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Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we reveal that intestinal GUCY2C is selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2CHigh neuropod cells associate with co-cultured dorsal root ganglia neurons and induce hyperexcitability, reducing the rheobase and increasing the resulting number of evoked action potentials. Conversely, the GUCY2C agonist linaclotide eliminated neuronal hyperexcitability produced by GUCY2C-sufficient, but not GUCY2C-deficient, neuropod cells, an effect independent of bulk epithelial cells or extracellular cGMP. Genetic elimination of intestinal GUCY2C amplified nociceptive signaling and VP that was comparable to chemically-induced VP but refractory to linaclotide. Importantly, eliminating GUCY2C selectively in neuropod cells also increased nociceptive signaling and VP that was refractory to linaclotide. In the context of loss of GUCY2C hormones in patients with VP, these observations suggest a specific role for neuropod GUCY2C signaling in the pathophysiology and treatment of these pain syndromes.

Diffuse peripheral neuropathy is a well-known complication of several conditions, whereas many patients have peripheral neuropathy of unknown etiology and pathophyisology. Increased knowledge of mechanisms may provide insight into enteric neuropathy with gastrointestinal dysmotility. The aim of the present systematic review was to identify mechanisms behind diffuse idiopathic peripheral neuropathies in humans. Searches were performed in PubMed, Embase, and Web of Science. Human original and review articles, written in English, describing mechanisms behind diffuse peripheral neuropathy verified by objective examinations were intended to be studied. Articles that described animal models, well-described hereditary diseases, drug-induced neuropathy, pain syndromes, malnutrition, and local neuropathy were excluded. In total, 4712 articles were identified. After scrutinizing titles and abstracts, 633 remained and were studied in full text. After the removal of articles not fulfilling inclusion or exclusion criteria, 52 were finally included in this review. The most frequently described neuropathy was diabetic neuropathy, with a wide range of mechanisms involving mitochondrial dysfunction such as oxidative stress and inflammation. Microvascular changes in diabetes and vasculitis lead to ischemia and secondary oxidative stress with inflammation. Structural changes in neurons and glial cells are observed, with abnormalities in different neurotrophic factors. Neuropathy induced by autoantibodies or immunological mechanisms is described in infectious and systemic inflammatory diseases. Several ion channels may be involved in painful neuropathy. No study identified why some patients mainly develop large fiber neuropathy and others small fiber neuropathy. Metabolic and immunological factors and channelopathy may be considered in diffuse idiopathic peripheral neuropathy.

Inflammatory bowel diseases (IBDs) are chronic, immune-mediated disorders that include Crohn's disease and ulcerative colitis. A pediatric onset of disease occurs in about 10% of all cases. Clinical presentation of IBD with rectal bleeding or perianal disease warrants direct referral for endoscopic evaluation. In the absence of red-flag symptoms, a combination of patient history and blood and fecal biomarkers can help to distinguish suspected IBD from other causes of abdominal pain or diarrhea. The therapeutic management of pediatric IBD has evolved by taking into account predictors of poor outcome, which justifies the upfront use of anti-tumor necrosis factor therapy for patients at high risk for complicated disease. In treating patients with IBD, biochemical or endoscopic remission, rather than clinical remission, is the therapeutic goal because intestinal inflammation often persists despite resolution of abdominal symptoms. Pediatric IBD comes with unique additional challenges, such as growth impairment, pubertal delay, the psychology of adolescence, and development of body image. Even after remission has been achieved, many patients with IBD continue to experience nonspecific symptoms like abdominal pain and fatigue. Transfer to adult care is a well-recognized risk for disease relapse, which highlights patient vulnerability and the need for a transition program that is continued by the adult-oriented IBD team. The general pediatrician is an invaluable link in integrating these challenges in the clinical care of patients with IBD and optimizing their outcomes. This state-of-the-art review aims to provide general pediatricians with an update on pediatric IBD to facilitate interactions with pediatric gastrointestinal specialists.

The pharmacological management of nonspecific chronic low back pain (NCLBP) aims to restore daily activities and improve the quality of life. No magic bullet exists for NCLBP; interventions to reduce pain and disability are available, but long-term results are unpredictable. Education in this regard needs to improve. This is often hard to accept for clinicians and patients, and provides a fertile soil to quacks, faith healers, and gurus to promote miraculous non-evidence-based solutions. The management of NCLBP is not well codified and extremely heterogeneous, and residual symptoms are common. Depending on the individual severity of NCLPB, pharmacological management may range from nonopioid to opioid analgesics. It is important to identify patients with generalized sensory hypersensitivity, who may benefit from a dedicated therapy. In this editorial, we provide an evidenced-based overview of the principles of pharmacological management of NCLPB.

Chronic musculoskeletal pain (CMP) is characterised by pain related to the muscles or the joints with a duration of three months or more and is associated with high symptomatic burden in patients in primary health care. CMP is commonly associated with impaired mental health, which may affect the rehabilitation process. The primary aim of this study was to compare symptoms of anxiety, depression, fatigue, and insomnia in patients in primary health care with and without CMP. The secondary aim was to assess difference in mental health symptoms related to number of pain sites and pain intensity.

