Acupuncture combined tuina for oculomotor paralysis: A protocol for systematic review and meta-analysis.

BACKGROUND: Oculomotor paralysis (OP) is a neurologic syndrome with multiple causes of oculomotor nerve and its dominant tissue and muscle dysfunction. Acupuncture combined with tuina is a wide-ranging used rehabilitation therapy, although there is short of supporting evidence for its efficacy and safety in patients with OP. The purpose of this systematic review was to estimate and synthesize evidence of the efficacy and safety of acupuncture combined with tuina in the treatment of OP. METHODS: Electronic databases, including PubMed, Web of Science, Cochrane Library, EMBASE, Technology Journal and China Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang,adopt an appropriate search strategy. RevMan V.5.3.5 software will be used for data synthesis, bias risk, and subgroup analyses. RESULTS: This study provides high-quality evidence to assess the effectiveness and safety of acupuncture combined with tuina for OP. CONCLUSION: This systematic review explores whether acupuncture combined with tuina is an effective and safe intervention for OP. ETHICS AND DISSEMINATION: Private information from individuals will not publish. This systematic review does not involve endangering participant rights. Ethical approval was not obtained. The results may be published in a peer-reviewed journal or disseminated at relevant conferences. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42021266447.

FGF21 is increased by inflammatory stimuli and protects leptin-deficient ob/ob mice from the toxicity of sepsis.

The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold. Although LPS, zymosan, and turpentine decrease the hepatic expression of FGF21, they increase FGF21 expression in adipose tissue and muscle, suggesting that extrahepatic tissues account for the increase in serum FGF21. After LPS administration, the characteristic decrease in plasma ketone levels is accentuated in FGF21-/- mice, but this is not due to differences in expression of carnitine palmitoyltransferase 1α or hydroxymethyglutaryl-CoA synthase 2 in liver, because LPS induces similar decreases in the expression of these genes in FGF21-/- and control mice. However, in FGF21-/- mice, the ability of LPS to increase plasma free fatty acid levels is blunted. This failure to increase plasma free fatty acid could contribute to the accentuated decrease in plasma ketone levels because the transport of fatty acids from adipose tissue to liver provides the substrate for ketogenesis. Treatment with exogenous FGF21 reduced the number of animals that die and the rapidity of death after LPS administration in leptin-deficient ob/ob mice and to a lesser extent in control mice. FGF21 also protected from the toxic effects of cecal ligation and puncture-induced sepsis. Thus, FGF21 is a positive APR protein that protects animals from the toxic effects of LPS and sepsis.

a-Methylacyl coenzyme A racemase is highly expressed in the intestinal-type adenocarcinoma and high-grade dysplasia lesions of the stomach.

To study a-Methylacyl coenzyme A racemase (AMACR) expression in gastric intestinal-type adenocarcinoma and its precursors, we performed an immunohistochemical assay (using an avidin-biotin-peroxidase complex method) on 106 paraffin-embedded gastric mucosal biopsy samples and 25 gastrectomy samples (37 negative for dysplasia; 30 indefinite for dysplasia; 22 low-grade dysplasia; 25 high-grade dysplasia; and 34 invasive intestinal adenocarcinoma). The results showed that AMACR staining was uniformly negative in the groups negative for dysplasia and indefinite for dysplasia. Only 1 of 22 (4.5%) low-grade dysplasia showed weak staining for AMACR. In the groups of high-grade dysplasia and invasive intestinal-type adenocarcinoma, however, 19 of 25 (76%) and 18 of 34 (52.9%) were positive for AMACR respectively. Expression of AMACR was not correlated with location, H. Pylori infection or intestinal metaplasia. These results suggested that AMACR may play a role in the intermediate stage of gastric carcinogenesis. The high level expression of AMACR in high-grade dysplasia and carcinoma suggests that it may be a useful biomarker in distinguishing high-grade dysplasia and carcinoma from low-grade dysplasia.

Effects of hyperglycemia and insulin therapy on outcome in a hyperglycemic septic model of critical illness.

