Sarcopenia Prevalence among Hospitalized Patients with Severe Obesity: An Observational Study.

Background: Sarcopenic obesity (SO) is the combination of excess fat, skeletal muscle and muscular strength/function deficit. The ESPEN/EASO have proposed new diagnostic criteria, but the SO prevalence in patients with severe obesity remains to be established. The aim of this study was to establish the SO prevalence in a large cohort of inpatients with obesity, considering sex, age, BMI, type, and number of concomitant diseases. Methods: Patient data of both genders aged between 18 and 90 years with a body mass index (BMI) of ≥30 kg/m2 underwent hospital evaluation including bioelectrical impedance analysis (BIA) and handgrip strength (HS). QoL scores were obtained by the Psychological General Well-Being Index questionnaire. The study was approved by the institutional Ethic Committee. Results: Among the 3858 patients, 444 (11.51%) exhibited a strength deficit, while 3847 (99.71%) had skeletal muscle mass deficit. The prevalence of SO was then 11.48%, with higher rates in women (12.39%), in individuals aged >70 years (27%), and in those reporting a 'poor' QoL (12.6%). No significant difference in SO prevalence was found when stratifying by BMI (30-40 kg/m2 vs. >40 kg/m2, p = 0.1710). In SO patients, osteoarticular diseases (57%), hypertension/heart failure (38%), type 2 diabetes mellitus (34%), and obstructive sleep apnea (32%) were the more frequent comorbidities. Conclusions: The application of ESPEN/EASO-SO criteria in a cohort of inpatients with severe obesity revealed 11.48% SO prevalence, which was associated with age (particularly > 70 years), gender (women), but not BMI, as determinants. Disease staging and QoL screening may improve the identification of SO high-risk patients.

Boosting teamwork between scrub nurses and neurosurgeons: exploring the value of a role-played hands-on, cadaver-free simulation and systematic review of the literature.

Background: Recently, non-technical skills (NTS) and teamwork in particular have been demonstrated to be essential in many jobs, in business as well as in medical specialties, including plastic, orthopedic, and general surgery. However, NTS and teamwork in neurosurgery have not yet been fully studied. We reviewed the relevant literature and designed a mock surgery to be used as a team-building activity specifically designed for scrub nurses and neurosurgeons. Methods: We conducted a systematic review by searching PubMed (Medline) and CINAHL, including relevant articles in English published until 15 July 2023. Then, we proposed a pilot study consisting of a single-session, hands-on, and cadaver-free activity, based on role play. Scrub nurses were administered the SPLINTS (Scrub Practitioners' List of Intraoperative Non-Technical Skills) rating form as a self-evaluation at baseline and 20-30 days after the simulation. During the experiment, surgeons and scrub nurses role-played as each other, doing exercises including a simulated glioma resection surgery performed on an advanced model of a cerebral tumor (Tumor Box, UpSurgeOn®) under an exoscope. At the end, every participant completed an evaluation questionnaire. Results: A limited number of articles are available on the topic. This study reports one of the first neurosurgical team-building activities in the literature. All the participating scrub nurses and neurosurgeons positively evaluated the simulation developed on a roleplay. The use of a physical simulator seems an added value, as the tactile feedback given by the model further helps to understand the actual surgical job, more than only observing and assisting. The SPLINTS showed a statistically significant improvement not only in "Communication and Teamwork" (p = 0.048) but also in "Situation Awareness" (p = 0.031). Conclusion: Our study suggests that team-building activities may play a role in improving interprofessional teamwork and other NTS in neurosurgery.

"I cannot see your fear!" Altered recognition of fearful facial expressions in anorexia nervosa.

Background: The evidence about facial emotion recognition in anorexia nervosa as the role of alexithymic traits on this emotional ability is conflicting and heterogeneous. Objective: We assessed the capability of recognizing facial expressions of two primary emotions, fear, and anger, in the context of anorexia nervosa. Methods: Women affected by anorexia nervosa were compared with healthy weight women in a well-established implicit facial emotion recognition task. Both reaction time and level of accuracy were computed. Moreover, the individual levels of alexithymia were assessed through a standard self-report questionnaire. Results: Participants with anorexia nervosa reported a significantly lower performance in terms of reaction time and accuracy when the emotion of fear-but not anger-was the target. Notably, such an alteration was linked to the levels of alexithymia reported in the self-report questionnaire. Conclusion: In anorexia nervosa, difficulties in processing facial fearful (but not angry) expressions may be observed as linked to higher expressions of alexithymic traits. We suggested future research in which emotional processing will be investigated taking into account the role of the bodily dimensions of emotional awareness.

