Structure‐Based Design and Synthesis of a Small Molecule that Exhibits Anti‐inflammatory Activity by Inhibition of MyD88‐mediated Signaling to Bacterial Toxin Exposure

Both Gram‐positive and Gram‐negative pathogens or pathogen‐derived components, such as staphylococcal enterotoxins (SEs) and endotoxin (LPS) exposure, activate MyD88‐mediated pro‐inflammatory cellular immunity for host defense. However, dysregulated MyD88‐mediated signaling triggers exaggerated immune response that often leads to toxic shock and death. Previously, we reported a small molecule compound 1 mimicking BB‐loop structure of MyD88 was capable of inhibiting pro‐inflammatory response to SEB exposure in mice. In this study, we designed a dimeric structure compound 4210 covalently linked with compound 1 by a non‐polar cyclohexane linker which strongly inhibited the production of pro‐inflammatory cytokines in human primary cells to SEB (IC₅₀ 1–50 μm ) or LPS extracted from Francisella tularensis, Escherichia coli, or Burkholderia mallei (IC₅₀ 10–200 μm ). Consistent with cytokine inhibition, in a ligand‐induced cell‐based reporter assay, compound 4210 inhibited Burkholderia mallei or LPS‐induced MyD88‐mediated NF‐kB‐dependent expression of reporter activity (IC₅₀ 10–30 μm ). Furthermore, results from a newly expressed MyD88 revealed that 4210 inhibited MyD88 dimer formation which is critical for pro‐inflammatory signaling. Importantly, a single administration of compound 4210 in mice showed complete protection from lethal toxin challenge. Collectively, these results demonstrated that compound 4210 inhibits toxin‐induced inflated pro‐inflammatory immune signaling, thus displays a potential bacterial toxin therapeutic.     

Blood pressure reduction does not reduce perihematoma oxygenation: a CT perfusion study

Blood pressure (BP) reduction after intracerebral hemorrhage (ICH) is controversial, because of concerns that this may cause critical reductions in perihematoma perfusion and thereby precipitate tissue damage. We tested the hypothesis that BP reduction reduces perihematoma tissue oxygenation.Acute ICH patients were randomized to a systolic BP target of <150 or <180 mm Hg. Patients underwent CT perfusion (CTP) imaging 2 hours after randomization. Maps of cerebral blood flow (CBF), maximum oxygen extraction fraction (OEF^max), and the resulting maximum cerebral metabolic rate of oxygen (CMRO₂^max) permitted by local hemodynamics, were calculated from raw CTP data.Sixty-five patients (median (interquartile range) age 70 (20)) were imaged at a median (interquartile range) time from onset to CTP of 9.8 (13.6) hours. Mean OEF^max was elevated in the perihematoma region (0.44±0.12) relative to contralateral tissue (0.36±0.11; P<0.001). Perihematoma CMRO₂^max (3.40±1.67 mL/100 g per minute) was slightly lower relative to contralateral tissue (3.63±1.66 mL/100 g per minute; P=0.025). Despite a significant difference in systolic BP between the aggressive (140.5±18.7 mm Hg) and conservative (163.0±10.6 mm Hg; P<0.001) treatment groups, perihematoma CBF was unaffected (37.2±11.9 versus 35.8±9.6 mL/100 g per minute; P=0.307). Similarly, aggressive BP treatment did not affect perihematoma OEF^max (0.43±0.12 versus 0.45±0.11; P=0.232) or CMRO₂^max (3.16±1.66 versus 3.68±1.85 mL/100 g per minute; P=0.857). Blood pressure reduction does not affect perihematoma oxygen delivery. These data support the safety of early aggressive BP treatment in ICH.     

Case report of open appendectomy in treating acute perforated appendicitis with necrotizing fasciitis of the abdominal wall: A rare complication of a common disease

Acute appendicitis can be associated with uncommon complications such as necrotizing fasciitis. We present a case of a 37‐year‐old woman referred to our hospital with a 1‐week history of significant weakness, anorexia, and mild abdominal pain. According to laboratory and radiographic data, the patient was diagnosed with perforated appendicitis and gangrene.     

Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 in the formation of postburn hypertrophic scar (HTS)

Recent data support the involvement of stromal cell-derived factor 1 (SDF-1) in the homing of bone marrow-derived stem cells to wound sites during skeletal, myocardial, vascular, lung, and skin wound repair as well as some fibrotic disorders via its receptor CXCR4. In this study, the role of SDF-1/CXCR4 signaling in the formation of hypertrophic scar (HTS) following burn injury and after treatment with systemic interferon α2b (IFNα2b) is investigated. Studies show SDF-1/CXCR4 signaling was up-regulated in burn patients, including SDF-1 level in HTS tissue and serum as well as CD14+ CXCR4+ cells in the peripheral blood mononuclear cells. In vitro, dermal fibroblasts constitutively expressed SDF-1 and deep dermal fibroblasts expressed more SDF-1 than superficial fibroblasts. Lipopolysaccharide increased SDF-1 gene expression in fibroblasts. Also, recombinant SDF-1 and lipopolysaccharide stimulated fibroblast-conditioned medium up-regulated peripheral blood mononuclear cell mobility. In the burn patients with HTS who received subcutaneous IFNα2b treatment, increased SDF-1/CXCR4 signaling was found prior to treatment which was down-regulated after IFNα2b administration, coincident with enhanced remodeling of their HTS. Our results suggest that SDF-1/CXCR4 signaling is involved in the development of HTS by promoting migration of activated CD14+ CXCR4+ cells from the bloodstream to wound sites, where they may differentiate into fibrocyte and myofibroblasts and contribute to the development of HTS.     

Correlation between creatinine clearance and Helicobacter pylori infection eradication with sequential and triple therapeutic regimens: A randomised clinical trial

Background and study aimsUraemic patients show susceptibility to gastrointestinal mucosal lesions and colonisation by Helicobacter pylori (HP). Antibiotic resistance constitutes a problem in treatment and bismuth preparations are toxic in uraemic patients. This study aimed to assess the correlation between creatinine clearance (CrCl) and eradication of HP infection with new sequential and standard triple therapeutic regimens.Patients and methodsA total of 120 HP-positive patients with renal function impairment and 60 control patients with HP infection were enrolled in this study. Patients were divided into four groups on the basis of CrCl and were randomly assigned to one of the two different regimens: A 14-day standard triple therapy with 20 mg omeprazole bid, 1000 mg amoxicillin bid and 500 mg clarithromycin bid and a new sequential regimen with 20 mg omeprazole bid and 1000 mg amoxicillin bid both for 14 days, 500 mg ciprofloxacin bid for the first 7 days and 200 mg furazolidone bid for the last 7 days. Doses of amoxicillin, clarithromycin and ciprofloxacin were reduced to 50% in the cases of CrCl <30 mg dl^?1.ResultsOne hundred and sixty two out of 180 HP-positive patients (54.3% male, 51.6 ± 12.1 years) completed treatment in the four groups and were studied. According to renal function they were classified into group A (n = 39), haemodialysis (HD) patients; group B (n = 37), CrCl <30 mg dl^?1 without HD; group C (n = 36), CrCl between 30 and 60 mg dl^?1; and group D (n = 50), control subjects with CrCl >90 mg dl^?1. HP was successfully eradicated in 77.7% of patients with standard triple therapy and in 81.4% of patients with the sequential therapy. There was no significant difference among the study groups in the rate of HP-infection eradication with both regimens.ConclusionHP eradication rates did not differ with both sequential and standard therapeutic regimens in uraemic and non-uraemic patients. We, therefore, prefer the standard triple therapy due to its simplicity and reported.     

A computer model for evaluating the osteotomy parameters of Chiari pelvic osteotomy

This study was conducted to evaluate the effect of the various osteotomy parameters on the biomechanical aspects of the hip joint on a computerised model. The data of the radiographs and a three-dimensional (3D) CT scan of six patients with coverage deficient hip joint were used to construct a 3D computer model. Then Chiari type osteotomies were simulated using various heights, angles and fibrocartilage thicknesses. A new angle called the mid acetabular center edge (MACE) angle was defined in a mid coronal CT cut. The optimum displacement for obtaining the maximum coverage averaged 73%. The angle and height of the osteotomy had a significant effect on the MACE angle (P value < 0.01). Our findings of these Chiari parameters may change the results of the osteotomy. The probability of adapting the proximal osteotomy segment to a deformed femoral head was explained by the model and a modified osteotomy “multiple height osteotomy” was proposed.