BACKGROUND: The effects of hyperglycemia and insulin therapy on septic outcome have not been well studied. METHODS: Septic hyperglycemia was induced by infusion of TPN (254 kcal/kg x d) immediately following cecal ligation and puncture (CLP) surgery in rats. Animals (N = 109) were monitored for blood glucose and followed for survival for 4 days. Separate cohorts (N = 36) were sacrificed at 22 hours post-CLP and analyzed for cytokines/chemokines, hormones, and organ damage markers. The effects of insulin treatment on 4 day survival were also examined (N = 60). RESULTS: Hyperglycemic septic animals had significantly higher blood glucose (p < 0.0001), plasma proinflammatory cytokine levels, serum organ damage markers (p < 0.05) and reduced mean survival time (p < 0.001). Insulin treatment (2 IU/kg/hr) resulted in significantly lower blood glucose (p < 0.01) and improved 4 day survival (p < 0.03). CONCLUSIONS: Hyperglycemia is associated with greater morbidity and mortality in sepsis. Insulin therapy significantly improved survival suggesting that management of hyperglycemia with insulin may improve outcome in septic patients.

Adoptive transfer of in vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis.

Regulatory CD4(+)CD25(+) T cells (Tregs) suppress autoimmune and inflammatory diseases through mechanisms that are only partly understood. Previous studies suggest that Tregs can suppress bacterially triggered intestinal inflammation and respond to LPS through TLRs with enhanced suppressive activity. In this study, we have used murine cecal ligation and puncture as a model of polymicrobial sepsis to explore the effects of adoptive transfer of Tregs on septic outcome. Adoptive transfer of in vitro-stimulated Tregs in both prevention and therapeutic modes significantly improved survival of cecal ligation and puncture mice. Furthermore, the effect was dependent on both the number of Tregs adoptively transferred and the presence of host T cells. Animals that received stimulated Tregs had significantly increased peritoneal mast cells and peritoneal TNF-alpha production. More importantly, adoptive transfer of in vitro-stimulated Tregs significantly improved bacterial clearance, which resulted in improved survival. Our results suggest a novel role for Tregs in sepsis.

Cecal ligation and puncture with total parenteral nutrition: a clinically relevant model of the metabolic, hormonal, and inflammatory dysfunction associated with critical illness.

BACKGROUND: Standard rat cecal ligation and puncture (CLP) results in only transient hyperglycemia, making an examination of the effects of glucoregulatory agents, such as insulin, on the morbidity and mortality of CLP problematic. Accordingly, we sought to develop a model of rat CLP with prolonged hyperglycemia through continuous infusion of total parenteral nutrition (TPN) post CLP. MATERIALS AND METHODS: Polyethylene catheters were implanted into the femoral vein of female Sprague Dawley rats (245-265 g) which were subsequently subjected to CLP. TPN was initiated at different intervals following CLP, and mortality, bacteremia, blood glucose, hormonal, and inflammatory responses were monitored. RESULTS: Without TPN, CLP resulted in significantly lower blood glucose at 22 h post CLP. In contrast, CLP rats receiving TPN exhibited significant prolonged hyperglycemia that was responsive to insulin treatment. Mortality and hyperglycemia tended to increase with puncture size in CLP TPN rats, with early initiation of TPN leading to poorer outcome. There were time-dependent differences in bacteremia and mortality based on time of TPN initiation. Levels of insulin, leptin, and glucagon were significantly elevated in CLP TPN rats, as were many inflammatory markers. Organ damage was evident as early as 12 h post CLP and blood cell kinetics indicated significantly depressed neutrophil and lymphocyte counts. CONCLUSIONS: Our results indicate that addition of TPN to CLP provides a clinically relevant animal model of critical illness with associated hyperglycemia that may provide utility for the testing of glucoregulatory and other therapeutic modalities.

Evaluation of protein C and other biomarkers as predictors of mortality in a rat cecal ligation and puncture model of sepsis.