Settlement dynamics, subsistence economies and climate change during the late Holocene at Nunura Bay (Sechura Desert, Peru): A multiproxy approach.

Long considered on the margins, far from the major cultural traditions, the Sechura Desert is situated at the crossroads between the cultures of southern Ecuador and those of the northern Peruvian coast and preserves a large number of varied archaeological sites. Despite this evidence, little is known about the societies that inhabited this region during the Holocene. Exposed to natural hazards, including El Niño events, and to major climatic changes, they were able to adapt and exploit the scarce resources that this extreme environment offered them. Because of this rich history, we have been conducting archaeological research in this region since 2012 in order to clarify the dynamics of human occupation and their links with climate oscillations and environmental changes. This paper present the results of a multidisciplinary study of Huaca Grande, a mound located on Nunura Bay, 300 m from the Pacific Ocean. The nature of the human occupations at Huaca Grande was varied, and several adjustments occurred over time. The subsistence economy was based mainly on local marine resources and a continual use of terrestrial vegetal resources. However, a major change occurred in the more recent occupations, with the apparition of non-local resources (maize and cotton) indicating that Huaca Grande was connected to trade networks. The results show two main phases of occupation separated by a long abandonment (mid-5th century CE to mid-7th century CE and mid-13th century to mid-15th century CE). The occupation of the site appears to have been influenced by changes in the local climate and by extreme El Niño events. Our results highlight the great adaptability of these human groups over the span of a millennium and their capacity to react to the climatic changes and hazards that characterise this region.

Affective touch in anorexia nervosa: Exploring the role of social anhedonia and lifespan experiences.

BACKGROUND: The pleasantness of a gentle and slow, namely affective, touch experienced in interpersonal interactions motivates social closeness. In anorexia nervosa (AN), independent evidence suggests lower pleasantness of affective touch, as well as social withdrawal. We aim to probe both the experience of affective touch and its possible association with social anhedonia and lifespan experiences of affective bodily contacts in AN. METHODS: The pleasantness of affective and non-affective touch was compared between fourteen women with AN and fourteen healthy women. Stimuli were traditionally delivered with a brush, with the experimenter's hand, as novelty, and with a stick, as control. The pleasantness of imagined and real touch was probed. Self-report questionnaires assessed social anhedonia and lifespan experiences of affective touch. RESULTS: A preserved pleasantness of affective touch emerged in AN in both the imagery and real task, despite higher social anhedonia and less lifespan experience of affective touch than healthy women. LIMITATIONS: Affective touch involves loved ones; thus, the experimenter's touch may not resemble real-life interactions. Future research may take advantage of imagery procedures to solve this issue. CONCLUSIONS: Body-oriented therapy for AN recognizes touch as a therapeutic tool: ascertaining how touch is experienced is crucial to maximize rehabilitative outcomes. Furthermore, clarifying the possible interplay between interpersonal difficulties in AN and affective touch is especially relevant considering the possible role of the attachment style, which is intensively debated in AN, on affective touch.

Let the Body Talk: Preliminary Data of an Open Trial of Dance Movement Therapy for Eating Disorders.

BACKGROUND: There is growing support for considering Dance Movement Therapy (DMT) as an effective approach to improving physical and psychological symptoms in eating disorders (ED), but additional evidence is needed. The current study aims to investigate the effectiveness of a DMT intervention for inpatients with ED during an in-hospital rehabilitation program for ED in reducing emotion dysregulation and alexithymia and improving interoceptive awareness. METHODS: Forty-nine consecutive inpatient young women with ED (aged between 18 and 34 years) recruited from a clinical center for the rehabilitation of obesity and ED received four group sessions of DMT intervention. All participants completed the Difficulties in Emotion Regulation Scale (DERS), the Toronto Alexithymia Scale (TAS), and the Multidimensional Assessment of Interoceptive Awareness Scale (MAIA) before (Time 0) and after the intervention (Time 1). Paired-sample t-tests were run to assess differences between Time 0 to Time 1. RESULTS: From pre-to-post interventions, there was a significant reduction in the means of all of the subscales of DERS, suggesting an improvement in emotion regulation competencies, with the only exception for difficulties in awareness that increased (p = 0.016). We also found a significant reduction in alexithymia, as proved by significant differences in all of the subscales and the total score of TAS (p < 0.001), and significant improvements in interoceptive awareness as suggested by increased scores of the noticing (p = 0.043), emotional awareness (p < 0.001), body listening (p < 0.001), and trusting (p < 0.001) subscales of MAIA. CONCLUSION: Overall, our results point towards the efficacy of dance/movement in reducing symptoms of eating disorders. Our findings also suggest that dancing can be considered a useful intervention to increase emotional regulation, reduce alexithymia, and enhance interoceptive awareness.

