Functional gastro-intestinal disorders (FGID) including irritable bowel syndrome (IBS) are frequently handled by self-management with over the counter (OTC) products such as hyoscine butylbromide (HBB), alone or in combination with paracetamol, and natural products such as peppermint oil. To obtain real-world information, we have performed an anonymous pharmacy-based patient survey among 1686 users of HBB, HBB + paracetamol and peppermint oil. Based on the distinct but overlapping indications for the three OTC products, multiple logistic regression was applied to compare them in users reporting gastrointestinal cramps and pain, bloating, flatulence, or IBS as cardinal symptom. All three treatments reduced symptoms and associated impairments of work/daily chores, leisure activities, and sleep by approximately 50%. Based on the four cardinal symptoms and the four dependent continuous variables of interest (change of intensity of symptoms and of the three impairment domains) a total of 16 logistic regression models were applied. HBB, HBB + paracetamol, and peppermint oil had similar reported overall effectiveness in those models. Gender, age, baseline symptom severity and impairment in one of three domains had small and inconsistent effects on perceived treatment success. We provide evidence that HBB, HBB + paracetamol, and peppermint oil have comparable effectiveness in their approved indications under real-world conditions in an OTC setting.

Pain is a multifaceted multisystem disorder that adversely affects neuro-psychological processes. This study compares the effectiveness of central-stimulation (tDCS) and peripheral-stimulation (TENS) in pain-inhibition during a cognitive-task in healthy volunteers and to observe potential neuro-cognitive improvements. Healthy eighty volunteers went through a complete experimental protocol comprising pain-induction (CPT), administration of tDCS/TENS, EEG-data acquisition, and cognitive assessments. The protocol for this study is categorized into 04-groups: G1(Control), G2(TENS), G3(Anodal-tDCS), and G4(Cathodal-tDCS). Paired t-tests (p

Oral mucosa is a key player in the cancer patient and during cancer treatment. The increasing prevalence of cancer and cancer therapy associated side effects are behind the major role that oral mucosa plays in the oncological patient. Oral mucositis is a debilitating severe complication caused by early toxicity of chemo and/or radiotherapy that can restrict treatment outcome possibilities, even challenging patient’s survival. It has been referred to as the most feared cancer treatment complication. Predictive variables as to who and to what extent will be affected are still unclear. Additionally, oral mucositis is one of the sources of the increasing economic burden of cancer, not only for patients and their families but also for institutions and governments. All efforts should be implemented in the search for new approaches to minimize the apparently ineluctable outburst of oral mucositis along the cancer treatment. New perspectives derived from different approaches in explaining the interrelation between oral mucositis and oral microbiome or the similarities with genitourinary mucosa may help elucidate the biomolecular pathways and mechanisms behind oral mucosa cancer-therapy related toxicity and what is more important its management in order to minimize treatment side effects and to provide enhanced cancer support.

The onset and progression of human inflammatory joint diseases are strongly controlled by the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived Mesenchymal Stem/Stromal Cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade Substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic ef-fects are largely exerted via their CD10-bound exosomal secretome (IFP-MSC EXOs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC EXOs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their exosomal miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low EXOs on stimulated by inflammatory/fibrotic cues synoviocytes monocultures and cocultures with IFP-MSC de-rived chondropellets. Finally, CD10High EXOs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low EXOs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in exosomes showed their involvement in the regulation of six gene groups, particularly the immune system. Stimulated synoviocytes exposed to IFP-MSC EXOs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High EXOs treatment of stimulated chondropellets/synoviocytes cocultures indicated a significant chondroprotective effects. Therapeutically, CD10High EXOs treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High EXOs possess immuno-modulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for EXOs-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).

