Dexketoprofen Trometamol and Tramadol Hydrochloride Fixed-Dose Combination in Moderate to Severe Acute Low Back Pain: A Phase IV, Randomized, Parallel Group, Placebo, Active-Controlled Study (DANTE).

INTRODUCTION: Dexketoprofen/tramadol 25/75 mg (DKP/TRAM) is a fixed-dose combination of a cyclooxygenase inhibitor and opioid receptor agonist. To better understand the efficacy and safety of DKP/TRAM in the treatment of moderate to severe acute lower back pain (LBP) with or without radiculopathy, we carried out a large explorative phase IV international, multicenter, prospective, randomized, double-blind, parallel group, placebo-controlled study (DANTE). METHODS: A total of 538 patients with or without a history of LBP and experiencing acute LPB of moderate to severe intensity [Numerical Rating Scale-Pain Intensity (NRS-PI) score > 5] were randomized 4:4:1:1 to DKP/TRAM 25/75 mg every 8 h (n = 211), tramadol (TRAM) 100 mg (n = 207), placebo-matched DKP/TRAM (n = 59), or placebo-matched TRAM (n = 61). RESULTS: The proportion of patients achieving the primary endpoint, defined as the time to first achieve NRS-PI score < 4 or pain intensity reduction ≥ 30% from drug intake up to 8 h after the first dose, was higher in the DKP/TRAM arm than in the placebo group, but the difference was not statistically significant (46.1% vs. 42.6%, respectively; hazard ratio 1.11; 95% confidence interval 0.775, 1.595; p = 0.566). DKP/TRAM achieved superiority over TRAM in total pain relief at 4, 6, and 8 h (p < 0.05). Conversely, in relation to the secondary endpoints, a significantly greater reduction in NRS-PI score was seen with DKP/TRAM versus placebo starting from 1 h, and this reduction remained numerically lower throughout 8 h. Summed pain intensity difference values were also significantly lower at 4, 6, and 8 h with DKP/TRAM compared to TRAM (p < 0.05). Overall, DKP/TRAM was well tolerated. CONCLUSION: Although the primary endpoint was not met, secondary efficacy analyses suggest the superiority of DKP/TRAM over placebo and TRAM alone in terms of total pain relief. DKP/TRAM can be considered to be an effective and safe option for the treatment of moderate to severe acute LBP. DANTE STUDY REGISTRATION: EudraCT number: 2019-003656-37; ClinicalTrials.gov Identifier: NCT05170841.

Immune Competence and Pain: A Narrative Review.

PURPOSE OF REVIEW: This review aims to summarize current knowledge on the pathophysiology of pain and the role of neuro-immune crosstalk in the development of acute and chronic pain (CP). Specifically, the review focuses on the role of immune cells involved in the innate and acquired immune response, emphasizing their bidirectional interactions with the nervous systems and discussing the implications of this crosstalk on acute and CP management. RECENT FINDINGS: In the last two decades, multiple studies have uncovered the important role of the immune system in initiating, maintaining, and resolving pain stimuli. Furthermore, researchers discovered that the immune system interacts tightly with the nervous system, creating a bidirectional crosstalk in which immune cells influence the response of peripheral and central nerve fibers while neurotransmitters and neuropeptides released by nociceptors directly and indirectly modulate the immune response. The neuro-immune crosstalk in acute and CP is a complex and not fully understood process that comprise the interactions of multiple diverse molecules, bidirectional interferences, and numerous redundant processes. Despite the complexity, important steps have been taken in recent years toward explaining the specific roles of each immune cell type and molecule in the initiation, maintenance and resolution of pain. These findings may set the basis for innovative therapeutic options that target the immune system, overcoming the limitations of current treatments in providing pain relief and the disadvantages associated with opioid therapy.

Is Fibromyalgia a Fashionable Diagnosis or a Medical Mystery?