Self-perception in anorexia nervosa: When the body becomes an object.

OBJECTIVE: Women with anorexia nervosa (AN) act as if they have a larger body, as evidenced in obstacle avoidance tasks, where an allocentric perspective is adopted. This alteration emerges not only when they perform, but also when they imagine movements. However, no previous study has investigated own body centered tasks. As such, in this study we aim at documenting if women with AN show an altered behaviour also when the task requires a first-person perspective. METHOD: We explored the performance of eleven woman affected by AN compared to eighteen matched controls, in two motor imagery tasks based on a self-frame of reference, the Hand Laterality Task and the Mental Motor Chronometry Task. Moreover, two control tasks relative to visual imagery were administered. RESULTS: In the Hand Laterality Task, affected participants did not adopt a motor strategy to judge hands laterality (i.e. no biomechanical constraints effect). Crucially, they also showed an altered behavior in the control task. Similarly, they did not show the expected isochrony in the Mental Motor Chronometry Task, when actions pertained the left (but not the right) hand, in absence of any difference in the control task. CONCLUSIONS: Our findings reveal altered imagery processes in AN. Specifically, affected participants adopt a third-person, rather than a first-person perspective, even when the task requires to imagine their own body in an internal frame of reference. In other words, participants with AN objectify body stimuli. Different mechanisms (i.e., checking behaviour; mirror self-reflection; altered multisensory integration) can explain such an altered imagery in AN.

The ACTyourCHANGE study protocol: promoting a healthy lifestyle in patients with obesity with Acceptance and Commitment Therapy-a randomized controlled trial.

BACKGROUND: As treatment of choice in promoting psychological flexibility, Acceptance and Commitment Therapy (ACT) was found to be effective in several conditions, and among different populations, including weight management in individuals with obesity. However, the mechanism of action of psychological flexibility is less known. The aim of the present study is, within the context of a brief ACT intervention for behavioral change and behavioral maintenance of a healthy lifestyle in a sample of inpatients with obesity, to explore the effect of each subcomponent of the psychological flexibility model on treatment processes and outcomes. METHODS: A randomized controlled trial will be conducted. Ninety Italian adult inpatients with obesity attending a rehabilitation program for weight loss will be randomly allocated into three experimental conditions targeting respectively each subcomponent of the psychological flexibility model: group Engage focused on values-oriented behaviors, group Openness focused on acceptance and cognitive defusion, and group Awareness focused on being present and aware of thoughts, feelings, and behaviors at every moment. Weight, BMI (kg/m2), the Psychological General Well-Being Inventory (PGWBI), the Outcome Questionnaire-45.2 (OQ-45.2), the Depression Anxiety and Stress Scale (DASS-21), the Difficulties in Emotion Regulation Scale (DERS), the Dutch Eating Behaviors Questionnaire (DEBQ), the Brief Values Inventory (BVI), the Committed Action Questionnaire (CAQ), the Italian-Cognitive Fusion Questionnaire (I-CFQ), the Five Facet Mindfulness Questionnaire (FFMQ), and the Acceptance and Action Questionnaire (AAQ-II) will be assessed at the beginning (time 0), at the end of psychological intervention (time 1), and after 3 (time 2) and 6 months (time 3) and 9 months (time 4) from discharge. During the following month after discharge, outpatients will be monitored in their adherence to a healthy lifestyle, using a wearable device. To assess the effectiveness of the intervention, mixed between-within 3 (conditions) × 4 (times) repeated measure ANOVAs will be conducted to examine changes from time 0 to time 1, 2, 3, and 4 in means of weight, BMI, and means of scores PGWBI, OQ-45.2, DASS, DERS, DEBQ, AAQ-II, BVI, CAQ, I-CFQ, and FFMQ, between three groups. DISCUSSION: This study will contribute to clarify the mechanism of action of each subcomponent of the psychological flexibility model and understand its impact on the promotion of a healthy lifestyle. TRIAL REGISTRATION: ClinicalTrials.gov NCT04474509 . Registered on July 4, 2020.

