Sequential treatment for diabetic foot ulcers in dialysis patients: A case report.

BACKGROUND: Diabetic foot ulcers (DFUs) are common in patients with diabetes, especially those undergoing hemodialysis. In severe cases, these ulcers can cause damage to the lower extremities and lead to amputation. Traditional treatments such as flap transposition and transfemoral amputation are not always applicable in all cases. Therefore, there is a need for alternative treatment methods. CASE SUMMARY: This report describes a 62-year-old female patient who was admitted to the hospital with plantar and heel ulcers on her left foot. The patient had a history of renal failure and was undergoing regular hemodialysis. Digital subtraction angiography showed extensive stenosis and occlusion in the left superficial femoral artery, left peroneal artery and left posterior tibial artery. Following evaluation by a multidisciplinary team, the patient was diagnosed with type 2 DFUs (TEXAS 4D). Traditional treatments were deemed unsuitable, and the patient was treated with endovascular surgery in the affected area, in addition to supportive medical treatment, local debridement, and sequential repair using split-thickness skin and tissue-engineered skin grafts combined with negative pressure treatment. After four months, the wound had completely healed, and the patient was able to walk with a walking aid. CONCLUSION: This study demonstrates a new treatment method for DFUs was successful, using angioplasty, skin grafts, and negative pressure.

Anthelmintic nitazoxanide protects against experimental pulmonary fibrosis.

BACKGROUND AND PURPOSE: Nitazoxanide is a therapeutic anthelmintic drug. Our previous studies found that nitazoxanide and its metabolite tizoxanide activated adenosine 5'-monophosphate-activated protein kinase (AMPK) and inhibited signal transducer and activator of transcription 3 (STAT3) signals. As AMPK activation and/or STAT3 inhibition are targets for treating pulmonary fibrosis, we hypothesized that nitazoxanide would be effective in experimental pulmonary fibrosis. EXPERIMENTAL APPROACH: The mitochondrial oxygen consumption rate of cells was measured by using the high-resolution respirometry system Oxygraph-2K. The mitochondrial membrane potential of cells was evaluated by tetramethyl rhodamine methyl ester (TMRM) staining. The target protein levels were measured by using western blotting. The mice pulmonary fibrosis model was established through intratracheal instillation of bleomycin. The examination of the lung tissues changes were carried out using haematoxylin and eosin (H&E), and Masson staining. KEY RESULTS: Nitazoxanide and tizoxanide activated AMPK and inhibited STAT3 signalling in human lung fibroblast cells (MRC-5 cells). Nitazoxanide and tizoxanide inhibited transforming growth factor-ß1 (TGF-ß1)-induced proliferation and migration of MRC-5 cells, collagen-I and α-smooth muscle cell actin (α-SMA) expression, and collagen-I secretion from MRC-5 cells. Nitazoxanide and tizoxanide inhibited epithelial-mesenchymal transition (EMT) and inhibited TGF-ß1-induced Smad2/3 activation in mouse lung epithelial cells (MLE-12 cells). Oral administration of nitazoxanide reduced the bleomycin-induced mice pulmonary fibrosis and, in the established bleomycin-induced mice, pulmonary fibrosis. Delayed nitazoxanide treatment attenuated the fibrosis progression. CONCLUSIONS AND IMPLICATIONS: Nitazoxanide improves the bleomycin-induced pulmonary fibrosis in mice, suggesting a potential application of nitazoxanide for pulmonary fibrosis treatment in the clinic.

Activatable unsaturated liposomes increase lipid peroxide of cell membrane and inhibit tumor growth.

The cancer chemodynamic therapy based on the Fenton reaction has been attracting more and more attention. However, the performance of the Fenton reaction is restricted by the unsuitable physiological pH value and inadequate H2O2 content in the tumor microenvironment (TME). In this study, we proposed a novel method of inducing lipid peroxide (LPO) of the cancer cell membrane, whose performance is not limited by the pH value and H2O2 in the TME. The activatable LPO-inducing liposomes were constructed by encapsulating Fe3+-containing compound ferric ammonium citrate (FC) in the unsaturated soybean phospholipids (SPC). It was found that the FC could be reduced by the overexpressed glutathione (GSH) in the TME and produce iron redox couple. The Fe3+/Fe2+ mediated the peroxidation of the unsaturated SPC and induced the LPO in the cancer cells. Finally, LPO accumulation led to cancer cell death and tumor growth inhibition. Furthermore, the activatable liposomes did not damage healthy tissues because of the low GSH content in normal tissues and the GSH-triggered activation of the nanocarrier. Together, our findings revealed that FC-SPC-lipo displayed excellent anti-tumor performance and its therapeutic effects are less influenced by the TME, compared with the traditional ferroptosis.

