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EBioMedicine Dec 2023Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised...
Local fistula injection of allogeneic human amnion epithelial cells is safe and well tolerated in patients with refractory complex perianal Crohn's disease: a phase I open label study with long-term follow up.
BACKGROUND
Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life.
METHODS
A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks.
FINDINGS
Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI -9.0 to -4.0, p = 0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI -3.9 to -0.6, p = 0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p = 0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders.
INTERPRETATION
Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing.
FUNDING
This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant 2018.
Topics: Adult; Humans; Amnion; Crohn Disease; Epithelial Cells; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Mesenchymal Stem Cell Transplantation; Quality of Life; Rectal Fistula; Treatment Outcome
PubMed: 38042747
DOI: 10.1016/j.ebiom.2023.104879 -
Journal of Dairy Science Mar 2024Amputation dehorning (AD) is a common practice performed on calves, causing harmful effects such as pain, distress, anxiety, and fear. These effects extend to...
Amputation dehorning (AD) is a common practice performed on calves, causing harmful effects such as pain, distress, anxiety, and fear. These effects extend to behavioral, physiological, and hematological responses, prompting serious ethical concerns regarding animal welfare, even when performed with local anesthesia. Meloxicam, a non-steroidal anti-inflammatory drug, has been widely used to mitigate the side effects of dehorning and disbudding in calves. However, there is a notable gap in research regarding the effects of meloxicam on calves aged 6 weeks to 6 mo undergoing AD procedures. This study was designed to assess the effectiveness of co-administering meloxicam with lidocaine, a cornual nerve anesthetic, in alleviating the adverse effects caused by the AD procedure in calves within this age range, compared with the use of lidocaine alone. Thirty Holstein calves were enrolled and randomly divided into 2 groups. The first group (Placebo) received a subcutaneous injection of 5 mL of lidocaine in the horn area and a subcutaneous injection of 0.9% saline at a dose of 0.025 mL/kg in the neck, administered 10 min before the AD procedure. The second group (MX) received a combination of lidocaine and meloxicam: a subcutaneous injection of 5 mL of lidocaine in the horn area and a subcutaneous injection of 20 mg/mL meloxicam at a dose of 0.025 mL/kg in the neck, also administered 10 min before the AD procedure. To avoid subjective bias, the researchers were blinded to the treatment groups. Pain-related behaviors, including tail flicking, head shaking, ear flicking, head rubbing, head crossing bar, and kicking, were observed, and physiological parameters, including heart rate, rectal temperature, respiration rate, mechanical nociceptive threshold (MNT), daily active steps, and food intake were monitored. Hematological conditions were determined using enzyme-linked immunosorbent assays and routine blood tests. The data were processed using a generalized linear mixed model (GLMM). The outcomes demonstrated that the AD procedure increased the frequencies of ear flicking and resulted in rises in the respiration rate, heart rate, rectal temperature, and daily active steps. It also led to decreases in total food intake, forage intake, hay intake, MNT, and increased concentrations of prostaglandin E2 (PgE2), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nitric oxide (NO), and malondialdehyde, as well as glutathione peroxidase activity. However, calves that received meloxicam treatment showed significant improvements in response to the AD procedure, including lower respiration rates, heart rates, and rectal temperatures; higher MNTs; and lower intermediate cell ratio. They also had higher red blood counts, hemoglobin levels, hematocrit values; larger mean platelet volumes; and lower concentrations of PgE2, IL-1β, TNF-α, and NO. These results suggest that co-administration of lidocaine and meloxicam may aid in mitigating the adverse impacts induced by the AD procedure on these calves, thereby supporting the use of meloxicam in conjunction with a local anesthetic in AD procedures for calves aged 6 weeks to 6 mo.
PubMed: 38554819
DOI: 10.3168/jds.2023-24280 -
The American Journal of Dermatopathology Apr 2024Monkeypox (Mpox) is a zoonotic Orthopoxvirus of the Poxviridae family, endemic to Africa. In August 2022, the US government declared it an emergency because of the...
