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Abstract Experimental studies identified a role of neuroinflammation in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, the role of inflammatory molecules as diagnostic and prognostic biomarkers in patients with ALS is unclear. In this cross-sectional study, the cerebrospinal fluid (CSF) levels of a set of inflammatory cytokines and chemokines were analyzed in 56 newly diagnosed ALS patients and in 47 age- and sex-matched control patients without inflammatory or degenerative neurological disorders. The molecules analyzed included: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-17, granulocyte colony stimulating factor (GCSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, tumor necrosis factors (TNF), eotaxin. Principal component analysis (PCA) was used to explore possible associations between CSF molecules and ALS diagnosis. In addition, we analyzed the association between CSF cytokine profiles and clinical characteristics, including the disease progression rate score, and peripheral inflammation assessed using the Neutrophil-to-lymphocyte ratio (NLR). PCA identified six principal components (PCs) explaining 70.67% of the total variance in the CSF cytokine set. The principal component (PC1) explained 26.8% of variance and showed a positive load with CSF levels of IL-9, IL-4, GCSF, IL-7, IL-17, IL-13, IL-6, IL-1β, TNF, and IL-2. Logistic regression showed a significant association between PC1 and ALS diagnosis. In addition, in ALS patients, the same component was significantly associated with higher disease progression rate score and positively correlated with NLR. CSF inflammatory activation in present in ALS at the time of diagnosis and may characterize patients at higher risk for disease progression.

Abstract The observation of action seems to involve the generation of the internal representation of that same action in the observer, a process named motor resonance (MR). The objective of this study was to verify whether an experimental paradigm of action observation in a laboratory context could elicit cortical motor activation in 21 early Parkinson’s disease (PD) patients compared to 22 controls. Participants were instructed to simply observe (observation-only session) or to respond (Time-to-contact detection session) at the instant the agent performed a grasping action toward a graspable or ungraspable object. We used functional near-infrared spectroscopy with 20 channels on the motor and premotor brain areas and event-related desynchronization of alpha-mu rhythm. In both groups, response times were more accurate in graspable than ungraspable object trials, suggesting that motor resonance is present in PD patients. In the Time-to-contact detection session, the oxyhemoglobin levels and alpha-mu desynchronization prevailed in the graspable object trials rather than in the ungraspable ones. This study demonstrates the preservation of MR mechanisms in early PD patients. The action observation finalized to a consequent movement can activate cortical networks in patients with early PD, suggesting early rehabilitation interventions taking into account specific observation paradigms preceding motor production.

Abstract Scientific evidence points to a shared neural representation between performing and observing an action. The action observation notoriously determines a modulation of the observer’s sensorimotor system, a phenomenon called Motor Resonance (MR). Fibromyalgia (FM) patients suffer from a condition characterized by generalized musculoskeletal pain in which even simple movement can exacerbate their symptoms. Maladaptive functioning of the primary motor cortex is a common finding in patients with chronic pain. Activation of the motor cortex is known to induce an analgesic effect in patients with chronic pain. In this exploratory study, we intend to verify if the mere observation of a movement could elicit activation of the motor cortical areas in patients with FM. Therefore, the purpose of this study was to examine the presence of MR in patients affected by fibromyalgia. We adopted a behavioral paradigm known for detecting the presence of MR and a neurophysiological experiment. Participants watched videos showing gripping movements towards a graspable or an ungraspable object, respectively, and were asked to press a button the instant the agent touched the object (Time-to-contact detection session). In a different experimental session, participants were only requested to observe and pay attention to the videos (Observation-only session). During each experimental session, the participants’ cerebral hemodynamic activity was recorded using the functional Near-Infrared Spectroscopy method. The behavioral task analysis revealed the presence of MR in both FM patients and healthy controls. Moreover, neurophysiological findings suggested that the observation of movement during the Observation-only session provoked activation and modulation of the cortical motor networks of FM patients. These results could represent evidence of the possible beneficial effects of movement observation in restarting motor activation, notoriously reduced, in FM patients.

