higher number of patients who achieved and maintained total alcohol abstinence was found in the baclofen group (10/12, 83.3%; p=0.0123). Furthermore, in the baclofen group, compared to placebo, there was a significantly higher increase in albumin values from baseline (p=0.0132) and a trend toward a significant reduction in INR levels from baseline (p=0.0716). In conclusion, baclofen was safe and significantly more effective than placebo in promoting alcohol abstinence, and improving some Liver Function Tests (LFTs) (i.e. albumin, INR) in alcohol-dependent HCV-infected cirrhotic patients. Baclofen may represent a clinically relevant alcohol pharmacotherapy for these patients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Animal studies suggest that the gut-brain peptide ghrelin plays an important role in the neurobiology of alcohol dependence (AD). Human studies show an effect of alcohol on ghrelin levels and a correlation between ghrelin levels and alcohol craving in alcoholics. This investigation consisted of two studies. Study 1 was a 12-week study with alcohol-dependent subjects, where plasma ghrelin determinations were assessed four times (T0-T3) and related to alcohol intake and craving [Penn Alcohol Craving Score (PACS) and Obsessive Compulsive Drinking Scale (OCDS)]. Serum growth hormone levels and assessment of the nutritional/metabolic status were also performed. Study 2 was a pilot case-control study to assess ghrelin gene polymorphisms (Arg51Gln and Leu72Met) in alcohol-dependent individuals. Study 1 showed no significant differences in ghrelin levels in the whole sample, while there was a statistical difference for ghrelin between non-abstinent and abstinent subjects. Baseline ghrelin levels were significantly and positively correlated with the PACS score at T1 and with all craving scores both at T2 and T3 (PACS, OCDS, obsessive and compulsive OCDS subscores). In Study 2, although there was a higher frequency of the Leu72Met ghrelin gene polymorphism in alcohol-dependent individuals, the distribution between healthy controls and alcohol dependent individuals was not statistically significant. This investigation suggests that ghrelin is potentially able to affect alcohol-seeking behaviors, such as alcohol drinking and craving, representing a new potential neuropharmacological target for AD., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Background: A relationship between some hypothalamic-pituitary-related hormones and craving for alcohol has been suggested, leading to hypothesize a role of some hormones in the neurobiology of alcohol dependence. Investigating this association in alcohol-dependent (AD) patients was the aim of this preliminary and exploratory study., Methods: Cortisol, adrenocorticotropic hormone, prolactin, thyroid-stimulating hormone (TSH), free T3, free T4, growth hormone, follicle-stimulating hormone, luteinizing hormone as well as administering the Obsessive-Compulsive Drinking Scale (OCDS) and Penn Alcohol Craving Scale (PACS) were assessed at baseline and after 12 weeks in 25 current AD patients. Patients were treated with baclofen (10 mg t.i.d.) for these 12 weeks. Sixteen patients remained totally abstinent for 12 weeks., Results: At baseline, a significant inverse correlation was found between TSH and PACS (r = -0.46; p = 0.022) and OCDS scores (r = -0.53; p = 0.007). A significant direct correlation was found between free T3 and OCDS score (r = 0.44; p = 0.026). In the 16 abstinent patients, craving scores were significantly decreased at 12 weeks (p < 0.01). At 12 weeks, no significant correlation was found between TSH and craving, but free T3 remained directly correlated with OCDS score (r = 0.60; p = 0.013)., Conclusions: A relationship between alcohol craving and free T3 and TSH was demonstrated in AD patients, suggesting the potential involvement of the hypothalamic-pituitary-thyroid axis in the neurobiology of alcohol craving.

Objectives: To evaluate state and trait form of anxiety and current depression in patients affected by gastrointestinal diseases., Methods: We studied 1641 outpatients with gastrointestinal disorders, consecutively referred to our Internal Medicine outpatients from 1997 to 2005. State and trait anxiety were assessed by the State and Trait Anxiety Inventory. Current depression was assessed by the Zung self-rating depression scale., Results: Among patients, 1379 (84.1%) showed state anxiety, 1098 (67%) showed trait anxiety and 442 (27%) showed current depression. The number of gastrointestinal diseases was directly correlated to state anxiety (p < 0.001) and trait anxiety (p = 0.04). Females showed higher levels of anxiety and depression than males (p < 0.001). State anxiety was related to food allergies (p < 0.001), small intestinal bacterial overgrowth (SIBO) (p = 0.001), Hp infection (p = 0.01) and ulcerative colitis in active phase (p = 0.03). Trait anxiety was related to irritable bowel syndrome (IBS) (p < 0.001), Helicobacter pylori (Hp) infection (p = 0.001), food allergies (p = 0.001) and SIBO (p = 0.001). Current depression was related to IBS (p < 0.001) and coeliac disease (p = 0.01), SIBO (p = 0.02). A predicted probability of 0.77 +/- 0.16 to have state anxiety, of 0.66 +/- 0.12 to have trait anxiety and of 0.39 +/- 0.14 to have depression was found in these patients., Conclusions: Most of the patients who seek medical consultation for gastrointestinal problems show an associated affective disorder. These patients should be managed by a team including gastroenterologists, psychologists and/or psychiatrists, or by a gastroenterologist having expertise in the treatment of psychological disorders.

Background: Preclinical data suggest that brain insulin and insulin growth factor-1 (IGF-1) may contribute to the development of addiction. The aim of this clinical study was to evaluate the relationships between insulin and IGF-1 plasma concentrations and alcohol craving., Methods: The correlations between insulin and craving in actively drinking alcoholics were evaluated in the experiment 1 retrospectively and in the experiment 2 in a case-control study. Experiment 3 evaluated the correlations between insulin and craving in 12-weeks abstinent alcoholics in a longitudinal study. C-peptide and IGF-1 were also investigated in experiments 2-3. Alcohol craving was evaluated by the Obsessive-Compulsive Drinking Scale (OCDS)., Results: Significant positive correlations between insulin concentrations and craving scores were found in actively drinkers (p < 0.05). Specifically, in the first experiment insulin significantly correlated with the compulsive scores. In the second experiment and in an analysis of experiments 1-2 together, insulin plasma concentration correlated with total OCDS craving (p < 0.05) and compulsive craving (p < 0.05) and showed a trend of correlation with the obsessive craving. At 12 weeks no correlation was found between insulin and craving scores. In all the experiments the correlations between C-peptide and craving were close to the ones between insulin and craving while IGF-1 never correlated with craving., Conclusions: This study suggests that insulin could be involved in the neurobiology of alcohol craving and addiction. This characteristic seems specific of insulin since similar data were found on C-peptide but not on IGF-1. Future confirming studies on larger samples are needed, also to investigate possible therapeutic implications.

It is possible to observe the changes of intestinal functions, in particular absorbent, immunologic and hormonal ones, correlated to inside action of a pathogenic noxa, in the cutaneous district, thanks to clinico-dermatological manifestations. The most evident cutaneous pathologies are present in progress of inflammatory bowel diseases, however the most representative manifestations are present especially in progress of celiac disease. The importance of these associations leads to conclude that skin is the "mirror" of the small intestine, and that remembering it can be necessary for specialist and generalist in their clinical practice.

Celiac disease (CD) is an autoimmune gluten-dependent enteropathy characterized by atrophy of intestinal villi that improves after gluten-free diet (GFD). CD is often associated with extra-intestinal manifestations; among them, several skin diseases are described in CD patients. The present review reports all CD-associated skin manifestations described in the literature and tries to analyze the possible mechanisms involved in this association. The opportunity to evaluate the possible presence of CD in patients affected by skin disorders is discussed.