Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis.

BACKGROUND: In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. OBJECTIVE: To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. METHODS: A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool. RESULTS: Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains. CONCLUSIONS: These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock.

Sphingosine-1-Phosphate Receptor 1, Expressed in Myeloid Cells, Slows Diet-Induced Atherosclerosis and Protects against Macrophage Apoptosis in Ldlr KO Mice.

We generated myeloid specific sphingosine-1-phosphate receptor 1 (S1pr1) deficient mice by crossing mice that had myeloid specific expression of Cre recombinase (lyzMCre) with mice having the S1pr1 gene flanked by loxP recombination sites. We transplanted bone marrow from these mice and control lyzMCre mice with intact macrophage S1pr1 gene expression into low-density lipoprotein (LDL) receptor gene (Ldlr) deficient mice. The resulting chimeras were fed a high fat atherogenic diet for nine or twelve weeks and evaluated for atherosclerosis development in the aortic sinus. Selective S1pr1 deficiency in bone marrow-derived myeloid cells resulted in accelerated development of atherosclerosis, necrotic core formation and the appearance of apoptotic cells within atherosclerotic plaques of Ldlr knockout mice in response to a high fat diet. Examination of macrophages in culture revealed that the sphingosine-1-phosphate receptor 1 selective agonist, SEW2871 or high density lipoprotein (HDL), protected macrophages against apoptosis induced by endoplasmic reticulum (ER) stress or oxidized LDL, through activation of phosphatidylinositol-3-kinase/Akt signaling. Targeted S1pr1-deletion prevented Akt activation and protection against apoptosis by either SEW2871 or HDL. Our data suggests that sphingosine-1-phosphate receptor 1 in macrophages plays an important role in protecting them against apoptosis in vitro and in atherosclerotic plaques in vivo, and delays diet induced atherosclerosis development in Ldlr deficient mice.

Surgical treatment in lumbar spondylolisthesis: experience with 45 patients.

BACKGROUND: Spondylolithesis is forward slipping of upper vertebra in relation to its lower one, which at times requires surgery. The objective of present study is to document the outcome of surgical treatment in spondylolisthesis of lumbosacral region. METHODS: We reviewed outcome of surgery in 45 patients with spondylolisthesis. Improvement in pain intensity, neurological status and union achieved after surgery was studied. All patients requiring surgical treatment were included in the study. The patients were operated by single spine surgeon. A Performa was made for each patient and records were kept in a custom built Microsoft access database. RESULTS: Majority of our patient were in 4th and 51th decade with some male domination. Pain was main indication for surgery which was excruciating in 6. severe in 33, and moderate in 6 cases. The neurological status was normal in 34 cases while 11 patients had some deficit. L5-S1 was affected in 26, L4-L5 in 13 and multi or high level was found in rest of cases. Slip grade was measured with Meyerding grades, 18 had grade II, 15 had I, 9 had III and 3 had IV spondylolisthesis. Posterior lumbar inter body fusion (PLIF) was done in 24 patients, posterolateral, transforaminal lumbar inter body and anterior inter body fusion in others. Translaminar screw fixation, transpedicular transdiscal transcorporial and Delta fixation in some cases. Pedicle screw fixation was done in most cases, AO fixator internae and 4.5 mm screw in others. Average follow up was 2 years and 5 months, max 5 years and minimum 6 months. Pain relief was achieved in 82%, neurological improvement 60% and union in 91% cases. There was no deterioration of neurological status, two implant failure and one wound infection. CONCLUSION: Surgical procedure for Spondylolisthesis must be individualised. Young patients with spondylolysis can be treated with osteosynthesis and sparing of motion segment. PLIF provides satisfactory results in majority of low to moderate cases with some reduction. Transpedicular transdiscal transcorprial and delta fixation is good procedure for severe slips in adult.