Rheumatoid arthritis is a chronic condition that is characterized by joint pain and inflammation. It is an autoimmune disorder in which the body tissues are erroneously attacked by the immune system of the host itself. It has been evident that rheumatoid arthritis symptoms follow a 24 h circadian rhythm and exhibit high thresholds of pain, functional disability, and stiffness predominantly early in the morning. Colon-specific drug delivery systems can be utilized in the formulations to be used in the treatment of rheumatoid arthritis. The colon-specific drug delivery system has shown promising results in the treatment of different diseases at the colonic site like Crohn's disease, ulcerative colitis, colon cancer, etc. The colon-specific drug delivery is capable of delivering the formulation at the predetermined location and predetermined time. The early morning symptoms of rheumatoid arthritis like pain and inflammation can be treated using the various approaches of the colon-specific drug delivery system because it will lead to patient compliance as the patient will not require administering the formulation immediately after waking up in the morning. This review also explains the immunological factors which may trigger rheumatoid arthritis in human beings. It further explores conventional approaches like pH-dependant, microorganisms-driven, pressure-controlled, and time-dependant formulations. By employing two or more conventional approaches given above the various novel approaches have been designed to eliminate the drawbacks of individual techniques.

Transcutaneous auricular vagus nerve stimulation (taVNS) has been investigated as a novel neuromodulation tool. Although taVNS is generally considered safe with only mild and transient adverse effects (AEs), those specifically caused by taVNS have not yet been investigated. This systematic review and meta-analysis on taVNS aimed to (1) systematically analyze study characteristics and AE assessment, (2) characterize and analyze possible AEs and their incidence, (3) search for predictable risk factors, (4) analyze the severity of AE, and (5) suggest an evidence-based taVNS adverse events questionnaire for safety monitoring. The articles searched were published through April 7, 2022, in Medline, Embase, Web of Science, Cochrane, and Lilacs databases. In general, we evaluated 177 studies that assessed 6322 subjects. From these, 55.37% of studies did not mention the presence or absence of any AEs; only 24.86% of the studies described that at least one adverse event occurred. In the 35 studies reporting the number of subjects with at least one adverse event, a meta-analytic approach to calculate the risk differences of developing an adverse event between active taVNS and controls was used. The meta-analytic overall adverse events incidence rate was calculated for the total number of adverse events reported on a 100,000 person-minutes-days scale. There were no differences in risk of developing an adverse event between active taVNS and controls. The incidence of AE, in general, was 12.84/100,000 person-minutes-days of stimulation, and the most frequently reported were ear pain, headache, and tingling. Almost half of the studies did not report the presence or absence of any AEs. We attribute this to the absence of AE in those studies. There was no causal relationship between taVNS and severe adverse events. This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical intervention.

Chikungunya virus (CHIKV) belongs to the genus Alphaviridae, with a single-stranded positive-sense RNA genome of 11.8 kbp encoding a polyprotein that generates both non-structural proteins and structural proteins. The virus is transmitted by the Aedes aegypti and A. albopictus mosquitoes, depending on the location. CHIKV infection leads to dengue-like musculoskeletal symptoms and has been responsible for several outbreaks worldwide since its discovery in 1952. Patients often experience fever, headache, muscle pain, joint swelling, and skin rashes. However, the ultrastructural and mechanical properties of CHIKV have not been fully characterized. Thus, this study aims to apply a physical approach to investigate CHIKV's ultrastructural morphology and mechanical properties, using atomic force microscopy and Raman spectroscopy as the main tools. Using nanomechanical assays of AFM and a gold nanoparticles substrate for Raman signal enhancement, we explored the conformational plasticity, morphology, vibrational signature, and nanomechanical properties of the chikungunya virus, providing new information on its ultrastructure at the nanoscale and offering a novel understanding of the virus' behavior upon mechanical disruptions besides its molecular composition.

Infection with varicella zoster virus typically occurs in children and it can cause primary varicella infection or "chickenpox", or it can reactivate later in life and cause herpes zoster or "shingles". Herpes zoster mainly occurs in older adults, causing a reduction in activities of daily living, impacting quality of life, and may lead to serious complications, including chronic pain. Two vaccines are marketed to prevent herpes zoster: the live zoster vaccine and the non-live, recombinant zoster vaccine. The pre-licensure clinical trials show the efficacy of the live zoster vaccine to be between 50 and 70% and for the recombinant vaccine to be higher at 90 to 97%. Real-world effectiveness studies, with a follow-up of approximately 10 years, were reviewed in this article. These data corroborated the efficacy studies, with vaccine effectiveness being 46% and 85% for the live and recombinant vaccines, respectively. Safety data from the effectiveness studies show similar results to the clinical trials with mostly local injection-site reactions and mild systemic reactions seen with both vaccines, although in larger proportions with the recombinant vaccine. Rare adverse events, occurring less than 1% of the time, have been seen with both vaccine types and include disseminated herpes zoster with the live zoster vaccine and Guillain-Barré syndrome with the recombinant vaccine. The wider use of preventative measures with vaccines will reduce the herpes zoster burden of illness seen in older adults.