Monkeypox (Mpox) is a zoonotic Orthopoxvirus of the Poxviridae family, endemic to Africa. In August 2022, the US government declared it an emergency because of the worldwide spread. Traditionally, Mpox infection spreads through contact with infected animals. However, the 2022 outbreak Centers for Disease Control and Prevention (CDC) data note that 94% of cases had recent male-to-male sexual or close intimate contact, suggesting a novel sexual transmission. In this article, we report a 39-year-old HIV-positive man presenting with a diffuse cutaneous rash, perianal pain, and bloody stool of 2-week duration. A medical history includes intravenous drug use and multiple sexual partners. Physical examination revealed umbilicated, tan-colored, crusted cutaneous papules scattered across the face, trunk, and genital regions. Perianal lesion biopsy showed an acanthotic epidermis with spongiosis, ballooning degeneration of keratinocytes, and the formation of multinucleated syncytial keratinocytes. A dermal superficial/lichenoid mixed inflammatory cell infiltrate with multinucleated giant cells was noted. Perianal lesion polymerase chain reaction (PCR) was positive for Mpox. Colonoscopy revealed a 3-cm circumferential rectal ulcer with gray exudate and necrosis. A rectal ulcer biopsy showed an ulcerated mucosa with acute proctitis and necrosis. There were scattered macrophages with intranuclear inclusion and glassy vacuolization, and Mpox infection was confirmed by immunostaining with a Mpox-specific anti-Vaccinia virus antibody.
Topics: United States; Animals; Humans; Male; Adult; Mpox (monkeypox); Ulcer; Proctitis; Antibodies, Viral; Necrosis
PubMed: 38457670
DOI: 10.1097/DAD.0000000000002643 -
Transplant Immunology Feb 2024Ulcerative colitis (UC) causes ulcers in the colon and rectum, leading to abdominal pain, diarrhea, and rectal bleeding, and if left untreated, can lead to serious...
BACKGROUND AND OBJECTIVE
Ulcerative colitis (UC) causes ulcers in the colon and rectum, leading to abdominal pain, diarrhea, and rectal bleeding, and if left untreated, can lead to serious complications. The therapeutic effects of mesenchymal stem cells (MSCs) on experimental models of UC have been proven. Since the microenvironment around these cells is crucial in maintaining cell proliferation, differentiation, metabolism, and overall function, this study aims to evaluation the role of caffeine and naloxone as a new microenvironment for MSCs in reducing inflammation and improving symptoms in an experimental model of UC.
MATERIAL AND METHOD
A group of 40 outbred NMRI mice were studied and divided randomly into four equal groups (N = 10 each group). UC was induced in all groups using acetic acid. The first group (control) was treated with phosphate buffer saline (PBS), the second group with MSCs-Caffeine, the third with MSCs-Naloxone, and the fourth with Mesalazine. The disease activity index (DAI), tissue damage, myeloperoxidase (MPO) activity, nitric oxide (NO) levels, and the production of IL-1, IL-6, and TNF-α cytokines were evaluated.
RESULT
Our research demonstrated that all treatments were effective in improving the symptoms and reducing inflammatory markers in mice with colitis. Among the two MSCs treatments, the MSCs-Caffeine was found to be the most potent in reducing the levels of NO, IL-1, IL-6, tissue damage (P < 0.001) and as well as TNF-α (P < 0.0001) in compared to the control group.
CONCLUSION
MSCs treated with caffeine and naloxone can enhance the immunoregulatory potential of these. As a result, treated MSCs can lead to improved clinical signs and reduced inflammatory parameters in mice with UC, making this approach a useful way for controlling and treating the disease. However, additional research is needed to access the mechanism behind the stronger immune system regulatory effects of treated MSCs in UC treatment.
Topics: Mice; Animals; Colitis, Ulcerative; Caffeine; Tumor Necrosis Factor-alpha; Interleukin-6; Inflammation; Cytokines; Mesenchymal Stem Cells; Interleukin-1; Disease Models, Animal
PubMed: 38184213
DOI: 10.1016/j.trim.2024.101986 -
Journal of Materials Chemistry. B Dec 2023Inflammatory bowel diseases (IBDs) like Crohn's disease and ulcerative colitis involve chronic gastrointestinal inflammation. The pro-inflammatory cytokine tumor...
