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Medicina (Kaunas, Lithuania) Mar 2024Oxidative stress is implicated in the pathogenesis of various acute disorders including ischemia/reperfusion injury, ultraviolet/radiation burn, as well as chronic...
Oxidative stress is implicated in the pathogenesis of various acute disorders including ischemia/reperfusion injury, ultraviolet/radiation burn, as well as chronic disorders such as dyslipidemia, atherosclerosis, diabetes mellitus, chronic renal disease, and inflammatory bowel disease (IBD). However, the precise mechanism involved remains to be clarified. We formerly identified a novel apoptosis-inducing humoral protein, in a hypoxia/reoxygenation-conditioned medium of cardiac myocytes, which proved to be 69th tyrosine-sulfated eukaryotic translation initiation factor 5A (eIF5A). We named this novel tyrosine-sulfated secreted form of eIF5A Oxidative Stress-Responsive Apoptosis-Inducing Protein (ORAIP). To investigate the role of ORAIP in a dextran sulfate sodium (DSS)-induced murine model of ulcerative colitis (UC), we analyzed the effects of in vivo treatment with anti-ORAIP neutralizing monoclonal antibody (mAb) on the DSS-induced disease exacerbation. The body weight in anti-ORAIP mAb-treated group was significantly heavier than that in a mouse IgG-treated control group on day 8 of DSS-treatment ((85.21 ± 1.03%) vs. (77.38 ± 2.07%); (mean ± SE0, = 5 each, < 0.01, -test). In vivo anti-ORAIP mAb-treatment also significantly suppressed the shortening of colon length as well as Disease Activity Index (DAI) score ((5.00 ± 0.44) vs. (8.20 ± 0.37); (mean ± SE), = 5 each, < 0.001, -test) by suppressing inflammation of the rectal tissue and apoptosis of intestinal mucosal cells. These data reveal the pivotal role of ORAIP in DSS-induced oxidative stress involved in an animal model of UC.
Topics: Animals; Colitis, Ulcerative; Dextran Sulfate; Mice; Disease Models, Animal; Oxidative Stress; Peptide Initiation Factors; Eukaryotic Translation Initiation Factor 5A; Apoptosis; Male; Mice, Inbred C57BL
PubMed: 38674185
DOI: 10.3390/medicina60040539 -
The American Journal of Case Reports Apr 2024BACKGROUND Infantile spondylodiscitis is a rare condition with a varied clinical presentation. Microbial infection may not always be identified, but early diagnosis and...
BACKGROUND Infantile spondylodiscitis is a rare condition with a varied clinical presentation. Microbial infection may not always be identified, but early diagnosis and management are required to prevent long-term and irreversible complications, including spinal deformities and vertebral instability. CASE REPORT This report is of a 21-month-old girl with a 3-week history of difficulty in walking and constipation due to L1-L2 spondylodiscitis following a gluteal skin burn. The family had sought medical advice multiple times, but results of all investigations were unremarkable. Her initial spine X-ray was negative but her spine magnetic resonance imaging (MRI) showed a picture suggestive of spondylodiscitis, which then responded to empiric treatment with broad-spectrum antibiotics. The patient showed complete resolution of clinical symptoms and her bowel habits came back to normal after 6 months of complete antibiotics treatment. Her repeat spine MRI showed a significant improvement of her spondylodiscitis. CONCLUSIONS This report has highlighted the importance of rapid diagnosis and management of infantile spondylodiscitis and the challenging approach to treatment when no infectious organism can be identified, as well as the early initiation of antibiotics therapy when appropriate in pediatric patients to avoid serious neurological complications associated with spondylodiscitis. Thus, it is essential to assess children with refusal to walk, gait problems, or back discomfort, especially when they are associated with high inflammatory markers.
Topics: Humans; Female; Discitis; Infant; Anti-Bacterial Agents; Magnetic Resonance Imaging; Early Diagnosis; Lumbar Vertebrae
PubMed: 38669213
DOI: 10.12659/AJCR.943010 -
The British Journal of Surgery Mar 2024Empty pelvis syndrome (EPS) is a significant source of morbidity following pelvic exenteration (PE), but is undefined. EPS outcome reporting and descriptors of...