Comparison of a Hemostatic Powder and Standard Treatment in the Control of Active Bleeding From Upper Nonvariceal Lesions : A Multicenter, Noninferiority, Randomized Trial.

BACKGROUND: The effectiveness of the hemostatic powder TC-325 as a single endoscopic treatment for acute nonvariceal upper gastrointestinal bleeding is uncertain. OBJECTIVE: To compare TC-325 with standard endoscopic hemostatic treatments in the control of active bleeding from nonvariceal upper gastrointestinal causes. DESIGN: One-sided, noninferiority, randomized, controlled trial. (ClinicalTrials.gov: NCT02534571). SETTING: University teaching hospitals in the Asia-Pacific region. PATIENTS: 224 adult patients with acute bleeding from a nonvariceal cause on upper gastrointestinal endoscopy. INTERVENTION: TC-325 (n = 111) or standard hemostatic treatment (n = 113). MEASUREMENTS: The primary outcome was control of bleeding within 30 days. Other outcomes included failure to control bleeding during index endoscopy, recurrent bleeding after initial hemostasis, further interventions, blood transfusion, hospitalization, and death. RESULTS: 224 patients were enrolled (136 with gastroduodenal ulcers [60.7%], 33 with tumors [14.7%], and 55 with other causes of bleeding [24.6%]). Bleeding was controlled within 30 days in 100 of 111 patients (90.1%) in the TC-325 group and 92 of 113 (81.4%) in the standard treatment group (risk difference, 8.7 percentage points [1-sided 95% CI, 0.95 percentage point]). There were fewer failures of hemostasis during index endoscopy with TC-325 (3 [2.7%] vs. 11 [9.7%]; odds ratio, 0.26 [CI, 0.07 to 0.95]). Recurrent bleeding within 30 days did not differ between groups (9 [8.1%] vs. 10 [8.8%]). The need for further interventions also did not differ between groups (further endoscopic treatment: 8 [7.2%] vs. 10 [8.8%]; angiography: 2 [1.8%] vs. 4 [3.5%]; surgery: 1 [0.9%] vs. 0). There were 14 deaths in each group (12.6% vs. 12.4%). LIMITATION: Clinicians were not blinded to treatment. CONCLUSION: TC-325 is not inferior to standard treatment in the endoscopic control of bleeding from nonvariceal upper gastrointestinal causes. PRIMARY FUNDING SOURCE: General Research Fund to the University Grants Committee, Hong Kong SAR Government.

Fate of Fat Grafting In Vivo and In Vitro: Does the Suction-Assisted Lipectomy Device Matter?

BACKGROUND: Recently, there has been increasing research interest in identifying the effect of liposuction procedures on fat graft survival in order to clarify whether different harvest techniques affect the quality of fat grafts. OBJECTIVES: The aim of this study was to investigate the effect of 2 liposuction methods on the survival and regeneration potential of grafted fat tissue. The proliferation and differentiation potentials of adipose-derived stem cells (ASCs) isolated by both methods was also investigated. METHODS: Fat grafts were collected from patients who underwent liposuction procedures by 2 different methods: traditional suction-assisted liposuction (TSAL) and vibration amplification of sound energy at resonance (VASER). One portion of the lipoaspirates was implanted into the subcutaneous layer of nu mice for 4 and 12 weeks. ASCs were isolated from the other portion of the lipoaspirate and subjected to proliferation and differentiation assays. RESULTS: Although in vivo fat grafting presented similar adipose tissue survival for the 2 different liposuction methods, more angiogenesis and less fibrosis was observed in the VASER group based on histologic evaluation. Furthermore, VASER-derived ASCs presented better quality in terms of cell differentiation capacity. CONCLUSIONS: The in vivo study confirmed better graft angiogenesis with less inflammation, apoptosis, and scar formation in the VASER group. ASCs harvested with VASER exhibited increased differentiation capacity compared with those obtained by TSAL, and represent an excellent source for fat grafting and regenerative medicine.

