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Patients with cholestatic liver diseases, such as primary biliary cirrhosis, usually suffer from pruritus. However, the pathogenesis of cholestatic pruritus is unclear, and there is no current effective treatment for it. In order to find a treatment for the condition, an appropriate mouse model should be developed. Therefore, here, we established a surgically-induced mouse model of cholestatic pruritus. The bile duct was ligated in order to block bile secretion from the anterior, right, and left lobes, with the exception of the caudate lobe. Serum levels of total bile acid increased after bile duct ligation (BDL). The spontaneous hind paw scratching was also increased in BDL mice. Spontaneous scratching was reduced in BDL mice by naloxone (µ-opioid receptor antagonist), U-50,488H (κ-opioid receptor agonist), and clonidine (α2-adrenoceptor agonist). Azelastine (H receptor antagonist with membrane-stabilizing activity) slightly reduced scratching. However, terfenadine (H receptor antagonist), methysergide (serotonin (5-HT) receptor antagonist), ondansetron (5-HT receptor antagonist), proteinase-activated receptor 2-neutralizing antibody, fluvoxamine (selective serotonin reuptake inhibitor), milnacipran (serotonin-noradrenalin reuptake inhibitor), and cyproheptadine (H and 5-HT receptor antagonist) did not affect scratching. These results suggested that partial obstruction of bile secretion in mice induced anti-histamine-resistant itching and that central opioid system is involved in cholestatic itching.
Learn More >German authorities reimburse migraine prevention with erenumab only in patients who previously did not have therapeutic success with at least five oral prophylactics or have contraindications to such. In this real-world analysis, we assessed treatment response to erenumab in patients with chronic migraine (CM) who failed five oral prophylactics and, in addition, onabotulinumtoxinA (BoNTA). We analyzed retrospective data of 139 CM patients with at least one injection of erenumab from two German headache centers. Patients previously did not respond sufficiently or had contraindications to β-blockers, flunarizine, topiramate, amitriptyline, valproate, and BoNTA. Primary endpoint of this analysis was the mean change in monthly headache days from the 4-weeks baseline period over the course of a 12-weeks erenumab therapy. Secondary endpoints were changes in monthly migraine days, days with severe headache, days with acute headache medication, and triptan intake in the treatment period. Erenumab (starting dose 70 mg) led to a reduction of -3.7 (95% CI 2.4-5.1) monthly headache days after the first treatment and -4.7 (95% CI 2.9-6.5) after three treatment cycles ( < 0.001 for both). All secondary endpoint parameters were reduced over time. Half of patients (51.11%) had a >30% reduction of monthly headache days in weeks 9-12. Only 4.3% of the patients terminated erenumab treatment due to side effects. In this treatment-refractory CM population, erenumab showed efficacy in a real-world setting similar to data from clinical trials. Tolerability was good, and no safety issues emerged. Erenumabis is a treatment option for CM patients who failed all first-line preventives in addition to BoNTA.
Learn More >The number of non-responders to treatment among patients with chronic pain (CP) is high, although intensive multimodal treatment is broadly accessible. One reason is the large variability in manifestations of CP. To facilitate the development of tailored treatment approaches, phenotypes of CP must be identified. In this study, we aim to identify subgroups in patients with CP based on several aspects of self-reported health.
Learn More >Atopic Dermatitis (AD) is a common inflammatory disease with a genetic background. The prevalence of AD has been increasing in many countries. AD patients often have manifestations of pruritus, generalized skin dryness, and eczematous lesions. The pathogenesis of AD is complicated. The impaired skin barrier and immune imbalance play significant roles in the development of AD. Environmental factors such as allergens and pollutants are associated with the increasing prevalence. Many genetic and environmental factors induce a skin barrier deficiency, and this can lead to immune imbalance, which exacerbates the impaired skin barrier to form a vicious cycle (outside-inside-outside view). Genetic studies find many gene mutations and genetic variants, such as filaggrin mutations, which may directly induce the deficiency of the skin barrier and immune system. Epigenetic studies provide a connection between the relationship of an impaired skin barrier and immune and environmental factors, such as tobacco exposure, pollutants, microbes, and diet and nutrients. AD is a multigene disease, and thus there are many targets for regulation of expression of these genes which may contribute to the pathogenesis of AD. However, the epigenetic regulation of environmental factors in AD pathogenesis still needs to be further researched.