In recent years, there has been a dramatic increase in the number of pregnancies complicated by gestational diabetes mellitus (GDM). GDM occurs when maternal insulin resistance develops and/or progresses during gestation, and it is not compensated by a rise in maternal insulin secretion. If not properly managed, this condition can cause serious short-term and long-term problems for both mother and child. Lifestyle changes are the first line of treatment for GDM, but if ineffective, insulin injections are the recommended pharmacological treatment choice. Some guidance authorities and scientific societies have proposed the use of metformin as an alternative pharmacological option for treating GDM, but there is not yet a unanimous consensus on this. Although the use of metformin appears to be safe for the mother, concerns remain about its long-term metabolic effects on the child that is exposed in utero to the drug, given that metformin, contrary to insulin, crosses the placenta. This review article describes the existing lines of evidence about the use of metformin in pregnancies complicated by GDM, in order to clarify its potential benefits and limits, and to help clinicians make decisions about who could benefit most from this drug treatment.

Abstract Introduction Hepatic abscess can be defined as an encapsulated collection of suppurative material within the liver parenchyma. Hepatic abscess can be distinguished as pyogenic, amebic, or fungal. Biliary tract disease remains the most common cause of hepatic abscess today, and the most common complications range from pleural effusion, empyema, and bronchohepatic fistula to subphrenic abscess and rupture into the peritoneal cavity, stomach, colon, vena cava, or kidney. A large abscess compressing the inferior vena cava and the hepatic veins may result in Budd-Chiari syndrome. In this report, we present a rare case of hepatic abscess with an unusual evolution that was treated with a noninvasive approach. Case presentation A 79-year-old Caucasian woman underwent endoscopic bile stone extraction and laparoscopic cholecystectomy. Six months later, a hepatic abscess in association with bilateral effusion was diagnosed. The prompt imaging-guided drainage solved the case. Three years later, she came to our attention complaining of dull, diffuse abdominal pain and high body temperature (38 °C). A retroperitoneal abscess was diagnosed that was spreading to the right lateral wall of the abdomen and extending across the muscular wall to the subcutaneous layer. The fluid collection also involved the right pleural cavity, forming an empyema. Also in this case, an imaging-guided drainage was performed, and the patient’s clinical picture resolved in a few days. The retroperitoneal abscess recurred 14 months later, and it was dealt with using the same treatment. Three months from the last follow-up, the patient came back to our attention with an evident swelling of her right lumbar region. Computed tomography revealed a right inferior lumbar hernia comprising adipose tissue and the right kidney. A surgical intervention was recommended to the patient, but, owing to her poor general health, she refused any invasive approach. Conclusions Retroperitoneal abscess is an uncommon complication of biliary tract surgery and represents a potential cause of death, especially in those patients with multiple diseases. Prompt drainage is crucial to the treatment. Failure in eliminating the primary infective focus could bring complications and, in general, a weakness of lumbar muscular wall, even resulting in a rare case of lumbar hernia.

Background: The prevalence of pre-psychotic symptoms and aberrant salience in BPD has not been systematically studied. The present study aims to investigate the intensity, frequency and correlation between basic symptoms, aberrant salience and borderline personality traits, in subjects that have not yet developed a frank psychotic episode. Methods: Twenty-eight subjects, 8 males and 20 females, aged between 24 and 55 years (M = 41.36 ± 9.9) has been individually tested throughout the Frankfurt Complaint Questionnaire (FBF), the Aberrant Salience Inventory (ASI) and the Personality Inventory for the DSM-5- Adult (PID-5). Results: Findings showed that 85.7% of the sample (n = 24) reported significant scores of the aberrant salience traits, which in turn were correlated to basic symptoms. Furthermore, emerged several correlations between pre-psychotic symptoms and PID-5 personality dimensions not only with Negative Affectivity and Detachment but also with Psychoticism. Conclusions: This study highlights the phenomenological continuity between the borderline personality traits and the attenuated manifestation of the psychotic disease.