Disability assessment in an Italian cohort of patients with obesity using an International Classification of Functioning, Disability and Health (ICF)-derived questionnaire.

BACKGROUND: Obesity is a clinical condition that contributes to the development of related disability in different areas (physical, psychological and social). Multidisciplinary treatment calls for specific instruments able to evaluate all related functional problems. We have developed a tool (an ICF-based assessment instrument, the ICF-OB schedule) to evaluate obesity-related disability, composed of an inventory of 71-items from the WHO International Classification of Functioning, Disability and Health (ICF). AIM: The aim of the present study was to validate this new tool for the definition of obesity-related disability. We also sought to examine the relationship between obesity disability, an index of multimorbidity (Cumulative Illness Rating Scale [CIRS]) and a well-validated score of perceived obesity-related disability (Italian Obesity Society Test for Obesity-Related Disability [TSD-OC]). DESIGN: Process validation of the ICF-OB schedule. SETTING: Baseline conditions of out- and in-patients. POPULATION: A large cohort of obese patients recruited from 9 multidisciplinary centers belonging to the Italian Obesity Society (SIO) network, which provide specialized obesity care. METHODS: A total of 353 patients (F: 70%, age: 50.2±12.7yrs, BMI: 41.4±8.3kg/m2) were enrolled between January 2017 and June 2018. The ICF-OB was used to define patients' functioning and disability profiles in order to set and appraise rehabilitation goals. RESULTS: We described the distribution of body functions (BF), body structures (BS) and activities and participations (A&P) categories and the agreement rates were significant for the majority of these. The ICF-OB was more often significantly associated, and with stronger coefficients, with patients' comorbidities as described by the CIRS rather than with Body Mass Index (BMI). The TSD-OC also presented a strong association with A&P indexes. CONCLUSIONS: The complexity of clinical condition, that generates disability in obesity might be well identified with the use of this new instrument that appear significant related to the perceived disability for each patients and also with their multimorbidity. CLINICAL REHABILITATION IMPACT: The ICF-OB shows great promise as a tool for goal setting in the rehabilitation of obese patients.

What Is the Role of the Placebo Effect for Pain Relief in Neurorehabilitation? Clinical Implications From the Italian Consensus Conference on Pain in Neurorehabilitation.

BACKGROUND: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. METHODS: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. RESULTS: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. CLINICAL IMPLICATIONS: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy.

Pharmacological activation of autophagy favors the clearing of intracellular aggregates of misfolded prion protein peptide to prevent neuronal death.

According to the "gain-of-toxicity mechanism", neuronal loss during cerebral proteinopathies is caused by accumulation of aggregation-prone conformers of misfolded cellular proteins, although it is still debated which aggregation state actually corresponds to the neurotoxic entity. Autophagy, originally described as a variant of programmed cell death, is now emerging as a crucial mechanism for cell survival in response to a variety of cell stressors, including nutrient deprivation, damage of cytoplasmic organelles, or accumulation of misfolded proteins. Impairment of autophagic flux in neurons often associates with neurodegeneration during cerebral amyloidosis, suggesting a role in clearing neurons from aggregation-prone misfolded proteins. Thus, autophagy may represent a target for innovative therapies. In this work, we show that alterations of autophagy progression occur in neurons following in vitro exposure to the amyloidogenic and neurotoxic prion protein-derived peptide PrP90-231. We report that the increase of autophagic flux represents a strategy adopted by neurons to survive the intracellular accumulation of misfolded PrP90-231. In particular, PrP90-231 internalization in A1 murine mesencephalic neurons occurs in acidic structures, showing electron microscopy hallmarks of autophagosomes and autophagolysosomes. However, these structures do not undergo resolution and accumulate in cytosol, suggesting that, in the presence of PrP90-231, autophagy is activated but its progression is impaired; the inability to clear PrP90-231 via autophagy induces cytotoxicity, causing impairment of lysosomal integrity and cytosolic diffusion of hydrolytic enzymes. Conversely, the induction of autophagy by pharmacological  blockade of mTOR kinase or trophic factor deprivation restored autophagy resolution, reducing intracellular PrP90-231 accumulation and neuronal death. Taken together, these data indicate that PrP90-231 internalization induces an autophagic defensive response in A1 neurons, although incomplete and insufficient to grant survival; the pharmacological enhancement of this process exerts neuroprotection favoring the clearing of the internalized peptide and could represents a promising neuroprotective tool for neurodegenerative proteinopathies.