Despite its prevalence, there is no clear-cut diagnostic path or treatment paradigm for fibromyalgia; this can lead to a multiplicity of symptoms and comorbid conditions that complicate care. "Overlapping symptoms" describe conditions that can occur concomitantly with fibromyalgia and include migraine, irritable bowel syndrome, obesity, and pelvic pain syndromes. A variety of pharmacologic and nonpharmacologic treatments are available for fibromyalgia, but treatment is best personalized for an individual and recognizes potential comorbidities. Opioids are not the recommended front-line treatment, cannabinoids hold promise but with limitations and nonpharmacologic options, such as aerobic or resistance exercise and cognitive behavior therapy, can play a very important but often underestimated role. Amitriptyline appears to be safe and effective in treating six of the main fibromyalgia domains: pain, disturbed sleep, fatigue, affective symptoms, functional limitations, and impaired cognition ("fibro fog"). Very low-dose naltrexone (2.5-4.5 mg) may offer analgesic and anti-inflammatory benefits to fibromyalgia patients, but further studies are needed. Fibromyalgia can be a devastating and debilitating condition for patients, and clinicians are challenged with its diagnosis and treatment as well. Further research as well as compassionate approaches to offering personalized care to those with fibromyalgia are required.

Primary Sjögren syndrome-related peripheral neuropathy: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Primary Sjögren syndrome (pSS) is a chronic, systemic, autoimmune disorder characterized by lymphocytic infiltrates of the exocrine organs, leading to sicca symptoms and parotid enlargement. pSS has been linked to various neurological manifestations, including peripheral neuropathy (PN). We aimed to provide a comprehensive analysis of the currently available evidence regarding pSS-related PN. METHODS: A literature search in the PubMed database was performed, and 49 papers were eligible to be included in this systematic review and meta-analysis. RESULTS: The pooled prevalence of PN in pSS is estimated to be 15.0% (95% confidence interval = 10.7%-20.7%). The mean age of pSS patients at PN diagnosis is 59 years. Among the patients with pSS and PN, 83% are females. Neuropathic symptoms usually precede or lead to the pSS diagnosis at a 2:1 ratio in patients with pSS-related PN. The commonest type of pSS-related PN is distal axonal polyneuropathy (80% of patients with pSS-related PN), followed by sensory ganglionopathy. Peripheral and cranial mononeuropathies-particularly trigeminal-are also frequent. Risk factors for developing PN include increasing age and presence of vasculitis. Immune-mediated pathogenetic mechanisms are discussed. Glucocorticoids are the most commonly used treatment option for managing pSS-related PN, when associated with vasculitis, followed by the use of intravenous immunoglobulin. CONCLUSIONS: PN is very common in pSS patients. Evidence on long-term prognosis of PN in pSS is limited, and further research is needed. Research into the use of immunosuppressive medication in nonvasculitic neuropathies in the context of pSS merits further consideration.

Osteoarthritis: New Insight on Its Pathophysiology.

Understanding of the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, as well as the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA physiopathology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms as underlying causes of pain chronicity has been characterized. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. To this aim, this review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insights on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.

Aerosol-Administered Adelmidrol Attenuates Lung Inflammation in a Murine Model of Acute Lung Injury.

Acute lung injury (ALI) is a common and devastating clinical disorder with a high mortality rate and no specific therapy. The pathophysiology of ALI is characterized by increased alveolar/capillary permeability, lung inflammation, oxidative stress and structural damage to lung tissues, which can progress to acute respiratory distress syndrome (ARDS). Adelmidrol (ADM), an analogue of palmitoylethanolamide (PEA), is known for its anti-inflammatory and antioxidant functions, which are mainly due to down-modulating mast cells (MCs) and promoting endogenous antioxidant defense. The aim of this study is to evaluate the protective effects of ADM in a mice model of ALI, induced by intratracheal administration of lipopolysaccharide (LPS) at the dose of 5 mg/kg. ADM 2% was administered by aerosol 1 and 6 h after LPS instillation. In this study, we clearly demonstrated that ADM reduced lung damage and airway infiltration induced by LPS instillation. At the same time, ADM counteracted the increase in MC number and the expression of specific markers of MC activation, i.e., chymase and tryptase. Moreover, ADM reduced oxidative stress by upregulating antioxidant enzymes as well as modulating the Nf-kB pathway and the resulting pro-inflammatory cytokine release. These results suggest that ADM could be a potential candidate in the management of ALI.