BACKGROUND
Empty pelvis syndrome (EPS) is a significant source of morbidity following pelvic exenteration (PE), but is undefined. EPS outcome reporting and descriptors of radicality of PE are inconsistent; therefore, the best approaches for prevention are unknown. To facilitate future research into EPS, the aim of this study is to define a measurable core outcome set, core descriptor set and written definition for EPS. Consensus on strategies to mitigate EPS was also explored.
METHOD
Three-stage consensus methodology was used: longlisting with systematic review, healthcare professional event, patient engagement, and Delphi-piloting; shortlisting with two rounds of modified Delphi; and a confirmatory stage using a modified nominal group technique. This included a selection of measurement instruments, and iterative generation of a written EPS definition.
RESULTS
One hundred and three and 119 participants took part in the modified Delphi and consensus meetings, respectively. This encompassed international patient and healthcare professional representation with multidisciplinary input. Seventy statements were longlisted, seven core outcomes (bowel obstruction, enteroperineal fistula, chronic perineal sinus, infected pelvic collection, bowel obstruction, morbidity from reconstruction, re-intervention, and quality of life), and four core descriptors (magnitude of surgery, radiotherapy-induced damage, methods of reconstruction, and changes in volume of pelvic dead space) reached consensus-where applicable, measurement of these outcomes and descriptors was defined. A written definition for EPS was agreed.
CONCLUSIONS
EPS is an area of unmet research and clinical need. This study provides an agreed definition and core data set for EPS to facilitate further research.
Topics: Humans; Treatment Outcome; Quality of Life; Pelvis; Pelvic Exenteration; Health Personnel; Delphi Technique; Research Design
PubMed: 38456677
DOI: 10.1093/bjs/znae042 -
Biomolecules Feb 2024Neurointestinal diseases represent a significant challenge in clinical management with current palliative approaches failing to overcome disease and treatment-related... (Review)
Review
Neurointestinal diseases represent a significant challenge in clinical management with current palliative approaches failing to overcome disease and treatment-related morbidity. The recent progress with cell therapy to restore missing or defective components of the gut neuromusculature offers new hope for potential cures. This review discusses the progress that has been made in the sourcing of putative stem cells and the studies into their biology and therapeutic potential. We also explore some of the practical challenges that must be overcome before cell-based therapies can be applied in the clinical setting. Although a number of obstacles remain, the rapid advances made in the enteric neural stem cell field suggest that such therapies are on the near horizon.
Topics: Enteric Nervous System; Neural Stem Cells; Intestine, Small; Cell- and Tissue-Based Therapy
PubMed: 38397466
DOI: 10.3390/biom14020229 -
EClinicalMedicine Mar 2024Lynch Syndrome (LS) is a cancer predisposition syndrome caused by constitutional pathogenic variants in the mismatch repair (MMR) genes. To date, fragmentation of...
BACKGROUND
Lynch Syndrome (LS) is a cancer predisposition syndrome caused by constitutional pathogenic variants in the mismatch repair (MMR) genes. To date, fragmentation of clinical and genomic data has restricted understanding of national LS ascertainment and outcomes, and precluded evaluation of NICE guidance on testing and management. To address this, via collaboration between researchers, the National Disease Registration Service (NDRS), NHS Genomic Medicine Service Alliances (GMSAs), and NHS Regional Clinical Genetics Services, a comprehensive registry of LS carriers in England has been established.
METHODS
For comprehensive ascertainment of retrospectively identified MMR pathogenic variant (PV) carriers (diagnosed prior to January 1, 2023), information was retrieved from all clinical genetics services across England, then restructured, amalgamated, and validated via a team of trained experts in NDRS. An online submission portal was established for prospective ascertainment from January 1, 2023. The resulting data, stored in a secure database in NDRS, were used to investigate the demographic and genetic characteristics of the cohort, censored at July 25, 2023. Cancer outcomes were investigated via linkage to the National Cancer Registration Dataset (NCRD).