BACKGROUND:Experimental and clinical studies suggested an analgesic effect on chronic pain by motor cortex activation. The present study explored the complex mechanisms of interaction between motor and pain during performing the slow and fast finger tapping task alone and in concomitant with nociceptive laser stimulation. METHOD:The participants were 38 patients with fibromyalgia (FM) and 21 healthy subjects. We used a simultaneous multimodal method of laser-evoked potentials and functional near-infrared spectroscopy to investigate metabolic and electrical changes during the finger tapping task and concomitant noxious laser stimulation. Functional near-infrared spectroscopy is a portable and optical method to detect cortical metabolic changes. Laser-evoked potentials are a suitable tool to study the nociceptive pathways function. RESULTS:We found a reduced tone of cortical motor areas in patients with FM compared to controls, especially during the fast finger tapping task. FM patients presented a slow motor performance in all the experimental conditions, requesting rapid movements. The amplitude of laser evoked potentials was different between patients and controls, in each experimental condition, as patients showed smaller evoked responses compared to controls. Concurrent phasic pain stimulation had a low effect on motor cortex metabolism in both groups nor motor activity changed laser evoked responses in a relevant way. There were no correlations between Functional Near-Infrared Spectroscopy (FNIRS) and clinical features in FM patients. CONCLUSION:Our findings indicated that a low tone of motor cortex activation could be an intrinsic feature in FM and generate a scarce modulation on pain condition. A simple and repetitive movement such as that of the finger tapping task seems inefficacious in modulating cortical responses to pain both in patients and controls. The complex mechanisms of interaction between networks involved in pain control and motor function require further studies for the important role they play in structuring rehabilitation strategies.

Background Thiazolidinediones (TZDs), also called glitazones, are five-membered carbon ring molecules commonly used for the management of insulin resistance and type 2 diabetes. Recently, many prospective studies have also documented the impact of these compounds as anti-proliferative agents, though several negative side effects such as hepatotoxicity, water retention and cardiac issues have been reported. In this work, we synthesized twenty-six new TZD analogues where the thiazolidinone moiety is directly connected to an N-heterocyclic ring in order to lower their toxic effects. Methods By adopting a widely applicable synthetic method, twenty-six TZD derivatives were synthesized and tested for their antiproliferative activity in MTT and Wound healing assays with PC3 (prostate cancer) and MCF-7 (breast cancer) cells. Results Three compounds, out of twenty-six, significantly decreased cellular viability and migration, and these effects were even more pronounced when compared with rosiglitazone, a well-known member of the TZD class of antidiabetic agents. As revealed by Western blot analysis, part of this antiproliferative effect was supported by apoptosis studies evaluating BCL-xL and C-PARP protein expression. Conclusion Our data highlight the promising potential of these TZD derivatives as anti-proliferative agents for the treatment of prostate and breast cancer.

Clinical islet transplantation effectively restores euglycemia and corrects glycosylated hemoglobin in labile type 1 diabetes mellitus (T1DM). Despite marked improvements in islet transplantation outcomes, acute islet cell death remains a substantial obstacle that compromises long-term engraftment outcomes. Multiple organ donors are routinely required to achieve insulin independence. Therapeutic agents that ameliorate cell death and/or control injury-related inflammatory cascades offer potential to improve islet transplant success. Apoptotic cell death has been identified as a major contributor to cellular demise and therapeutic strategies that subvert initiation and consequences of apoptotic cell death have shown promise in pre-clinical models. Indeed, in numerous pathologies and diseases apoptosis has been the most extensively described form of regulated cell death. However, recent identification of novel, alternative regulated cell death pathways in other disease states and solid organ transplantation suggest that these additional pathways may also have substantial relevance in islet transplantation. These regulated, non-apoptotic cell death pathways exhibit distinct biochemical characteristics but have yet to be fully characterized within islet transplantation. We review herein the various regulated cell death pathways and highlight their relative potential contributions to islet viability, engraftment failure and islet dysfunction.

Islet transplantation is an established clinical procedure for select patients with type 1 diabetes and severe hypoglycemia to stabilize glycemic control. Post-transplant, substantial beta cell mass is lost, necessitating multiple donors to maintain euglycemia. A potential strategy to augment islet engraftment is the co-transplantation of islets with multipotent mesenchymal stem cells to capitalize upon their pro-angiogenic and anti-inflammatory properties. Herein, we examine the in vitro and in vivo effect of co-culturing murine islets with human adipose-derived mesenchymal stem cells (Ad-MSCs). Islets co-cultured with Ad-MSCs for 48 hours had decreased cell death, superior viability as measured by membrane integrity, improved glucose stimulated insulin secretion and reduced apoptosis compared to control islets. These observations were recapitulated with human islets, albeit tested in a limited capacity. Recipients of marginal mouse islet mass grafts, co-transplanted with Ad-MSCs without a co-culture period, did not reverse to normoglycemia as efficiently as islets alone. However, utilizing a 48-hour co-culture period, marginal mouse islets grafts with Ad-MSCs achieved a superior percent euglycemia rate when compared to islets cultured and transplanted alone. A co-culture period of human islets with human Ad-MSCs may have a clinical benefit improving engraftment outcomes.