DANTE Study: The First Randomized, Double-Blind, Placebo and Active-Controlled, Parallel Arm Group Study Evaluating the Analgesic Efficacy and Safety of Dexketoprofen TrometAmol aNd Tramadol Hydrochloride Oral FixEd Dose Combination on Moderate to Severe Acute Pain in Patients with Acute Low Back Pain-Rationale and Design.

INTRODUCTION: Despite a wide range of treatment approaches and the availability of treatment recommendations or guidelines, no consensus on the most effective pharmacological therapy of low back pain (LBP) has been reached yet. Therefore, additional clinical evidence, particularly if built upon a rigorous clinical trial design, an evidence-based medication choice, and broader inclusion criteria better acknowledging the heterogeneity and intrinsic variability of LBP is needed. The DANTE study has been designed to comprehensively assess the analgesic efficacy and tolerability of dexketoprofen/tramadol (DKP/TRAM) 75/25 mg in a large cohort of patients with moderate to severe acute LBP. METHODS: The DANTE study is a phase IV, multicenter, randomized, double-blind, double-dummy parallel group, placebo, and active controlled study. The DANTE study encompasses a single-dose phase (day 1, t0-t8h) and a multiple-dose phase (from t8h to 8 h after intake of last dose at day 5). The DANTE study population includes patients naïve to LBP or patients with previous history of LBP experiencing a new episode of moderate to severe intensity with or without radiculopathy. The clinical phase of the DANTE study started in September 2020 and the anticipated completion date is April 2022. PLANNED OUTCOMES: The primary endpoint is the time to first achieve a numeric rating scale-pain intensity (NRS-PI) score of < 4 or a pain intensity reduction ≥ 30% from drug intake up to 8 h after the first dose (t8h). Secondary objectives aim are: (1) to evaluate the analgesic efficacy of TRAM/DKP 75/25 mg versus TRAM 100 mg after the first dose; (2) to evaluate the analgesic efficacy of TRAM/DKP 75/25 mg versus TRAM 100 mg after the multiple doses (from t8h until day 5, multiple dose); and (3) to assess the safety and tolerability of the TRAM/DKP 75/25 mg fixed combination after single and multiple doses. DANTE STUDY REGISTRATION: EudraCT number: 2019-003656-37.

Diagnostic and therapeutic care pathway for fibromyalgia.

Early diagnosis and timely and appropriate treatments positively influence the history of fibromyalgia syndrome (FM), with favourable repercussions at clinical, psychological, social and economic levels. Notwithstanding, there are still significant problems with timeliness of diagnosis, access to pharmacological therapies - particularly to innovative ones - and appropriate and effective taking in charge of patients. All the aforementioned factors have a great impact on FM patients' quality of life. Indeed, even though the World Health Organisation recognised FM as a chronic condition in the International Classification of Diseases 10th edition (ICD-10), many countries still fail to recognise the syndrome, and this negatively influences the capability to appropriately protect and care for patients. This is the case in several European Countries. In Italy, a few Regions have started to put in place precise indications for people suffering from FM, aiming at the implementation of diagnostic-therapeutic pathways. The Diagnostic-Therapeutic Care Pathway (DTCP) provides an important tool to meet the needs of patients suffering from chronic diseases. They present the organisation of an integrated assistance network. This includes a seamless path for disease prevention, diagnosis and treatment, by means of cooperation among physicians and other healthcare professionals.

Fibromyalgia position paper.

Fibromyalgia syndrome is one of the most common causes of chronic widespread pain, but pain accompanies a wide range of ancillary symptoms. To date, its aetiopathogenesis remains elusive, and diagnosis is exquisitely clinical, due to the lack of biomarkers or specific laboratory alterations in fibromyalgia patients. This position paper has the purpose to summarise the current scientific knowledge and expert opinions about the main controversies regarding fibromyalgia syndrome, namely: (i) fibromyalgia definition and why it is still not recognised in many countries as a distinct clinical entity; (ii) fibromyalgia severity and how to evaluate treatment outcome; (iii) how to treat fibromyalgia and which is a correct approach to fibromyalgia patients.