Learn More >Osteoarthritis (OA) is one of the most debilitating diseases and is associated with a high personal and socioeconomic burden. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects. Efforts to identify more tailored treatment options led to the development of strategies that enabled the classification of patient subgroups from the pool of heterogeneous phenotypes that display distinct common characteristics. To this end, the classification differentiates the structural endotypes into cartilage and bone subtypes, which are predominantly driven by structure-related degenerative events. In addition, further classifications have highlighted individuals with an increased inflammatory contribution (inflammatory phenotype) and pain-driven phenotypes as well as senescence and metabolic syndrome phenotypes. Most probably, it will not be possible to classify individuals by a single definite subtype, but it might help to identify groups of patients with a predominant pathology that would more likely benefit from a specific drug or cell-based therapy. Current clinical trials addressed mainly regeneration/repair of cartilage and bone defects or targeted pro-inflammatory mediators by intra-articular injections of drugs and antibodies. Pain was treated mostly by antagonizing nerve growth factor (NGF) activity and its receptor tropomyosin-related kinase A (TrkA). Therapies targeting metabolic disorders such as diabetes mellitus and senescence/aging-related pathologies are not specifically addressing OA. However, none of these therapies has been proven to modify disease progression significantly or successfully prevent final joint replacement in the advanced disease stage. Within this review, we discuss the recent advances in phenotype-specific treatment options and evaluate their applicability for use in personalized OA therapy.
Learn More >Vestibular migraine (VM) is a multidisciplinary disease under exploration. Multiple temporal patterns of vertigo and migraine make it difficult to diagnose VM, and their effect on the clinical features of VM is still unclear. Here we investigated the clinical features of VM under three temporal patterns. 172 VM patients were enrolled in this study and divided into three groups: 86 patients in group A had an earlier onset of migraine than vertigo, 35 patients in group B had an earlier onset of vertigo than migraine, and 51 patients in group C had concurrent vertigo and migraine. No significant difference was found among three groups regarding types, intensity and accompanying symptoms of the vestibular attack. Patients in group C presented higher frequency and longer duration of vertigo than group A and B, while patients in group A presented lower frequency and shorter duration of headaches than group B and C. Additionally, the frequency, duration, intensity and accompanying symptoms of headache in group A decreased significantly after the onset of vertigo, especially in women around menopause. We hypothesized that vestibular stimulation could inhibit the trigeminal pain pathway, while painful trigeminal stimulation could excite the vestibular system. Our findings may contribute to the clinical identification of VM and further clarification of its pathogenesis.
Learn More >Psychosocial variables are known risk factors for the development and chronification of low back pain (LBP). Psychosocial stress is one of these risk factors. Therefore, this study aims to identify the most important types of stress predicting LBP. Self-efficacy was included as a potential protective factor related to both, stress and pain.
Learn More >Neuromyelitis optica (NMO) is a disease characterised by severe relapses of optic neuritis and longitudinally extensive transverse myelitis and it has a strong female predilection. Pain is one of the most typical symptom in NMO. However, few studies have been conducted to examine the neuropathic pain mechanism of NMO patients or gender-specific effects using magnetic resonance imaging technique. A total of 38 female patients with NMO, 28 with pain (NMOWP) and 10 without pain (NMOWoP), were classified using the Brief Pain Inventory (BPI); 22 healthy females were also recruited. We used the FSL Image Registration and Segmentation Toolbox (FIRST) for subcortical region volumes quantifications, and voxel-based morphometry analysis for cortical gray matter (GM) volume, to examine the brain morphology in NMOWP patients. In addition, correlation test between structural measurements of NMO patients and clinical indexes was also performed. The results showed: 1) no significant differences in cortical GM density between the NMOWP and NMOWoP groups; 2) significantly smaller hippocampus and pallidum volumes in the NMOWP group compared with the NMOWoP group; 3) significant negative correlation between the average BPI and volumes of the accumbens nucleus and thalamus in NMO patients. These results revealed that structural abnormality exists in NMO female patients who have pain, with significant implications for our understanding of the brain morphology in NMO patients with pain.
Learn More >Emerging studies have demonstrated that interleukin (IL)-33 and its receptor ST2 act as key factors in inflammatory diseases. Moreover, accumulating evidence has suggested that cytokines, including tumor necrosis factor (TNF)-α and IL-1β, trigger an inflammatory cascade. SIRT1 has been shown to suppress the expression of inflammatory cytokines. However, the effects of SIRT1 on IL-33/ST2 signaling and initiation of the inflammatory cascade modulation of TNF-α and IL-1β by IL-33 remain unclear. In the present study, we found that the dorsal root ganglion (DRG) IL-33 and ST2 were upregulated in a rat model of spared nerve injury (SNI) and intrathecal injection of either IL-33 or ST2 antibodies alleviated mechanical allodynia and downregulated TNF-α and IL-1β induced by SNI. In addition, activation of SIRT1 decreased enhanced DRG IL-33/ST2 signaling in SNI rats. Artificial inactivation of SIRT1 intrathecal injection of an SIRT1 antagonist could induce mechanical allodynia and upregulate IL-33 and ST2. These results demonstrated that reduction in SIRT1 could induce upregulation of DRG IL-33 and ST2 and contribute to mechanical allodynia induced by SNI in rats.
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