Circulating oxidative stress and pro-inflammatory markers change after regular physical exercise; however, how a short session of acute physical activity affects the inflammatory status and redox balance in sedentary individuals is still unclear. Aim of this study is to assess antioxidant and inflammatory parameters, both at rest and after acute exercise, in sedentary young men with or without obesity. Thirty sedentary male volunteers, aged 20-45 (mean age 32 ± 7 years), were recruited, divided into 3 groups (normal weight: BMI < 25 kg/m2; overweight to moderate obesity: 25-35 kg/m2; severe obesity: 35-40 kg/m2), and their blood samples collected before and after a 20-min run at ~ 70% of their VO2max for the measurement of Glutathione Reductase, Glutathione Peroxidase, Superoxide Dismutase, Total Antioxidant Status (TAS) and cytokines (IL-2, IL-4, IL-6, IL-8, IL-10, IL-1α, IL-1β, TNFα, MCP-1, VEGF, IFNγ, EGF). Inter-group comparisons demonstrated significantly higher Glutathione Reductase activity in severely obese subjects in the post-exercise period (P = 0.036), and higher EGF levels in normal weight individuals, either before (P = 0.003) and after exercise (P = 0.05). Intra-group comparisons showed that the acute exercise stress induced a significant increase in Glutathione Reductase activity in severely obese subjects only (P = 0.007), a significant decrease in MCP-1 in the normal weight group (P = 0.02), and a decrease in EGF levels in all groups (normal weight: P = 0.025, overweight/moderate obesity: P = 0.04, severe obesity: P = 0.018). Altogether, these findings suggest that in sedentary individuals with different ranges of BMI, Glutathione Reductase and distinct cytokines are differentially involved into the adaptive metabolic changes and redox responses induced by physical exercise. Therefore, these biomarkers may have the potential to identify individuals at higher risk for developing diseases pathophysiologically linked to oxidative stress.

The increasing prevalence of multi-resistant bacteria is a major public health concern. Infections acquired during ophthalmic surgery are devastating. The purpose of the current study is to compare the proportion of eyes with negative bacterial cultures on all tested media after 1 versus 3 sequential drops of povidone-iodine (PI) 5% into the inferior conjunctival fornix.Patients were randomly assigned to receive 1 (PI group) drop (at time 28 minutes) or 3 (PI plus group) sequential drops (at time 0, 20 minutes and 28 minutes) of PI 5% into the inferior conjunctival sac of one randomly selected eye. A swab culture was obtained from the inferior conjunctival fornix 5 minutes before and 30 minutes after time 0. Central corneal thickness (CCT) was measured shortly before time 0 and shortly after time 30. Conjunctival swabs were incubated aerobically in enriched Thioglycolate liquid medium (meat broth) and in three solid culture media (chocolate agar, trypticase soy agar with 5% sheep blood, and Sabouraud agar).There was no significant difference in the proportion of negative cultures after intervention between groups (p = 0.1638). Also in the PI group (n = 59), the proportion of eyes with negative cultures after PI (79.7%) did not differ significantly from baseline (76.3%; p = 0.7539). However in the PI plus group (n = 61), the proportion of eyes with all negative cultures after PI (85.3%) was significantly higher than before PI (70.5%) (p = 0.0177). There was no significant difference in mean CCT before and after the intervention in both groups.Instillation of 3 sequential drops of PI was associated with a significant increase in the proportion of eyes with all negative cultures, while instillation of a single drop of PI was not associated with a significant increase in the proportion of negative cultures. Further study is warranted to determine whether the difference between the PI administration regimens is also associated with differences in the rates of postoperative ocular infections.

There is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. Endocrine micro-pancreata (EMPs) made up of acellular organ-derived micro-scaffolds seeded with human islets have been shown to express high levels of key beta-cell specific genes and secrete quantities of insulin per cell similar to freshly isolated human islets in a glucose-regulated manner for more than three months in vitro. The aim of this study was to investigate the capacity of EMPs to restore euglycemia in vivo after transplantation of mouse or human islets in chemically diabetic mice. We proposed that the organ-derived EMPs would restore the extracellular components of the islet microenvironment, generating favorable conditions for islet function and survival. EMPs seeded with 500 mouse islets were implanted intraperitoneally into streptozotocin-induced diabetic mice and reverted diabetes in 67% of mice compared to 13% of controls (p = 0.018, n = 9 per group). Histological analysis of the explanted grafts 60 days post-transplantation stained positive for insulin and exhibited increased vascular density in a collagen-rich background. EMPs were also seeded with human islets and transplanted into the peritoneal cavity of immune-deficient diabetic mice at 250 islet equivalents (IEQ), 500 IEQ and 1000 IEQ. Escalating islet dose increased rates of normoglycemia (50% of the 500 IEQ group and 75% of the 1000 IEQ group, n = 3 per group). Human c-peptide levels were detected 90 days post-transplantation in a dose-response relationship. Herein, we report reversal of diabetes in mice by intraperitoneal transplantation of human islet seeded on EMPs with a human islet dose as low as 500 IEQ.