Inflammatory bowel diseases (IBDs) like Crohn's disease and ulcerative colitis involve chronic gastrointestinal inflammation. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) drives IBD pathogenesis. Anti-TNF-α therapies using monoclonal antibodies (mAbs) like infliximab (INF) help treat IBD but have limitations. We developed inflammation-targeting polyphenol-poloxamer nanoparticles loaded with the anti-inflammatory mAb INF (INF@PPNP) as a novel IBD therapy. Characterization showed that INF@PPNP had favorable stability and purity. Radiolabeling INF@PPNP with Zr enabled tracking localization with positron emission tomography (PET) imaging. Rectal administration of Zr-INF@PPNP led to colon delivery with remarkably reduced systemic exposure intravenous INF revealed by non-invasive PET imaging. Zr-INF@PPNP retention at inflamed foci indicated prolonged INF@PPNP action. INF@PPNP rectally achieved similar anti-inflammatory effects as intravenously injected INF, demonstrating the high therapeutic potential. Our findings support the use of nanoparticle-based rectal administration for localized drug delivery, prolonging drug activity and minimizing systemic exposure, ultimately offering an effective approach for treating IBD.
Topics: Humans; Infliximab; Tumor Necrosis Factor Inhibitors; Inflammatory Bowel Diseases; Antibodies, Monoclonal; Inflammation; Anti-Inflammatory Agents; Positron-Emission Tomography
PubMed: 37990919
DOI: 10.1039/d3tb02128a -
Cureus Apr 2024Jejunoileal atresia, a common cause of neonatal intestinal obstruction, typically manifests shortly after birth. This case report highlights a rare instance of a late...
Jejunoileal atresia, a common cause of neonatal intestinal obstruction, typically manifests shortly after birth. This case report highlights a rare instance of a late preterm female neonate presenting with type 4 jejunoileal atresia along with proximal rectal atresia, an exceedingly uncommon combination. Initial symptoms included bilious emesis and failure to pass meconium, leading to surgical correction of jejunoileal atresia. However, postoperative complications, including vomiting and jaundice, prompted further investigation, revealing rectal atresia during a fluoroscopic study on day 29. Subsequent surgery was required to address the rectal atresia, resulting in additional challenges such as short bowel syndrome and infection. The complexity of diagnosis and management underscores the importance of thorough evaluation of the lower gastrointestinal tract in neonates with jejunoileal atresia to prevent misdiagnosis and reduce the need for multiple surgeries. Rectal atresia, which is a very rare anorectal abnormality, in combination with jejunoileal atresia is considered an incredibly unusual, exceptionally unique case; as to our knowledge, no similar presentation had previously occurred. Prompt identification and simultaneous treatment of both conditions can help mitigate complications, minimize the risk of necrosis and perforation, and improve overall outcomes. Comprehensive management strategies that encompass thorough diagnostic evaluation and coordinated surgical interventions are crucial for optimizing the care of neonates with complex intestinal malformations, ensuring timely resolution of symptoms, and reducing long-term morbidity.
PubMed: 38741810
DOI: 10.7759/cureus.58141 -
Scientific Reports Sep 2023Bacteroides fragilis, one of the potential next-generation probiotics, but its protective mechanism is not yet known. We aimed to characterize the anti-inflammatory...