FINDINGS
A total of 11,722 retrospective and 570 prospective data submissions were received, resulting in a comprehensive English National Lynch Syndrome Registry (ENLSR) comprising 9030 unique individuals. The most frequently identified pathogenic MMR genes were and at 37.2% (n = 3362) and 29.1% (n = 2624), respectively. 35.9% (n = 3239) of the ENLSR cohort received their LS diagnosis before their first cancer diagnosis (presumptive predictive germline test). Of these, 6.3% (n = 204) developed colorectal cancer, at a median age of initial diagnosis of 51 (IQR 40-62), compared to 73 years (IQR 64-80) in the general population (p < 0.0001).
INTERPRETATION
The ENLSR represents the first comprehensive national registry of PV carriers in England and one of the largest cohorts of MMR PV carriers worldwide. The establishment of a secure, centralised infrastructure and mechanism for routine registration of newly identified carriers ensures sustainability of the data resource.
FUNDING
This work was funded by the Wellcome Trust, Cancer Research UK and Bowel Cancer UK. The funder of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
PubMed: 38356732
DOI: 10.1016/j.eclinm.2024.102465 -
European Journal of Human Genetics :... May 2024It is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued in 2017...
It is believed that >95% of people with Lynch syndrome (LS) remain undiagnosed. Within the National Health Service (NHS) in England, formal guidelines issued in 2017 state that all colorectal cancers (CRC) should be tested for DNA Mismatch Repair deficiency (dMMR). We used a comprehensive population-level national dataset to analyse implementation of the agreed diagnostic pathway at a baseline point 2 years post-publication of official guidelines. Using real-world data collected and curated by the National Cancer Registration and Analysis Service (NCRAS), we retrospectively followed up all people diagnosed with CRC in England in 2019. Nationwide laboratory diagnostic data incorporated somatic (tumour) testing for dMMR (via immunohistochemistry or microsatellite instability), somatic testing for MLH1 promoter methylation and BRAF status, and constitutional (germline) testing of MMR genes. Only 44% of CRCs were screened for dMMR; these figures varied over four-fold with respect to geography. Of those CRCs identified as dMMR, only 51% underwent subsequent diagnostic testing. Overall, only 1.3% of patients with colorectal cancer had a germline MMR genetic test performed; up to 37% of these tests occurred outside of NICE guidelines. The low rates of molecular diagnostic testing in CRC support the premise that Lynch syndrome is underdiagnosed, with significant attrition at all stages of the testing pathway. Applying our methodology to subsequent years' data will allow ongoing monitoring and analysis of the impact of recent investment. If the diagnostic guidelines were fully implemented, we estimate that up to 700 additional people with LS could be identified each year.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; England; Colorectal Neoplasms; Female; Genetic Testing; Male; DNA Mismatch Repair; MutL Protein Homolog 1; Microsatellite Instability; Middle Aged; Proto-Oncogene Proteins B-raf; Aged; Adult
PubMed: 38355963
DOI: 10.1038/s41431-024-01550-w -
Nano Convergence Feb 2024Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a family of chronic disorders along the gastrointestinal tract. Because of its...
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a family of chronic disorders along the gastrointestinal tract. Because of its idiopathic nature, IBD does not have a fundamental cure; current available therapies for IBD are limited to prolonged doses of immunomodulatory agents. While these treatments may reduce inflammation, limited therapeutic efficacy, inconsistency across patients, and adverse side effects from aggressive medications remain as major drawbacks. Recently, excessive production and accumulation of neutrophil extracellular traps (NETs) also known as NETosis have been identified to exacerbate inflammatory responses and induce further tissue damage in IBD. Such discovery invited many researchers to investigate NETs as a potential therapeutic target. DNase-I is a natural agent that can effectively destroy NETs and, therefore, potentially reduce NETs-induced inflammations even without the use of aggressive drugs. However, low stability and rapid clearance of DNase-I remain as major limitations for further therapeutic applications. In this research, polymeric nanozymes were fabricated to increase the delivery and therapeutic efficacy of DNase-I. DNase-I was immobilized on the surface of polymeric nanoparticles to maintain its enzymatic properties while extending its activity in the colon. Delivery of DNase-I using this platform allowed enhanced stability and prolonged activity of DNase-I with minimal toxicity. When administered to animal models of IBD, DNase-I nanozymes successfully alleviated various pathophysiological symptoms of IBD. More importantly, DNase-I nanozyme administration successfully attenuated neutrophil infiltration and NETosis in the colon compared to free DNase-I or mesalamine.