OBJECTIVE: To evaluate protein C and other factors associated with the septic response as predictors of mortality in a clinically relevant animal model of sepsis. DESIGN: Laboratory investigation. SETTING: Eli Lilly and Company discovery research laboratory. SUBJECTS: Forty female Sprague Dawley rats weighing 245-265 g. INTERVENTIONS: Polyethylene catheters were surgically implanted into the femoral vein and sepsis was induced by cecal ligation and puncture (CLP). A solution of 5% dextrose in 0.9 % saline was continuously infused via femoral catheters immediately following surgery. Blood sampling was done before surgery and at 6 and 20 hrs after surgery. Rats were then monitored for survival out to 4 days. MEASUREMENTS AND MAIN RESULTS: Blood collections were used to measure blood glucose, bacteremia, plasma protein C, D-dimer, hormones, chemokines, cytokines, and myoglobin (as a marker of organ damage). Mortality was categorized into three groups: early death (before 30 hrs post-CLP), late death (after 30 hrs post-CLP), and survivors (96 hrs post-CLP). Compared with survivors, early death rats had statistically significant differences in 30 variables indicative of severe inflammation, coagulopathy, and muscle damage including less bacterial clearance, hypoglycemia, lower plasma protein C, higher plasma D dimer, higher plasma cytokine/ chemokines, and higher plasma myoglobin concentrations. Twenty variables had a moderate to strong correlation with time of death. Receiver operator characteristic curves generated from a simple logistic regression model indicated that KC and macrophage inflammatory protein-2, rodent homologues of the human growth related oncogene CXC chemokine family, and protein C were the best predictors of mortality in this model. CONCLUSIONS: The data from this study indicate that an early decrease in protein C concentration predicts poor outcome in a rat sepsis model. The data further indicate that increases in the CXC chemokines macrophage inflammatory protein-2 and KC precede poor outcome.

Enhanced B cell expansion, survival, and humoral responses by targeting death receptor 6.

Targeted disruption of death receptor (DR)6 results in enhanced CD4(+) T cell expansion and T helper cell type 2 differentiation after stimulation. Similar to T cells, DR6 is expressed on resting B cells but is down-regulated upon activation. We examined DR6(-/-) B cell responses both in vitro and in vivo. In vitro, DR6(-/-) B cells undergo increased proliferation in response to anti-immunoglobulin M, anti-CD40, and lipopolysaccharide. This hyperproliferative response was due, at least in part, to both increased cell division and reduced cell apoptosis when compared with wild-type B cells. Consistent with these observations, increased nuclear levels and activity of nuclear factor kappaB transcription factor, c-Rel, and elevated Bcl-x(l) expression were observed in DR6(-/-) B cells upon stimulation. In addition, DR6(-/-) B cells exhibited higher surface levels of CD86 upon activation and were more effective as antigen-presenting cells in an allogeneic T cell proliferation response. DR6(-/-) mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. This is the first demonstration of a regulatory role of DR6 in the activation and function of B cells.

Accelerated onset and increased severity of acute graft-versus-host disease following adoptive transfer of DR6-deficient T cells.

DR6 is a recently identified member of the TNFR family. In a previous study, we have shown that DR6 KO mice have enhanced CD4(+) T cell proliferation and Th2 cytokine production. Acute graft-vs-host disease (GVHD) results from the activation and expansion of alloreactive donor T cells following bone marrow transplantation. In this article, we demonstrate that the transfer of donor T cells from DR6 KO mice into allogeneic recipient mice in a parent into an F(1) model of acute GVHD results in a more rapid onset of GVHD with increased severity. Recipients of DR6 KO T cells exhibit earlier systemic symptoms of GVHD, more rapid weight loss, earlier histopathological organ damage in the thymus, spleen, and intestines, and earlier mortality. The rapid onset of GVHD in these mice may be attributable to the enhanced activation and expansion of DR6 KO CD4(+) and CD8(+) T cells. Our findings support the hypothesis that DR6 serves as an important regulatory molecule in T cell immune responses. The identification and use of DR6 ligands and/or agonistic Abs to DR6 may represent useful therapeutics in the treatment of T cell-mediated diseases such as GVHD.