Aidi injection induces apoptosis of hepatocellular carcinoma cells through the mitochondrial pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality rates of hepatocellular carcinoma are very high all over the world, which seriously threatens human life and health. Aidi injection as a Chinese medicine preparation has a positive curative effect on hepatocellular carcinoma, but its mechanism remains unclear. AIM OF THE STUDY: The purpose of this study is to evaluate the anti-hepatocellular carcinoma effects of Aidi injection and explore its mechanism of action vitro and vivo. MATERIALS AND METHODS: The main components of Aidi injection were determined by LC-MS/MS. The effects of Aidi injection on the viability of HepG2 and PLC/PRF/5 cells were detected via CCK-8 analysis and Calcein AM/PI staining. DAPI staining and flow cytometry were applied to analyze the apoptosis-induced effects of Aidi injection on hepatocellular carcinoma cells (HCCs). The growth inhibition of Aidi injection on hepatocellular carcinoma was observed in nude mice bearing PLC/PRF/5 cells. The related signal transduction and apoptosis pathways were investigated through assays for JC-1 mitochondrial membrane potential (MMP), RNA-seq, KEGG, PPI and WB. RESULTS: There were 12 main chemical components contained in Aidi injection, viz. cantharidin, syringin, calycosin-7-o-ß-Dglucoside, isozinpidine, ginsenosides Rd, Rc, Rb1, Re, and Rg1, astragalosides II and IV, and eleutheroside E. Aidi injection significantly inhibited the proliferation of HepG2 and PLC/PLF/5 cells with IC50 of 20.66 mg/ml and 27.5 mg/ml at 48h, respectively, increased the proportion of dead cells, induced cell apoptosis, suppressed the tumor growth of nude mice bearing PLC/PLF/5 cells, reduced MMP, activated PI3K/Akt and MAPK signal transduction pathways, down-regulated the expression of p-PI3K and Bcl-xL, and up-regulated the expression of p-JNK, p-p38 and Bim. CONCLUSION: Aidi injection inhibits the growth of liver cancer probably through regulating PI3K/Akt and MAPK signal transduction pathways, inducing MMP collapse to activate the mitochondrial apoptosis pathway, and then eliciting apoptosis of HCCs.

A fixed nitrous oxide/oxygen mixture as an analgesic for trauma patients in emergency department: study protocol for a randomized, controlled trial.

BACKGROUND: Acute pain is always the most common complaint in Emergency Department admissions and options for analgesia are limited. Nitrous oxide/oxygen possess many properties showing it may be an ideal analgesic method for the Emergency Department; it is quick-acting, well-tolerated, and does not mask signs and symptoms. The aim of this study is to evaluate the safety and analgesic effect of the fixed nitrous oxide/oxygen mixture for trauma patients in a busy emergency environment. METHODS: The randomized, double-blind, prospective, placebo-controlled study will be carried out in the Emergency Department of General Hospital of Ningxia Medical University. The target research objects are trauma patients who present to the Emergency Department and report moderate to severe intensities of acute pain. A total of 90 patients will be recruited and randomly assigned into the treatment and control group. The treatment group will receive conventional pain treatment plus nitrous oxide/oxygen mixture and the control group will receive conventional pain treatment plus oxygen. Neither patients, nor investigators, nor data collectors will know the nature of the gas mixture in each cylinder and the randomization list. Outcomes will be monitored at baseline(T0), 5 min (T1), and 15 min (T2) after the beginning of intervention and at 5 min post intervention (T3) for each group. The primary outcome is the level of pain relief after the initial administering of the intervention at T1, T2, and T3. Secondary outcomes include adverse events, physiological parameters, total time of the gas administration, satisfaction from both patients and healthcare professionals, and the acceptance of patients. DISCUSSION: Our previous studies suggested that a fixed nitrous oxide/oxygen mixture was an efficacious analgesic for the management of burning dressing pain and breakthrough cancer pain. The results of this study will provide a more in-depth understanding of the effect of this gas. If this treatment proves successful, it could help to generate preliminary guidelines and be implemented widely in trauma patients with pain in Emergency Departments. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR-INR-16007807 . Registered on 21 January 2016.

The prognostic value of phosphatase and tensin homolog negativity in breast cancer: A systematic review and meta-analysis of 32 studies with 4393 patients.

The prognostic value of phosphatase and tensin homolog (PTEN) negativity in breast cancer has been evaluated by many studies but remains controversial. We conducted a meta-analysis to assess the association of PTEN negativity with overall survival and disease-free survival. Thirty-two studies with 4393 patients were identified. PTEN negativity was significantly associated with unfavorable overall survival in breast cancer (hazard ratio=1.89, 95% confidence interval 1.58-2.26), with low heterogeneity among the studies (I(2)=25%, P=0.160) and no evidence for publication bias. Meta-analysis of multivariate hazard ratios and sensitivity analyses did not materially change the results. The data on disease-free survival was heterogeneous (I(2)=61.9%, P<0.001), with a summary hazard ratio of 1.57 (95% confidence interval 1.31-1.89). The exact source of heterogeneity remains unclear. We thus concluded that PTEN negativity was significantly associated with unfavorable prognosis in terms of overall survival in breast cancer.