Functional gastrointestinal disorders (FGIDs) are common in children and adolescents. In recent years, interest in the role of diet in the treatment of FGIDs has increased. Currently, interest focus-es on the low-FODMAP diet (LFD), the fructose- or lactose-restricted diet (FRD or LRD), the glu-ten-free diet (GFD), and the Mediterranean diet (MD). In this review, we focus on the role of these dietary patterns in the FGIDs most commonly diagnosed in clinical practice, namely irritable bowel syndrome (IBS), functional abdominal pain (FAP), functional dyspepsia (FD), and func-tional constipation (FC). Fifteen clinical trials were systematically reviewed (both RCTs and sin-gle arm clinical trials). We demonstrated the lack of high-quality intervention trials. Based on current evidence, low-FODMAP diet, LRD, FRD, or GFD have no place in daily practice for the management of children and adolescents with FGIDs. Nevertheless, some patients with IBS or RAP may have some benefit from the use of a low-FODMAP diet or FRD/LRD. Limited data sug-gest that MD may be promising in the management of FGIDs, especially in IBS patients, but more data are required to investigate the mechanisms of its protective effects.

People with sickle cell disease (SCD) are at greater risk of severe illness and death from respiratory infections, including COVID-19 than people without SCD (Centers for Disease Control and Prevention, USA). Vaso-occlusive crises (VOC) in SCD and severe SARS-CoV-2 infection are both characterized by thrombo-inflammation mediated by endothelial injury, complement activation, inflammatory lipid storm, platelet activation, platelet-leukocyte adhesion, and activation of the coagulation cascade. Notably, lipid mediators, including thromboxane A2, significantly increase in severe COVID-19 and SCD. In addition, the release of thromboxane A2 from endothelial cells and macrophages stimulates platelets to release microvesicles which are harbingers of multicellular adhesion and thrombo-inflammation. Currently, there are limited therapeutic strategies targeting platelet-neutrophil activation and thrombo-inflammation in either SCD or COVID-19 during acute crisis. However, due to many similarities between the pathobiology of thrombo-inflammation in SCD and COVID-19, therapies targeting one disease may likely be effective in the other. Therefore, the preclinical and clinical research spurred by the COVID-19 pandemic, including clinical trials of anti-thrombotic agents, are potentially applicable to VOC. Here, we first outline the parallels between SCD and COVID-19; second, review the role of lipid mediators in the pathogenesis of these diseases and lastly, examine the therapeutic targets and potential treatments for the two diseases.

Different nutraceuticals are often considered by parents of infants and children with abdominal pain and disorders of the gut-brain interaction. Herb extracts and natural compounds have long been used in traditional medicine, but clinical pediatric trials are very limited. This narrative review based on relevant studies identified through Pubmed-Medline literature search updated to October 2023, focused on the effect of nutraceuticals in infantile colic, functional abdominal pain and irritable bowel syndrome in children and adolescents. Significant reduction of colic episodes and crying time was reported in two studies on fennel (seeds oil or tea), in three studies on different multiple herbal extracts (all including fennel), in one study on Mentha piperita, and in at least two double-blind randomized controlled studies on Lactobacillus reuteri DSM 17938 and Bifidobacterium lactis BB-12 (108 CFU/day for at least 21 days) in breast-fed infants. Compared to placebo, in children with functional abdominal pain or irritable bowel syndrome a significant reduction of pain was reported in two studies supplementing peppermint oil capsules or psyllium fibers, in one study on corn fiber cookies or partial hydrolysed guar gum or a specific multiple herbal extract (STW-5) or vitamin D supplementation. To date, there is a moderate certainty of evidence with a weak grade of recommendation for Lactobacillus reuteri DSM 17938 (108 CFU/day) for reducing pain intensity in children with functional abdominal pain and for Lactobacillus rhamnosus GG (1-3 x109 CFU twice daily) for reducing pain frequency and intensity in children with IBS. Further large and well-designed pediatric studies are needed to prove efficacy and safety of different herbal extracts and prolonged use of studied products in infants and children with pain disorders of the gut-brain interaction.