Expert Consensus on Clinical Use of an Orally Administered Dexketoprofen Plus Tramadol Fixed-Dose Combination in Moderate-To-Severe Acute Pain: A Delphi Study.

INTRODUCTION: In 2016, the orally administered fixed-dose combination of dexketoprofen 25 mg and tramadol 75 mg (DKP/TRAM FDC) was approved in Europe for short-term treatment of moderate-to-severe acute pain, an indication that encompasses a wide range of post-operative and non-surgical painful conditions. This has suggested the necessity to have a clearer indication on its clinical use, with the support of expert pain clinicians, working in different medical specialities, and reinforced by the data present in the literature. METHODS: With the aim of assisting clinicians in the use of DKP/TRAM FDC in daily practice, two rounds of a modified Delphi process were conducted. In the first round, a board of nine experts developed a series of consensus statements based on available evidence, and their clinical experience, with DKP/TRAM FDC. In the second round, 75 clinicians with extensive experience in pain management expressed individually their agreement with the statements, using a dedicated online platform. Consensus was defined as at least 70% agreement. RESULTS: Twenty-eight statements were developed. Of these, 19 reached the defined level of consensus. CONCLUSION: The agreed consensus statements may assist clinicians in applying the results of clinical studies and clinical experience to routine care settings, providing guidance for use of this new analgesic combination in moderate-to-severe post-operative and non-surgical acute pain. FUNDING: Menarini Group.

Tapentadol in the treatment of osteoarthritis: pharmacological rationale and clinical evidence.

Osteoarthritis (OA) is the most prevalent joint disease in older people worldwide. Pain owing to OA is considered one of the most frequent causes of chronic pain; however, current pharmacological approaches have some limitations in terms of efficacy and safety. Of note, descending inhibitory pain pathways are often disrupted in chronic OA pain, and pharmacotherapies targeting those pathways - eg, those that block norepinephrine reuptake may be more appropriate for managing chronic pain than pure µ-opioid receptor (MOR) agonists. Tapentadol is an analgesic molecule, which combines two synergistic mechanisms of action, MOR, and norepinephrine reuptake inhibition. This narrative review will briefly discuss the mechanisms contributing to the onset and maintenance of pain in OA patients; clinical data on the use of tapentadol in this setting will then be presented and commented.

Where should analgesia lead to? Quality of life and functional recovery with tapentadol.

Chronic pain is a major health-care problem worldwide, affecting more than one out of five adults in Europe. Although multiple analgesic agents have been extensively investigated in terms of clinical response and tolerability profile, few studies have focused on the impact of these therapies on patients' quality of life (QoL). Of note, improvement in QoL, together with functional recovery, has been recognized since the late 1990s as two main goals of analgesic therapy. Tapentadol is a novel analgesic molecule that synergistically combines two mechanisms of action, µ-opioid receptor agonism and norepinephrine reuptake inhibition, and for which multiple literature data are available that confirm its efficacy and safety in controlling pain. This narrative review summarizes the information available on the impact of tapentadol on QoL, with the aim to provide clinicians with a comprehensive overview of the analgesic effects of tapentadol prolonged release beyond the reduction of pain.

Epidemiology of Chronic Pain in the Latium Region, Italy: A Cross-Sectional Study on the Clinical Characteristics of Patients Attending Pain Clinics.