Decreased diabetes risk over 9 year after 18-month oral L-arginine treatment in middle-aged subjects with impaired glucose tolerance and metabolic syndrome (extension evaluation of L-arginine study).

PURPOSE: This study aimed to determine whether L-arginine supplementation lasting for 18 months maintained long-lasting effects on diabetes incidence, insulin secretion and sensitivity, oxidative stress, and endothelial function during 108 months among subjects at high risk of developing type 2 diabetes. METHODS: One hundred and forty-four middle-aged subjects with impaired glucose tolerance and metabolic syndrome were randomized in 2006 to an L-arginine supplementation (6.4 g orally/day) or placebo therapy lasting 18 months. This period was followed by a 90-month follow-up. The primary outcome was a diagnosis of diabetes during the 108 month study period. Secondary outcomes included changes in insulin secretion (proinsulin/c-peptide ratio), insulin sensitivity (IGI/HOMA-IR), oxidative stress (AOPPs), and vascular function. After the 18 month participation, subjects that were still free of diabetes and willing to continue their participation (104 subjects) were further followed until diabetes diagnosis, with a time span of about 9 years from baseline. RESULTS: Although results derived from the 18 month of the intervention study demonstrated no differences in the probability of becoming diabetics, at the end of the study, the cumulative incidence of diabetes was of 40.6% in the L-arginine group and of 57.4% in the placebo group. The adjusted HR for diabetes (L-arginine vs. placebo) was 0.66; 95% CI 0.48, 0.91; p < 0.02). Proinsulin/c-peptide ratio (p < 0.001), IGI/HOMA-IR (p < 0.01), and AOPP (p < 0.05) levels were ameliorated in L-arginine compared to placebo. CONCLUSIONS: These results may suggest that the administration of L-arginine could delay the development of T2DM for a long period. This effect could be mediated, in some extent, by L-arginine-induced reduction in oxidative stress.

Different Molecular Mechanisms Mediate Direct or Glia-Dependent Prion Protein Fragment 90-231 Neurotoxic Effects in Cerebellar Granule Neurons.

Glia over-stimulation associates with amyloid deposition contributing to the progression of central nervous system neurodegenerative disorders. Here we analyze the molecular mechanisms mediating microglia-dependent neurotoxicity induced by prion protein (PrP)90-231, an amyloidogenic polypeptide corresponding to the protease-resistant portion of the pathological prion protein scrapie (PrPSc). PrP90-231 neurotoxicity is enhanced by the presence of microglia within neuronal culture, and associated to a rapid neuronal [Ca++] i increase. Indeed, while in "pure" cerebellar granule neuron cultures, PrP90-231 causes a delayed intracellular Ca++ entry mediated by the activation of NMDA receptors; when neuron and glia are co-cultured, a transient increase of [Ca++] i occurs within seconds after treatment in both granule neurons and glial cells, then followed by a delayed and sustained [Ca++] i raise, associated with the induction of the expression of inducible nitric oxide synthase and phagocytic NADPH oxidase. [Ca++] i fast increase in neurons is dependent on the activation of multiple pathways since it is not only inhibited by the blockade of voltage-gated channel activity and NMDA receptors but also prevented by the inhibition of nitric oxide and PGE2 release from glial cells. Thus, Ca++ homeostasis alteration, directly induced by PrP90-231 in cerebellar granule cells, requires the activation of NMDA receptors, but is greatly enhanced by soluble molecules released by activated glia. In glia-enriched cerebellar granule cultures, the activation of inducible nitric oxide (iNOS) and NADPH oxidase represents the main mechanism of toxicity since their pharmacological inhibition prevented PrP90-231 neurotoxicity, whereas NMDA blockade by D(-)-2-amino-5-phosphonopentanoic acid is ineffective; conversely, in pure cerebellar granule cultures, NMDA blockade but not iNOS inhibition strongly reduced PrP90-231 neurotoxicity. These data indicate that amyloidogenic peptides induce neurotoxic signals via both direct neuron interaction and glia activation through different mechanisms responsible of calcium homeostasis disruption in neurons and potentiating each other: the activation of excitotoxic pathways via NMDA receptors and the release of radical species that establish an oxidative milieu.