Morphine-induced antinociception is partially reduced in interleukin-31 (IL-31) receptor A (IL-31RA)-deficient mice, indicating that IL-31RA is crucial for morphine-induced peripheral antinociception. Herein, we examined the combined effects of IL-31 and morphine on antinociceptive activity and itch-associated scratching behavior (LLS) in mice, and elucidated the regulatory mechanisms. A hot-plate test was used to assess antinociception. LLS was automatically detected and recorded via computer. IL-31RA mRNA expression was assessed using real-time polymerase chain reaction. Repeated pre-treatment with IL-31 resulted in significant antinociceptive activity. Repeated administration of morphine decreased the morphine-induced antinociceptive activity, LLS counts, and regular dose, and inhibited IL-31-induced LLS. These results suggested that repeated administration of morphine depleted inter-neuronal IL-31RA levels, preventing morphine-induced antinociception. Therefore, IL-31 may be helpful as an adjunct analgesic to morphine. To explore the benefits of IL-31, its influence on morphine-induced antinociceptive tolerance in mice was examined. IL-31 and morphine combination increased analgesic action which increased the expression of DRG neuronal IL-31RA, elucidating the site of peripheral antinociception of morphine. This site may induce exocytosis of IL-31RA in the sensory nervous system. Collectively, the suppressive effect of IL-31 on morphine-induced antinociceptive tolerance may result from IL-31RA supplementation in sensory nerves.

The theory that an itch inhibits pain has been refuted; however, previous research did not investigate this theory for interleukin-31 (IL-31)-induced itch. Previously, we have found that morphine-induced antinociception was partially reduced in IL-31 receptor A (IL-31RA)-deficient (IL-31RAKI) mice, indicating that IL-31RA may play an important role in morphine-induced peripheral antinociception. In the present study, we evaluated the effect of IL-31-induced analgesia on a 2,4,6-trinitrochlorobenzene (TNCB)-sensitized mice using a hot-plate test. This test evaluated the antinociceptive activity of morphine, and non-steroidal anti-inflammatory drugs (NSAIDs). Repeated pretreatment with IL-31 showed significant antinociceptive action. Furthermore, its combination with morphine, but not with NSAIDs, increased the analgesic action. In contrast, treatment with TNCB and capsaicin decreased antinociception. Moreover, TNCB increased IL-31RA expression in the dorsal root ganglia at 24 h, whereas capsaicin inhibited it. The comparative action of several analgesics on TNCB or capsaicin was evaluated using a hot-plate test, which revealed that the antinociceptive activity was decreased or disappeared in response to capsaicin-induced pain and in IL-31RAKI mice. These results indicate that the analgesic action of IL-31 involves the peripheral nervous system, which affects sensory nerve. These results provide a basis for developing novel analgesics using this mechanism.

Objectives: 1) to demonstrate the anti-inflammatory and anabolic effect of Ozone by determining in serum samples the biochemical levels of IL-6 and IGF-1 in knee osteoarthritis (OA) patients in a real world in Rehabilitation Setting; 2) to evaluate clinical effectiveness by Visual Analog Scale (VAS) and WOMAC scale, and biochemical effect by C-reactive protein (CRP), uric acid and erythrocyte sedimentation rate (ESR). Material and methods: 65 patients with knee OA Kellgren Lawrence (KL) grade 2 or more were analyzed in a retrospective observational study. The study run from January 2018 to September 2021. Inclusion criteria: a) patients 18 years or older; b) with knee OA KL 2º or more; c) biochemical analysis before-and-after treatment; d) pain more than 3 on VAS. Exclusion Criteria: a) previous knee surgery; b) favism; c) pregnancy; d) any other disease that originates lack of collaboration for infiltration. Primary Outcome variables: a) IL-6; b) IGF-1 in diabetes mellitus (DM)/obese and non-DM/non-obese patients; both before-and-after Ozone treatment. Secondary Outcome variables: a) CRP, b) ESR, c) uric acid, d) VAS pain, e) WOMAC pain, function and stiffness. Ozone protocol consisted of 4 sessions (once a week) of an intra-articular infiltration of 20 mL (20µg/mL concentration) of a gas mixture of Oxygen-Ozone 95-5% (produced by Ozone generator Ozonosan-α Plus ®). For biochemical evaluation, SNIBE MAGLUMI ™ IL-6 (CLIA) and SNIBE MAGLUMI ™ IGF-1 (CLIA) kits were used. CRP and uric acid were analyzed by Abbott Alinity c kit; and ESR was evaluated by DIESSE VES MATIC CUBE 30. Results: There is a linear correlation between age and OA severity. IL-6 decreased both in DM and non-DM patients and in all OA KL grades (from 2.7 to 1.59 pg/mL). IGF-1 decreased in total group (OA + DM + obesity) from 112.09 to 107.19 ng/mL. When only knee OA patients were analyzed, Ozone improved IGF-1 levels (from 100.17 to 102.03 ng/mL). Ozone decreased CRP, ESR, uric acid, and improved VAS pain, WOMAC pain, function and stiffness (p<0.05). Conclusions: Ozone is a valid option for the management of knee osteoarthritis in real world Rehabilitation Setting, because of its anti-inflammatory, metabolic and anabolic properties. Ozone downregulates pro-inflammatory IL-6 cytokine. Ozone has a metabolic/hypoglycemic effect on obese/diabetic knee osteoarthritis patients by reducing IGF-1. Ozone has an anabolic effect on non-diabetic/non-obese patients by improving IGF-1. Ozone reduces other biomarkers of inflammation (CRP, ESR and uric acid) and improves, pain, function and quality of life.

