Rejected

Baclofen and Lamotrigine via PLGA nanoparticles were developed for nose-to-brain delivery for treatment of Neuropathic pain.

In children with hematological malignancies, chronic HCV infection has been associated with more rapid liver disease progression and higher risk of malignancy relapse due to chemotherapy interruption. We evaluated the safety and efficacy of ledipasvir-sofosbuvir for 12 weeks in these patients.

Staphylococcus aureus causes severe infections associated with inflammation, such as sepsis or osteomyelitis. Inflammatory processes are regulated by distinct lipid mediators (LM) but how their biosynthetic pathways are orchestrated in S. aureus infections is elusive. We show that S. aureus strikingly modulates pro-inflammatory but also inflammation-resolving LM pathways in murine osteomyelitis and osteoclasts as well as in human monocyte-derived macrophages (MDM) with different phenotype. Targeted LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed massive generation of LM with distinct LM signature profiles in acute and chronic phases of S. aureus-induced murine osteomyelitis in vivo. In human MDM, S. aureus elevated cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), but impaired levels of 15-lipoxygenase-1 (15-LOX-1), with respective changes in LM signature profiles initiated by these enzymes, i.e., elevated PGE and impaired specialized pro-resolving mediators, along with reduced M2-like phenotypic macrophage markers. The cell wall component lipoteichoic acid (LTA) mimicked the impact of S. aureus elevating COX-2/mPGES-1 expression via NF-κB and p38 MAPK signalling in MDM, while the impairment of 15-LOX-1 correlates with reduced expression of Lamtor1. In conclusion, S. aureus dictates LM pathways via LTA resulting in a shift from anti-inflammatory M2-like towards pro-inflammatory M1-like LM signature profiles.

BACKGROUND: In addition to the available medical treatment options, multiple sclerosis (MS) patients may tend toward complementary and integrative therapies. Relaxation techniques are a nonpharmacological and side-effect-free therapy option currently available to alleviate the symptoms of many different chronic diseases. The aim of this study was to examine and compare the effects of relaxation techniques on the pain, fatigue, and kinesiophobia in MS patients. METHODS: This 3-arm randomized controlled trial consisted of 80 MS patients. Relaxation techniques, progressive muscle relaxation and Benson relaxation technique were applied to 2 intervention groups, the third was the control group. The study lasted 12 weeks, and the patient information form, visual analog scale, Fatigue Severity Scale, and Tampa Scale for Kinesiophobia were used for data collection. RESULTS: There was a statistically significant decrease in pain, fatigue, and kinesiophobia levels in the intervention groups compared with the control group (P < .05). Progressive muscle relaxation was more effective than Benson relaxation technique (P < .05). CONCLUSION: Relaxation techniques are recommended for the management of symptoms of pain, fatigue, and kinesiophobia, which can often cause disability in MS patients, because they have no side effects and are practical administrations. These exercises are also promising in the rehabilitation process of MS patients.

Medication overuse headache (MOH) is a prevalent secondary headache, bringing heavy economic burden and neuropsychological damage. Neuroimaging studies on the disease reported divergent results. To merge the reported neuroimaging alterations in MOH patients and explore a pathophysiological mechanism of this disorder. A meta-analytic activation likelihood estimation (ALE) analysis method was used. We systematically searched English and Chinese databases for both morphological and functional neuroimaging studies published before Nov 18, 2021. Reported altered brain regions and the stereotactic coordinates of their peaks were extracted and pooled by GingerALE using Gaussian probability distribution into brain maps, illustrating converged regions of alteration among studies. We identified 927 articles, of which five studies on gray matter changes, using voxel-based morphometry (VBM) were eventually included for ALE analysis, with 344 subjects and 54 coordinates put into GingerALE. No functional magnetic resonance imaging (fMRI) or positron emission topography (PET) studies were included for pooling. Compared with healthy controls (HCs), MOH featured increased gray matter density in midbrain, striatum, cingulate, inferior parietal cortex and cerebellum (P < 0.001 uncorrected), whereas decreased gray matter density in orbitofrontal cortex (P < 0.05, family-wise error), frontal, insular and parietal cortices (P < 0.001 uncorrected). Withdrawal of analgesics led to decreased gray matter density in superior temporal gyrus, cuneus, midbrain and cerebellum (P < 0.001 uncorrected). This meta-analysis confirmed that medication overuse headache is associated with morphologic alteration in the reward system, the prefrontal cortex and a reversible modification in the pain network. Further functional imaging paradigms and longitudinal studies are required for a more definite conclusion and a causal mechanism.

To investigate the complication rate of chronic prostatitis/chronic pelvic pain syndrome in men with lower urinary tract symptoms, and to clarify their clinical features and urodynamic findings.