Preoperative colonization in pediatric cardiac surgery and its impact on postoperative infections.

BACKGROUND: Patients with congenital heart defects are frequently hospitalized before surgery. This exposes them to a high risk for pathogen colonization. There are limited data on colonization prevalence in the pediatric cardiac population, and limited data concerning its potential role in the risk of developing infections after cardiac surgery. AIM: This study aimed to verify the impact of preoperative colonization on postoperative infections in a population of pediatric cardiac surgery patients coming from Italy and developing countries. METHODS: This was a retrospective study conducted in all the patients aged ≤18 years who underwent pediatric open-heart surgery in the year 2015. Clinical data were retrieved from the institutional database for cardiac surgery patients. Data on swab cultures were retrieved from the laboratory database. Swab colonization was tested for association with infection and other outcomes. RESULTS: Among 169 children who performed the screening for pathogen colonization, 50% had at least one positive swab. Italian patients were (P=.001) less likely to be colonized with respect to foreign patients (relative risk 0.17, 95% CI 0.09-0.35). Postoperative infections in colonized patients occurred at a similar rate as in noncolonized patients (relative risk 1.24, 95% CI 0.64-2.39; P=.532). Colonized patients had a preoperative stay (P=.021) longer than noncolonized patients (mean difference 2 days, 95% CI 0.3-3.8 days). CONCLUSION: The results of our study suggest that the impact of preoperative colonization on outcome and postoperative infections may be negligible; larger series are required to clearly define this issue.

Novel celecoxib analogues inhibit glial production of prostaglandin E2, nitric oxide, and oxygen radicals reverting the neuroinflammatory responses induced by misfolded prion protein fragment 90-231 or lipopolysaccharide.

We tested the efficacy of novel cyclooxygenase 2 (COX-2) inhibitors in counteracting glia-driven neuroinflammation induced by the amyloidogenic prion protein fragment PrP90-231 or lipopolysaccharide (LPS). In search for molecules with higher efficacy than celecoxib, we focused our study on its 2,3-diaryl-1,3-thiazolidin-4-one analogues. As experimental models, we used the immortalized microglial cell line N9, rat purified microglial primary cultures, and mixed cultures of astrocytes and microglia. Microglia activation in response to PrP90-231 or LPS was characterized by growth arrest, morphology changes and the production of reactive oxygen species (ROS). Moreover, PrP90-231 treatment caused the overexpression of the inducible nitric oxide synthase (iNOS) and COX-2, with the consequent nitric oxide (NO), and prostaglandin E2 (PGE2) accumulation. These effects were challenged by different celecoxib analogues, among which Q22 (3-[4-(sulfamoyl)phenyl]-2-(4-tolyl)thiazolidin-4-one) inhibited microglia activation more efficiently than celecoxib, lowering both iNOS and COX-2 activity and reducing ROS release. During neurodegenerative diseases, neuroinflammation induced by amyloidogenic peptides causes the activation of both astrocytes and microglia with these cell populations mutually regulating each other. Thus the effects of PrP90-231 and LPS were also studied on mixed glial cultures containing astrocytes and microglia. PrP90-231 treatment elicited different responses in the co-cultures induced astrocyte proliferation and microglia growth arrest, resulting in a differential ability to release proinflammatory molecules with the production of NO and ROS mainly attributable on microglia, while COX-2 expression was induced also in astrocytes. Q22 effects on both NO and PGE2 secretion were more significant in the mixed glial cultures than in purified microglia, demonstrating Q22 ability to revert the functional interaction between astrocytes and microglia. These results demonstrate that Q22 is a powerful drug able to revert glial neuroinflammatory responses and might represent a lead to explore the chemical space around celecoxib frameworks to design even more effective agents, paving the way to novel approaches to contrast the neuroinflammation-dependent toxicity.

Canine osteosarcoma cell lines contain stem-like cancer cells: biological and pharmacological characterization.