Regional anesthesia in postoperative pain management have developed in recent years, especially with the advent of fascial plane blocks. This study aims to compare the ultrasound-guided bilateral erector spinae plane block (ESPB) versus bilateral transversus abdominis plane block (TAPB) on postoperative analgesia after laparoscopic or robotic urologic surgery. This was a retrospective observational study; 97 patients (ESPB-group) received bilateral ultrasound-guided ESPB with 20 mL of ropivacaine 0.375% plus 0.5 mcg/kg of dexmedetomidine in each side at the level of T7-T9, and 93 patients (TAPB-group) received bilateral ultrasound-guided TAPB with ropivacaine 0.375% or 0.25%. The primary outcome was post-operative numeric rating scale (NRS) pain score, which was significantly lower in the ESPB-group on postoperative days 0, 2, and 3 (p=0.012, p=0.016 and p=0.004). Concerning the secondary outcomes, consumption of ropivacaine was significantly lower in ESPB-group (p<0.001) and the total amount of analgesic rescue doses was significantly lower in the ESPB-group than TAPB-group in postoperative days from 2 to 4 (1 vs 3, p>0.001). Incidence of postoperative nausea and vomiting was higher in the TAPB-group and no block related complications were observed. We conclude that ESPB provide better postoperative pain control with less consumption of local anesthetic and less total rescue analgesic therapies.

Breast cancer is the most common malignant disease in women. Preclinical studies have confirmed that the local anesthetic levobupivacaine has a cytotoxic effect on breast cancer cells. We examined whether postoperative wound infiltration with levobupivacaine influences survival in 120 patients who were operated on for breast cancer and underwent quadrantectomy or mastectomy with axillary lymph node dissection. Groups with continuous levobupivacaine wound infiltration, bolus wound infiltration, and diclofenac analgesia were compared. Long-term outcomes examined were quality of life, shoulder disability, and hand grip strength (HGS) after one year, and survival after 5 and 10 years. Groups that had infiltration analgesia had better shoulder function compared to diclofenac after one year. Levobupivacaine PCA group had the best preserved HGS after 1 year (P=0.022). The most significant predictor of the 5-year outcome was HGS (P=0.03). Although the best survival after 5 and 10 years was registered in the bolus levobupivacaine group, statistical significance was not reached (P=0.36). The extent of the disease at the time of surgery is the most important predictor of long-term survival. A larger prospective clinical study could better confirm the effect of levobupivacaine wound infiltration on outcomes after breast cancer surgery observed in this pilot study. Trial number NCT05829707

Background: Symptomatic Pelvic Congestion Syndrome (PCS) is often underdiagnosed and undertreated. We investigate a symptoms-based screening algorithm and treatment algorithm focused on position and location of pain for each type of PCS. Methods: This study is a retrospective, single-institution, multi-site review of 343 female patients who presented with pelvic pain. Results: Following a symptoms-based algorithm, 302 patients fulfilled criteria for inclusion; 299 patients had positional symptoms with a positive predictive value (PPV) of 97.99%, sensitivity of 98.99% and Odds Ratio (OR) of 48.83 (p=0.0003) while duplex ultrasonography (DUS) had a PPV of 98.84%, sensitivity of 86.49%, and OR of 6.4 (p=0.0396) confirmed by contrast venography. Patients with Type I PCS were treated with embolization and 87.5% reported total relief of anterior symptoms. Patients with Type II PCS were treated with embolization and/or vascular stenting based on their associated lesion, May-Thurner syndrome or Nutcracker syndrome, and 88.54% reported ≥50% symptom relief and 59.03% reported ≥80% symptom relief. Full treatment resulted in a mean “overall satisfaction” score of 96.07%. Conclusions: Algorithmic approaches are essential for PCS evaluation, diagnosis, and treatment. Patients with positional pelvic symptoms consistent with PCS should undergo diagnostic venography. Distinguishing between the types of PCS and using symptoms as a guide may be beneficial over a “one-size-fits-all” approach.