PubMed: 38332364
DOI: 10.1186/s40580-024-00414-9 -
Spinal Cord Feb 2024Consensus process.
The revised zone of partial preservation (ZPP) in the 2019 International Standards for Neurological Classification of Spinal Cord Injury: ZPP applicability in incomplete injuries.
STUDY DESIGN
Consensus process.
OBJECTIVES
To provide a reference for the Zone(s) of Partial Preservation (ZPP) in the 2019 International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and analyze the initial impact of applicability of the revised ZPPs. Revisions include the use of ZPPs in selected incomplete injuries (in addition to prior use in sensorimotor complete injuries). Specifically, the revised motor ZPPs are applicable bilaterally in injuries with absent voluntary anal contraction (VAC) and the revised sensory ZPP for a given side is applicable if deep anal pressure (DAP), light touch and pin prick sensation in S4-5 are absent on that side.
SETTING
Committee with 16 ISNCSCI experts and datasets from the European Multicenter Study about Spinal Cord Injury (EMSCI).
METHODS
Occurrence frequencies of applicable ZPPs were determined in an EMSCI cohort consisting of two ISNCSCI examinations from 665 individuals with traumatic SCI.
RESULTS
Motor ZPPs were derived in 35.2% of all datasets of incomplete injuries, while sensory ZPPs are much less frequent (1.0%). Motor ZPPs are applicable in all American Spinal Injury Association Impairment Scale (AIS) B datasets (mean ZPP length: 0.9 ± 1.0 segments), in 55.4% of all AIS C datasets (ZPP length: 11.8 ± 8.2 segments) and in 9.9% of the AIS D datasets (ZPP length: 15.4 ± 7.9 segments).
CONCLUSIONS
The revised ZPP allows for determining motor ZPPs in approximately 1/3 of all incomplete injuries. The broadened applicability enables the use of ZPPs beyond complete injuries for complementary description of residual functions in more individuals.
SPONSORSHIP
N/A.
Topics: Humans; Spinal Cord Injuries; Physical Examination; Anal Canal; Consensus
PubMed: 38191920
DOI: 10.1038/s41393-023-00950-x -
Journal of Nanobiotechnology Jan 2024There is a growing body of evidence indicating a close association between inflammatory bowel disease (IBD) and disrupted intestinal homeostasis. Excessive production of... (Review)
Review
There is a growing body of evidence indicating a close association between inflammatory bowel disease (IBD) and disrupted intestinal homeostasis. Excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), along with an increase in M1 proinflammatory macrophage infiltration during the activation of intestinal inflammation, plays a pivotal role in disrupting intestinal homeostasis in IBD. The overabundance of ROS/RNS can cause intestinal tissue damage and the disruption of crucial gut proteins, which ultimately compromises the integrity of the intestinal barrier. The proliferation of M1 macrophages contributes to an exaggerated immune response, further compromising the intestinal immune barrier. Currently, intestinal nanomaterials have gained widespread attention in the context of IBD due to their notable characteristics, including the ability to specifically target regions of interest, clear excess ROS/RNS, and mimic biological enzymes. In this review, we initially elucidated the gut microenvironment in IBD. Subsequently, we delineate therapeutic strategies involving two distinct types of nanomedicine, namely inorganic nanoparticles and natural product nanomaterials. Finally, we present a comprehensive overview of the promising prospects associated with the application of nanomedicine in future clinical settings for the treatment of IBD (graphic abstract). Different classes of nanomedicine are used to treat IBD. This review primarily elucidates the current etiology of inflammatory bowel disease and explores two prominent nanomaterial-based therapeutic approaches. First, it aims to eliminate excessive reactive oxygen species and reactive nitrogen species. Second, they focus on modulating the polarization of inflammatory macrophages and reducing the proportion of pro-inflammatory macrophages. Additionally, this article delves into the treatment of inflammatory bowel disease using inorganic metal nanomaterials and natural product nanomaterials.
Topics: Humans; Reactive Oxygen Species; Biological Products; Inflammatory Bowel Diseases; Nanoparticles; Reactive Nitrogen Species
PubMed: 38172992
DOI: 10.1186/s12951-023-02246-x