The high-mobility group A1 (HMGA1) gene has been previously identified as a potential novel candidate gene for susceptibility to insulin resistance and type 2 diabetes (T2D) mellitus. For this reason, several studies have been conducted in recent years examining the association of the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) with T2D. Because of non-univocal data and non-overlapping results among laboratories, we conducted the current meta-analysis with the aim to yield a more precise and reliable conclusion for this association. Using predetermined inclusion criteria, MEDLINE, PubMed, Web of Science, Scopus, Google Scholar and Embase were searched for all relevant available literature published until November 2014. Two of the authors independently evaluated the quality of the included studies and extracted the data. Values from the single studies were combined to determine the meta-analysis pooled estimates. Heterogeneity and publication bias were also examined. Among the articles reviewed, five studies (for a total of 13,789 cases and 13,460 controls) met the predetermined criteria for inclusion in this meta-analysis. The combined adjusted odds ratio estimates revealed that the rs146052672 variant genotype had an overall statistically significant effect on increasing the risk of development of T2D. As most of the study subjects were Caucasian, further studies are needed to establish whether the association of this variant with an increased risk of T2D is generalizable to other populations. Also, in the light of this result, it would appear to be highly desirable that further in-depth investigations should be undertaken to elucidate the biological significance of the HMGA1 rs146052672 variant.

We aimed to assess whether Internet addiction (IA) severity was related to alexithymia scores among high school students, taking into account the role of gender differences and the possible effect of anxiety, depression, and age. Participants in the study were 600 students (ages ranging from 13 to 22; 48.16% girls) recruited from three high schools in two cities from Southern Italy. Participants completed a sociodemographic questionnaire, the Toronto Alexithymia Scale, the Internet Addiction Test, the Hamilton Anxiety Scale, and the Hamilton Depression Scale. The findings of the study showed that IA scores were associated with alexithymia scores, over and above the effect of negative emotions and age. Students with pathological levels of alexithymia reported higher scores on IA severity. In particular, results showed that difficulty in identifying feelings was significantly associated with higher scores on IA severity. No effect of gender was found. Implications for clinicians were discussed.

The High-Mobility Group AT-Hook 1 (HMGA1) protein is an architectural transcription factor that binds to AT-rich sequences in the promoter region of DNA and functions as a specific cofactor for gene activation. Previously, we demonstrated that HMGA1 is a key regulator of the insulin receptor (INSR) gene and an important downstream target of the INSR signaling cascade. Moreover, from a pathogenic point of view, overexpression of HMGA1 has been associated with human cancer, whereas functional variants of the HMGA1 gene have been recently linked to type 2 diabetes mellitus and metabolic syndrome. However, despite of this biological and pathological relevance, the mechanisms that control HMGA1 gene expression remain unknown. In this study, to define the molecular mechanism(s) that regulate HMGA1 gene expression, the HMGA1 gene promoter was investigated by transient transfection of different cell lines, either before or after DNA and siRNA cotransfections. An octamer motif was identified as an important element of transcriptional regulation of this gene, the interaction of which with the octamer transcription factors Oct-1 and Oct-2 is crucial in modulating HMGA1 gene and protein expression. Additionally, we demonstrate that HMGA1 binds its own promoter and contributes to its transactivation by Oct-2 (but not Oct-1), supporting its role in an auto-regulatory circuit. Overall, our results provide insight into the transcriptional regulation of the HMGA1 gene, revealing a differential control exerted by both Oct-1 and Oct-2. Furthermore, they consistently support the hypothesis that a putative defect in Oct-1 and/or Oct-2, by affecting HMGA1 expression, may cause INSR dysfunction, leading to defects of the INSR signaling pathway.