Heel pain in the “funnel-shaped” space between the calcaneus, talus, and talocalcaneonavicular and subtalar joints may be representative of Sinus Tarsi syndrome. The pain is often characterized by a burning, numbness, or tingling sensation that can stem from strains and tears on the ligaments in that area. Injury treatment typically includes balance training, muscle exercises, bracing, foot orthosis, and non-steroidal anti-inflammatory drugs (NSAIDs). This study presents Wharton Jelly (WJ) tissue allografts as an alternative intervention for patients who fail standard-care treatments. WJ targets tissue defects, unlike other therapies, which aim to reduce swelling and symptomatic pain. This study includes five female patients who have previously failed standard-of-care treatment. Each received extracorporeal pulse-activated therapy (EPAT), WJ, laser therapy, and an orthotic. After an average of 80 days, the cohort had an overall 85.29% improvement in pain. The study's limitations include a small cohort size and a non-blinded design. Given the significant improvement in pain, WJ tissue allograft, combined with other techniques, presents an optimal patient care plan for tissue defects associated with Sinus Tarsi syndrome when standard-of-care treatments fail. These results provide evidence for a more extensive, randomized study to define dosage protocols further and confirm safety and efficacy.

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nevertheless, the responder rates of recently approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and receptor inhibitors remain around 50 percent. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge on PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines.

Background: COVID-19 vaccines have been linked to myocarditis which in some circumstances can be fatal. This systematic review aims to investigate potential causal links between COVID-19 vaccines and death from myocarditis using post-mortem analysis. Methods: We performed a systematic review of all published autopsy reports involving COVID-19 vaccination-related myocarditis through July 3^rd, 2023. All autopsy studies that include COVID-19 vaccine-induced myocarditis as a possible cause of death were included, without imposing any additional restrictions. Causality in each case was determined by three independent reviewers with cardiac pathology experience and expertise. Results: We initially identified 1,691 studies and, after screening for our inclusion criteria, included 14 papers that contained 28 autopsy cases. The cardiovascular system was the only organ system affected in 26 cases. In 2 cases, myocarditis was characterized as a consequence from multisystem inflammatory syndrome (MIS). The mean and median number of days from last COVID-19 vaccination until death was 6.2 and 3 days, respectively. Most of the deaths occurred within a week from the last injection. We established that all 28 deaths were causally linked to COVID-19 vaccination by independent adjudication. Conclusions: The temporal relationship, internal and external consistency seen among cases in this review with known COVID-19 vaccine-induced myocarditis, its pathobiological mechanisms and related excess death, complemented with autopsy confirmation, independent adjudication, and application of the Bradford Hill criteria to the overall epidemiology of vaccine myocarditis, suggests there is a high likelihood of a causal link between COVID-19 vaccines and death from suspected myocarditis in cases where sudden, unexpected death has occurred in a vaccinated person. Urgent investigation is required for the purpose of risk stratification and mitigation in order to reduce the population occurrence of fatal COVID-19 vaccine-induced myocarditis.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal diseases in humans. It is characterized by visceral pain and/or discomfort, hypersensitivity and abnormal motor responses along with change in gut habits. Although the etio-pathogenesis of IBS is only partially understood, a main role has been attributed to psychosocial stress of different origin. Animals models such as neonatal maternal separation, water avoidance stress and wrap restraint stress have been developed as psychosocial stressors in the attempt to reproduce the IBS symptomatology and identify the cellular mechanisms responsible for the disease. The study of these models has led to the production of drugs potentially useful for IBS treatment. This review intends to give an overview on the results obtained with the animal models; to emphasize the role of the enteric nervous system in IBS appearance and evolution and as a possible target of drug therapies.