In Italy, chronic pain affects more than a quarter of the population, whereas the average European prevalence is 21%. This high prevalence might be due to the high percentage of Italian people who do not receive treatment, even after the passing of law 38/2010 (the right to access pain management in Italy), which created a regional network for the diagnosis and treatment of noncancer chronic pain. Italian epidemiologic studies on chronic pain are scanty, and this observational, multicenter, cross-sectional study is the first to investigate the clinical characteristics of patients who attended the pain management clinics in the Latium Region, Italy, for the management of their noncancer chronic pain. A total of 1,606 patients (mean age 56.8 years, standard deviation ± 11.4), 67% women, were analyzed. Severe pain was present in 54% of the sample. Women experienced pain and had it in two or more sites more often than men (57% vs. 50%, p = .02; and 55.2% vs. 45.9%, p < .001, respectively). Chronic pain was musculoskeletal (45%), mixed (34%), and neuropathic (21%). In more than 60% of the cases, chronic pain was continuous, and in 20% it had lasted for more than 48 months; long-lasting pain was often neuropathic. Low back (33.4%) and lower limbs (28.2%) were the main locations. Severe intensity of pain was statistically significantly associated with female gender (odds ratio [OR] 1.39; 95% confidence interval [CI] 1.06-1.84); with International Classification of Diseases, Ninth Revision, codes for chronic pain syndrome (OR 2.14; 95% CI 1.55-2.95); and with continuous pain (OR 2.02; 95% CI 1.54-2.66). Neuropathic pain and mixed pain were significantly associated with number of sites, and a trend seemed to be present (OR 2.11 and 3.02 for 2 and 3 + sites; 95% CI 1.59-2.79 and 2.00-4.55, respectively).

A Pharmacological Rationale to Reduce the Incidence of Opioid Induced Tolerance and Hyperalgesia: A Review.

Chronic pain is an important health and social problem. Misuse and abuse of opioids in chronic non-cancer pain management seem to be a huge problem, in some countries. This could probably affect the normal use of such analgesics in patients in need of them. Basic and clinical researches should find the solution to mitigate the potential damage. Dysregulation of mast cell and microglia activation plays an important role in the pathogenesis and management of chronic pain. Persistent mast cell activation sensitizes nociceptors and initiates central nervous system inflammatory processes, involving microglial cell activation and sensitization of spinal somatosensory neurons. Exposure of mast cells and microglia to opioids is well known to provoke activation of these non-neuronal immune cell populations, thereby contributing to an exacerbation of pro-inflammatory and pro-nociceptive processes and promoting, over the long-term, opioid-induced hyperalgesia and tolerance. This review is intended to provide the reader with an overview of the role for these non-neuronal cells in opioid-induced chronic pain and tolerance as a consequence of prolonged exposure to these drugs. In addition, we will examine a potential strategy with the aim to modulate opioid-induced over-activation of glia and mast cells, based on endogenous defense mechanisms and fatty acid amide signaling molecules.

Assessment of chronic pain and access to pain therapy: a cross-sectional population-based study.

BACKGROUND: Chronic pain (CP) has been shown as an important public health problem, and several studies emphasize the need to strengthen the health care and social systems to reduce its marginalization. This study aimed to: evaluate the epidemiology of CP in the general population in an Italian area; and assess the awareness of a specific law, unanimously approved in Parliament, which provides citizens the right to access pain management (Italian Law 38/2010). METHODS: A cross-sectional population-based study carried out during the spring of 2014 at Narni, Umbria, Italy. All the citizens residing in that area, aged >18, were enrolled in the study. Outcome measures were: prevalence of CP and therapies. The awareness of the Italian Law 38/2010 was also recorded. RESULTS: Data of 1293 questionnaires were analyzed. The prevalence of CP was 28.4%. In 51.5% of cases, pain was severe, with higher prevalence in females (p<0.001). Moreover, pain was generally increasing with age (p<0.001). The risk of suffering from severe pain was modeled using logistic regression. Significant predictors were female gender (OR 2.59; 95% CI: 1.77-3.79), living in an urban area (OR 0.63; 95% CI 0.45-0.88), and age (OR 1.06; 95% CI: 1.04-1.08). Among people with CP, 77.9% were receiving therapy; the proportion of individuals in therapy for severe pain significantly increased with age (OR 1.03; 95% CI: 1.02-1.05) and was smaller in individuals with light pain (OR 0.21; 95% CI: 0.07-0.66). The majority of subjects (61.9%) are not aware of the existence of a specific law stating their rights to receive pain management. CONCLUSION: CP, at least in the rural part of the community investigated in Italy, is not perceived as a chronic disease in its own right. A socio-cultural transformation in patients and in the health care system seems necessary.

Palmitoylethanolamide in the Treatment of Failed Back Surgery Syndrome.