Bacteroides fragilis, one of the potential next-generation probiotics, but its protective mechanism is not yet known. We aimed to characterize the anti-inflammatory effect of B. fragilisATCC25285 and to elucidate its mechanism through in vivo and in vitro experiments. An in vitro model of inflammation by induction of colonic cells with TNF-a, and co-cultured with B. fragilis to detect cell viability, apoptosis and invasive capacity. Furthermore, critical proteins of the TLR/NF-κB pathway and the inflammatory cytokines were measured. For animal trials, C57BL/6 J male mice were orally administered B. fragilis or PBS once daily for 21 days. Colitis was induced by drinking 2.5% DSS from days 0 to 7. The mice were weighed daily and rectal bleeding, stool condition and blood in the stool were recorded. We found that B. fragilis treatment alone was harmless and had no effect on cell viability or apoptosis. While predictably TNF-α decreased cell viability and increased apoptosis, B. fragilis attenuated this deterioration. The NF-κB pathway and inflammatory cytokines IL-6 and IL-1β activated by TNF-α were also blocked by B. fragilis. Notably, the metabolic supernatant of B. fragilis also has an anti-inflammatory effect. Animal studies showed that live B. fragilis rather than dead strain ameliorated DSS-induced colitis, as evidenced by weight loss, shortened colon length and enhanced barrier function. The colonic tissue levels of inflammatory cytokines (TNF-α, IL-1β, IL-6) were decreased and IL-10 was increased as a result of B. fragilis administration. In conclusion, B. fragilis ATCC25285 exhibited anti-inflammatory effects whether in vivo or in vitro, and it may be a potential probiotic agent for improving colitis.
Topics: Male; Animals; Mice; Mice, Inbred C57BL; Bacteroides fragilis; Interleukin-6; NF-kappa B; Tumor Necrosis Factor-alpha; Colitis; Cytokines; Bacterial Infections; Anti-Inflammatory Agents
PubMed: 37740010
DOI: 10.1038/s41598-023-42481-8 -
American Journal of Physiology.... Mar 2024Ulcerative colitis (UC) is linked with inflammation of the large intestine due to an overactive response of the colon-immune system. UC is associated with weight loss,...
Ulcerative colitis (UC) is linked with inflammation of the large intestine due to an overactive response of the colon-immune system. UC is associated with weight loss, rectal bleeding, diarrhea, and abdominal pain. Given that γ-amino butyric acid (GABA) suppresses immune cell activity and the excitability of colonic afferents, and that there is a decrease in colonic GABA during UC, we hypothesized that UC pain is due to a decrease in the inhibition of colonic afferents. Thus, restoring GABA in the colon will attenuate inflammatory hypersensitivity. We tested this hypothesis in a mouse model of colitis. Colon inflammation was induced with seven days of dextran sodium sulfate (DSS, 3%) in the drinking water. GABA (40 mg/kg) was administered orally for the same period as DSS, and body weight, colon length, colon permeability, clinical progression of colitis (disease activity index or DAI), and colon histological score (HS) were assessed to determine the effects of GABA on colitis. A day after the end of GABA treatment, visceral sensitivity was assessed with balloon distention (of the colon)-evoked visceromotor response and colon samples were collected for the measurement of GABA and cytokines. Treatment with GABA reduced the DSS-induced increase in the colon permeability, DAI, HS, and decrease in body weight and colon length. Furthermore, GABA inhibited the DSS-induced increase in the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-12 (IL-12), and increased the expression of the anti-inflammatory cytokine IL-10 in the colon tissue. Importantly, GABA reduced DSS-induced visceral hypersensitivity. These data suggest that increasing gastrointestinal levels of GABA may be useful for the treatment of colitis. GABA treatment reduces the severity of colitis and inflammation and produces inhibition of visceral hypersensitivity in colon-inflamed mice. These results raise the promising possibility that GABA treatment may be an effective therapeutic strategy for the management of symptoms associated with colitis. However, clinical studies are required to corroborate whether this mouse-model data translates to human colon.
Topics: Humans; Animals; Mice; Colon; Colitis; Colitis, Ulcerative; Cytokines; Inflammation; Disease Models, Animal; Body Weight; Dextran Sulfate; Mice, Inbred C57BL
PubMed: 38193198
DOI: 10.1152/ajpgi.00012.2023 -
Artificial Organs Aug 2023Existing artificial anal sphincter studies have shown that biomechanical compatibility problem between artificial anal sphincter and rectum caused by long-term...
BACKGROUND
Existing artificial anal sphincter studies have shown that biomechanical compatibility problem between artificial anal sphincter and rectum caused by long-term morphological changes of the tissue surrounding the implanted prosthesis can lead to device failure or tissue ischemic necrosis. In this article, a mechanical artificial anal sphincter with constant force clamping is designed based on the superelasticity of shape memory alloys, which improved the biomechanical compatibility of implantable artificial anal sphincter.