Enhanced Recovery After Surgery (ERAS) protocols have been developed in several fields to reduce hospitalization lengths and overall costs. There have also been developments in multimodal analgesia methods to curtail opioid usage after surgery. Herein, we present the results of our initiation of an ERAS protocol for robotic-assisted laparoscopic partial and radical nephrectomies, employing a quadratus lumborum (QL) regional anesthetic block. We retrospectively reviewed 614 patients in our Institutional Review Board approved database who underwent robotic-assisted laparoscopic partial or radical nephrectomies from January 2017 to February 2020. An ERAS protocol utilizing multimodal analgesia (acetaminophen and gabapentin) and a QL block was developed and introduced in February 2019. We then compared the opioid consumption and perioperative outcomes of patients before and after ERAS protocol initiation. 192 ERAS patients (February 2019 to February 2020) were compared to 422 non-ERAS patients (January 2017 to January 2019). Baseline characteristics and the proportion of preoperative opioids users were similar between the two groups. There were no statistically significant differences in surgery length, hospitalization length, or complication rates. There were statistically significant differences in our primary endpoint, opioid consumption, on post-operative days 0 (p < 0.001), 1 (p < 0.001), and 2 (p < 0.001). The total opioid requirements over the course of admission were lower in the ERAS group compared to the non-ERAS group (p = 0.03). The initiation of an ERAS protocol employing multimodal analgesia and a QL block, for patients undergoing robotic-assisted laparoscopic partial or radical nephrectomies, can decrease opioid requirements without compromising perioperative outcomes.

Low back pain (LBP) is a major musculoskeletal disorder and the socioeconomic problem with a high prevalence that mainly involves intervertebral disc (IVD) degeneration, characterized by progressive nucleus pulposus (NP) cell death and the development of an inflammatory microenvironment in NP tissue. Excessively accumulated cytosolic DNA acts as a damage-associated molecular pattern (DAMP) that is monitored by the cGAS-STING axis to trigger the immune response in many degenerative diseases. NLRP3 inflammasome-dependent pyroptosis is a type of inflammatory programmed death that promotes a chronic inflammatory response and tissue degeneration. However, the relationship between the cGAS-STING axis and NLRP3 inflammasome-induced pyroptosis in the pathogenesis of IVD degeneration remains unclear. Here, we used magnetic resonance imaging (MRI) and histopathology to demonstrate that cGAS, STING, and NLRP3 are associated with the degree of IVD degeneration. Oxidative stress induced cGAS-STING axis activation and NLRP3 inflammasome-mediated pyroptosis in a STING-dependent manner in human NP cells. Interestingly, the canonical morphological and functional characteristics of mitochondrial permeability transition pore (mPTP) opening with the cytosolic escape of mitochondrial DNA (mtDNA) were observed in human NP cells under oxidative stress. Furthermore, the administration of a specific pharmacological inhibitor of mPTP and self-mtDNA cytosolic leakage effectively reduced NLRP3 inflammasome-mediated pyroptotic NP cell death and microenvironmental inflammation in vitro and degenerative progression in a rat disc needle puncture model. Collectively, these data highlight the critical roles of the cGAS-STING-NLRP3 axis and pyroptosis in the progression of IVD degeneration and provide promising therapeutic approaches for discogenic LBP.

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Pre-clinical release inspections of hAMSCs, efficacy, and safety assessment including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the pre-clinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature non-calcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis with effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multi-differentiation, re-epithelialization, and restoration of integrity.

Post-COVID19 complications such as pediatric inflammatory multisystem syndrome (PIMS) and Long-COVID19 move increasingly into focus, potentially causing more harm in young adolescents than the acute infection. To better understand the symptoms of long-term mental health outcomes in adolescents and distinguish infection-associated symptoms from pandemic-associated symptoms, we conducted a 12 question Long-COVID19 survey. Using this survey, we compared the responses on neurocognitive, general pain and mood symptoms from seropositive and seronegative adolescents in a cross-sectional study design. Since May 2020, students grade 8-12 in fourteen secondary schools in Eastern Saxony were enrolled in the SchoolCovid19 study. Serostatus was assessed regularly in all participants. In March/April 2021, 1560 students with a median age of 15 years participated at the regular study visit after re-opening of the schools in mid-March and responded to our Long-COVID19 survey as part of this visit. 1365 (88%) students were seronegative, 188 (12%) were seropositive. Each symptom asked in the Long-COVID19 survey was present in at least 35% of the students within the last seven days before the survey. With the exception of seropositive students being less sad, there was no significant difference comparing the reported symptoms between seropositive students and seronegative students. The lack of differences comparing the reported symptoms between seropositive and seronegative students suggests that Long-COVID19 might be less common than previously thought and emphasizes on the impact of pandemic-associated symptoms regarding the well-being and mental health of young adolescents.Clinical Trial Registration: SchoolCoviDD19: Prospektive Erfassung der SARS-CoV-2 Seropositivität bei Schulkindern nach Ende der unterrichtsfreien Zeit aufgrund der Corona-Schutz-Verordnung (COVID-19), DRKS00022455, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022455.