INTRODUCTION: This observational study was designed to evaluate the efficacy of ultramicronized palmitoylethanolamide (um-PEA) (Normast®) administration, as add-on therapy for chronic pain, in the management of pain-resistant patients affected by failed back surgery syndrome. METHODS: A total of 35 patients were treated with tapentadol (TPD) and pregabalin (PGB). One month after the start of standard treatment, um-PEA was added for the next two months. Pain was evaluated by the Visual Analogue Scale (VAS) at the time of enrollment (T0) and after one (T1), two (T2), and three (T3) months. RESULTS: After the first month with TDP + PGB treatment only, VAS score decreased significantly from 5.7 ± 0.12 at the time of enrollment (T0) to 4.3 ± 0.11 (T1) (p < 0.0001); however, it failed to provide significant subjective improvement in pain symptoms. Addition of um-PEA led to a further and significant decrease in pain intensity, reaching VAS scores of 2.7 ± 0.09 (T2) and 1.7 ± 0.11 (T3, end of treatment) (p < 0.0001) without showing any side effects. CONCLUSIONS: This observational study provides evidence, albeit preliminary, for the efficacy and safety of um-PEA (Normast) as part of a multimodal therapeutic regimen in the treatment of pain-resistant patients suffering from failed back surgery syndrome.

Treatment for chronic low back pain: the focus should change to multimodal management that reflects the underlying pain mechanisms.

Chronic low back pain: Chronic pain is the most common cause for people to utilize healthcare resources and has a considerable impact upon patients' lives. The most prevalent chronic pain condition is chronic low back pain (CLBP). CLBP may be nociceptive or neuropathic, or may incorporate both components. The presence of a neuropathic component is associated with more intense pain of longer duration, and a higher prevalence of co-morbidities. However, many physicians' knowledge of chronic pain mechanisms is currently limited and there are no universally accepted treatment guidelines, so the condition is not particularly well managed. DIAGNOSIS: Diagnosis should begin with a focused medical history and physical examination, to exclude serious spinal pathology that may require evaluation by an appropriate specialist. Most patients have non-specific CLBP, which cannot be attributed to a particular cause. It is important to try and establish whether a neuropathic component is present, by combining the findings of physical and neurological examinations with the patient's history. This may prove difficult, however, even when using screening instruments. Multimodal management: The multifactorial nature of CLBP indicates that the most logical treatment approach is multimodal: i.e. integrated multidisciplinary therapy with co-ordinated somatic and psychotherapeutic elements. As both nociceptive and neuropathic components may be present, combining analgesic agents with different mechanisms of action is a rational treatment modality. Individually tailored combination therapy can improve analgesia whilst reducing the doses of constituent agents, thereby lessening the incidence of side effects. CONCLUSIONS: This paper outlines the development of CLBP and the underlying mechanisms involved, as well as providing information on diagnosis and the use of a wide range of pharmaceutical agents in managing the condition (including NSAIDs, COX-2 inhibitors, tricyclic antidepressants, opioids and anticonvulsants), supplemented by appropriate non-pharmacological measures such as exercise programs, manual therapies, behavioral therapies, interventional pain management and traction. Surgery may be appropriate in carefully selected patients.

Degenerative Joint Diseases and Neuroinflammation.

Rheumatic and joint diseases, as exemplified by osteoarthritis and rheumatoid arthritis, are among the most widespread painful and disabling pathologies across the globe. Given the continuing rise in life expectancy, their prevalence is destined to grow. Osteoarthritis, a degenerative joint disease, is, in particular, on its way to becoming the fourth leading cause of disability worldwide by 2020, with the rising incidence of obesity in addition to age being important factors. It is estimated that 25% of osteoarthritic individuals are unable to perform daily activities. Accompanying osteoarthritis is rheumatoid arthritis, which is a chronic systemic disease that often causes pain and deformity. At least 50% of those affected are unable to remain gainfully employed within 10 years of disease onset. A growing body of evidence now points to inflammation, locally and more systemically, as a promoter of damage to joints and bones, as well as joint-related functional deficits. The pathogenesis underlying joint diseases remains unclear; however, it is currently believed that cross-talk between cartilage and subchondral bone-and loss of balance between these two structures in joint diseases-is a critical element. This view is amplified by the presence of mast cells, whose dysregulation is associated with alterations of junction structures (cartilage, bone, synovia, matrix, nerve endings, and blood vessels). In addition, persistent activation of mast cells facilitates the development of spinal neuroinflammation mediated through their interaction with microglia. Unfortunately, current treatment strategies for rheumatic and articular disease are symptomatic and do little to limit disease progression. Research now should be directed at therapeutic modalities that target osteoarticular structural elements and thereby delaying disease progression and joint replacement.