METHODS
Firstly, the anatomical structure and the biomechanical properties of the rectum are analyzed to obtain the size parameters and material parameters of the rectal model. Secondly, a novel artificial anal sphincter with constant force is designed to improve the biomechanical compatibility between the artificial sphincter and the rectum. Thirdly, the static analysis of artificial anal sphincter is carried out by finite element analysis.
RESULTS
The simulation results show that the artificial anal sphincter can maintain a constant clamping force of 4 N within a certain variation range of intestinal tissue thickness, which verifies the constant force characteristic of the artificial anal sphincter. The constant clamping force of the artificial anal sphincter to the rectum is 4 N that is greater than the clamping force 3.99 N required to close the rectum, which verifies the effectiveness the artificial anal sphincter. The surface contact stress and the minimum principal stress of the rectum in the clamping state are less than the pressure threshold, which verifies the safety of the artificial anal sphincter.
CONCLUSIONS
The novel artificial anal sphincter has better biomechanical compatibility and improves the mechanical match between artificial sphincter and intestinal tissue. This study may provide more reasonable and effective simulation data for in vivo experiments of artificial anal sphincter in future, which may provide theoretical and technical support for further research about clinical application of artificial anal sphincter.
Topics: Humans; Anal Canal; Rectum; Prostheses and Implants; Urinary Sphincter, Artificial; Fecal Incontinence
PubMed: 36869693
DOI: 10.1111/aor.14517 -
European Journal of Gastroenterology &... Apr 2024Vedolizumab is an anti-α4β7 integrin antibody used to treat moderate to severe ulcerative colitis (UC) and Crohn's disease (CD). This post hoc analysis of...
Efficacy of vedolizumab during intravenous induction therapy in ulcerative colitis and Crohn's disease: post hoc analysis of patient-reported outcomes from the VISIBLE 1 and 2 studies.
BACKGROUND
Vedolizumab is an anti-α4β7 integrin antibody used to treat moderate to severe ulcerative colitis (UC) and Crohn's disease (CD). This post hoc analysis of patient-reported outcomes (PROs) from the VISIBLE 1 (NCT02611830) and 2 (NCT02611817) phase 3 studies evaluated onset of treatment effect on patient-reported symptoms during 6-week vedolizumab induction.
METHODS
Patient-reported stool frequency (SF) and rectal bleeding (RB) (UC Mayo score), and SF and abdominal pain (AP) in CD were collected via electronic diary from VISIBLE patients receiving one or more open-label intravenous (IV) vedolizumab induction doses (weeks 0 and 2). PRO data were analyzed using descriptive statistics.
RESULTS
Data from 994 patients (UC 383, CD 611) showed mean ratings for all PROs declined consistently week-on-week from baseline through week 6, with early onset of improvement. By week 2, 22% of patients with UC reported RB improvement (≥1-point reduction in RB subscore, 7-day mean), rising to 45% by week 6. By week 6, 18% of patients with UC achieved SF improvement (SF subscore 0; 21% antitumor necrosis factor alpha [anti-TNFα] naive, 13% anti-TNFα experienced). SF improvement in patients with CD (reduction of ≥3 stools, 7-day mean) was achieved by 32% at week 6 (34% anti-TNFα naive, 30% anti-TNFα experienced). Fewer patients with CD reported severe/moderate AP at week 6 (5.1%/28.5%) than baseline (14.6%/61.5%). SF decline appeared greater and faster for anti-TNFα-naive vs. anti-TNFα-experienced patients (UC and CD).
CONCLUSION
Results indicate early onset of patient-reported UC and CD symptom improvement during vedolizumab IV induction in VISIBLE 1 and 2.
Topics: Humans; Colitis, Ulcerative; Crohn Disease; Induction Chemotherapy; Tumor Necrosis Factor-alpha; Patient Reported Outcome Measures; Gastrointestinal Agents; Treatment Outcome; Remission Induction; Antibodies, Monoclonal, Humanized
PubMed: 38417060
DOI: 10.1097/MEG.0000000000002728