Cancer stem cells (CSCs) represent a small subpopulation of cells responsible for tumor formation and progression, drug resistance, tumor recurrence and metastasization. CSCs have been identified in many human tumors including osteosarcoma (OSA). CSC distinctive properties are the expression of stem cell markers, sustained growth, self-renewal and tumorigenicity. Here we report the isolation of stem-like cells from two canine OSA cultures, characterized by self-renewal, evaluated by sphere formation ability, differential marker expression, and in vitro proliferation when cultured in a medium containing EGF and bFGF. Current therapies for OSA increased survival time, but prognosis remains poor, due to the development of drug resistance and metastases. Chemotherapy shrinks the tumor mass but CSCs remain unaffected, leading to tumor recurrence. Metformin, a drug for type 2 diabetes, has been shown to possess antitumor properties affecting CSC survival in different human and animal cancers. Here we show that metformin has a significant antiproliferative effect on canine OSA stem-like cells, validating this in vitro model for further pre-clinical drug evaluations. In conclusion, our results demonstrate the feasibility of obtaining CSC-enriched cultures from primary canine OSA cells as a promising model for biological and pharmacological studies of canine and human OSAs.

Psychological Considerations in the Assessment and Treatment of Pain in Neurorehabilitation and Psychological Factors Predictive of Therapeutic Response: Evidence and Recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation.

BACKGROUND: In order to provide effective care to patients suffering from chronic pain secondary to neurological diseases, health professionals must appraise the role of the psychosocial factors in the genesis and maintenance of this condition whilst considering how emotions and cognitions influence the course of treatment. Furthermore, it is important not only to recognize the psychological reactions to pain that are common to the various conditions, but also to evaluate how these syndromes differ with regards to the psychological factors that may be involved. As an extensive evaluation of these factors is still lacking, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) aimed to collate the evidence available across these topics. OBJECTIVES: To determine the psychological factors which are associated with or predictive of pain secondary to neurological conditions and to assess the influence of these aspects on the outcome of neurorehabilitation. METHODS: Two reviews were performed. In the first, a PUBMED search of the studies assessing the association between psychological factors and pain or the predictive value of these aspects with respect to chronic pain was conducted. The included papers were then rated with regards to their methodological quality and recommendations were made accordingly. In the second study, the same methodology was used to collect the available evidence on the predictive role of psychological factors on the therapeutic response to pain treatments in the setting of neurorehabilitation. RESULTS: The first literature search identified 1170 results and the final database included 189 articles. Factors such as depression, anxiety, pain catastrophizing, coping strategies, and cognitive functions were found to be associated with pain across the various conditions. However, there are differences between chronic musculoskeletal pain, migraine, neuropathy, and conditions associated with complex disability with regards to the psychological aspects that are involved. The second PUBMED search yielded 252 studies, which were all evaluated. Anxiety, depression, pain catastrophizing, coping strategies, and pain beliefs were found to be associated to different degrees with the outcomes of multidisciplinary programs, surgery, physical therapies, and psychological interventions. Finally, sense of presence was found to be related to the effectiveness of virtual reality as a distraction tool. CONCLUSIONS: Several psychological factors are associated with pain secondary to neurological conditions and should be acknowledged and addressed in order to effectively treat this condition. These factors also predict the therapeutic response to the neurorehabilitative interventions.

Cellular prion protein controls stem cell-like properties of human glioblastoma tumor-initiating cells.

Prion protein (PrPC) is a cell surface glycoprotein whose misfolding is responsible for prion diseases. Although its physiological role is not completely defined, several lines of evidence propose that PrPC is involved in self-renewal, pluripotency gene expression, proliferation and differentiation of neural stem cells. Moreover, PrPC regulates different biological functions in human tumors, including glioblastoma (GBM). We analyzed the role of PrPC in GBM cell pathogenicity focusing on tumor-initiating cells (TICs, or cancer stem cells, CSCs), the subpopulation responsible for development, progression and recurrence of most malignancies. Analyzing four GBM CSC-enriched cultures, we show that PrPC expression is directly correlated with the proliferation rate of the cells. To better define its role in CSC biology, we knocked-down PrPC expression in two of these GBM-derived CSC cultures by specific lentiviral-delivered shRNAs. We provide evidence that CSC proliferation rate, spherogenesis and in vivo tumorigenicity are significantly inhibited in PrPC down-regulated cells. Moreover, PrPC down-regulation caused loss of expression of the stemness and self-renewal markers (NANOG, Sox2) and the activation of differentiation pathways (i.e. increased GFAP expression). Our results suggest that PrPC controls the stemness properties of human GBM CSCs and that its down-regulation induces the acquisition of a more differentiated and less oncogenic phenotype.