Enteric glial cells are susceptible to Clostridium difficile toxin B.

Clostridium difficile causes nosocomial/antibiotic-associated diarrhoea and pseudomembranous colitis. The major virulence factors are toxin A and toxin B (TcdB), which inactivate GTPases by monoglucosylation, leading to cytopathic (cytoskeleton alteration, cell rounding) and cytotoxic effects (cell-cycle arrest, apoptosis). C. difficile toxins breaching the intestinal epithelial barrier can act on underlying cells, enterocytes, colonocytes, and enteric neurons, as described in vitro and in vivo, but until now no data have been available on enteric glial cell (EGC) susceptibility. EGCs are crucial for regulating the enteric nervous system, gut homeostasis, the immune and inflammatory responses, and digestive and extradigestive diseases. Therefore, we evaluated the effects of C. difficile TcdB in EGCs. Rat-transformed EGCs were treated with TcdB at 0.1-10 ng/ml for 1.5-48 h, and several parameters were analysed. TcdB induces the following in EGCs: (1) early cell rounding with Rac1 glucosylation; (2) early G2/M cell-cycle arrest by cyclin B1/Cdc2 complex inactivation caused by p27 upregulation, the downregulation of cyclin B1 and Cdc2 phosphorylated at Thr161 and Tyr15; and (3) apoptosis by a caspase-dependent but mitochondria-independent pathway. Most importantly, the stimulation of EGCs with TNF-α plus IFN-γ before, concomitantly or after TcdB treatment strongly increased TcdB-induced apoptosis. Furthermore, EGCs that survived the cytotoxic effect of TcdB did not recover completely and showed not only persistent Rac1 glucosylation, cell-cycle arrest and low apoptosis but also increased production of glial cell-derived neurotrophic factor, suggesting self-rescuing mechanisms. In conclusion, the high susceptibility of EGCs to TcdB in vitro, the increased sensitivity to inflammatory cytokines related to apoptosis and the persistence of altered functions in surviving cells suggest an important in vivo role of EGCs in the pathogenesis of C. difficile infection.

CGRP and Visceral Pain: The Role of Sex Hormones in In Vitro Experiment.

A large number of studies have showed that women reported feeling pain more acutely than men. In support of this hypothesis, many research groups proved that in different animals model of pain the sex hormones regulate the somatic and visceral sensitivity to different noxious stimuli. Therefore, in this study, we went to evaluate if estrogen hormones by regulating the CGRP levels are implicated during the visceral pain transmission. Toward this aim, we have investigated the effect of 17ß-estradiol in regulating the synthesis and release of CGRP, as well as the expression levels of the opioid receptor of type K. In order to gain information about the potential effects of 17ß-estradiol on K-opioid receptor expression and activity, we have cultured F11 cells. Our results revealed that, when F11 cells were short-term exposed (30 min) to 17ß-estradiol, the expression of the opioid K receptor was not significantly modified. We carried out enzyme immunoassay analysis to evaluate the potential effects of short-term exposure to 17-estradiol (30 min) on the release of CGRP in F11 cells. The results obtained showed that 17ß-estradiol at the dose of 100 nM is able to induce the release of CGRP from F11 cells; whereas, a higher dose of 17ß-estradiol (200 nM) did not produce significant effects when compared to control. In conclusion, all these findings suggest that the 17ß-estradiol-regulated release of CGRP could at least in part provide a rational explanation for the difference of gender in the visceral pain sensitivity. J. Cell. Biochem. 118: 510-517, 2017. © 2016 Wiley Periodicals, Inc.