Concordant analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression between primary colorectal cancer and matched metastases.

Current data on the concordance of KRAS, BRAF, PIK3CA mutation status or PTEN expression status between primary tumors and metastases in colorectal cancer (CRC) are conflicting. We conducted a systematic review and meta-analysis to examine concordance and discordance of the status of these four biomarkers between primary tumors and corresponding metastases in CRC patients. The biomarker status in primary tumors was used as the reference standard. Concordance data for KRAS, BRAF, PIK3CA and PTEN were provided by 43, 16, 9 and 7 studies, respectively. The pooled concordance rate was 92.0% (95% CI: 89.7%-93.9%) for KRAS, 96.8% (95% CI: 94.8%-98.0%) for BRAF, 93.9% (95% CI: 89.7%-96.5%) for PIK3CA and 71.7% (95% CI: 57.6%-82.5%) for PTEN. The pooled false positive and false negative rates for KRAS were 9.0% (95% CI: 6.5%-12.4%) and 11.3% (95% CI: 8.0%-15.8%), respectively. KRAS, BRAF and PIK3CA mutations are highly concordant between primary tumors and corresponding metastases in CRC, but PTEN loss is not. Nine percent of patients with wild-type KRAS in primary tumors who received anti-EGFR treatment had mutant KRAS in metastases, while 11.3% patients with mutant KRAS primary tumors had wild-type KRAS in the metastases. These 11.3% patients currently do not receive potentially beneficial anti-EGFR treatment.

Synthesis and properties of a novel methoxy poly(ethylene glycol)-modified galactosylated chitosan derivative.

Chitosan and its derivatives are attractive non-viral vectors. To produce target-cell specificity and improve the solubility of chitosan, a novel chitosan derivative, modified with galactose and methoxy poly(ethylene glycol) (mPEG) was synthesized, and structure changes of chitosan and its derivatives were characterized. Compared to chitosan, the solution viscosity of the novel chitosan derivative drastically decreased. And, the degree of substitution (DS) of chitosan by galactose and mPEG were calculated as 0.09 and 0.30. The average diameter and zeta potential of mPEGylated galactosylated chitosan (GaC) nanoparticle containing VRMFat plasmid were 178 nm and +2.93 mV, suggesting suitable properties for gene delivery system. The gel electrophoresis confirmed that the plasmid DNA was remained completely by the mPEGylated GaC nanoparticle. And, the cytotoxic effect of mPEGylated GaC nanoparticles on human embryonic kidney (HEK 293) cells was negligible in comparison with that of control chitosans. Therefore, it is expected that the mPEGylated GaC will have the potential as a targeting gene delivery system for a further application.

cDNA microarray analysis of differential gene expression and regulation in clinically drug-resistant isolates of Candida albicans from bone marrow transplanted patients.

Fungi have emerged as the fourth most common pathogens isolated in nosocomial bloodstream infections, and Candida albicans is the most common human fungal pathogen. Only a few antibiotics are effective in the treatment of fungal infections. In addition, the repetition and lengthy duration of fluconazole therapy has led to an increased incidence of azole resistance and treatment failure associated with C. albicans. To investigate the mechanism of drug resistance and explore new targets to treat clinically resistant fungal pathogens, we examined the large-scale gene expression profile of two sets of matched fluconazole-susceptible and -resistant bloodstream C. albicans isolates from bone marrow transplanted (BMT) patients for the first time by microarray analysis. More than 198 differentially expressed genes were identified and they were confirmed and validated by RT-PCR independently. Not surprisingly, the resistant phenotype is associated with increased expression of CDR mRNA, as well as some common genes involved in drug resistance such as CaIFU5, CaRTA2 and CaIFD6. Meanwhile, some special functional groups of genes, including ATP binding cassette (ABC) transporter genes (IPF7530, CaYOR1, CaPXA1), oxidative stress response genes (CaALD5, CaGRP1, CaSOD2, IPF10565), copper transport and iron mobilization-related genes (CaCRD1/2, CaCTR1/2, CaCCC2, CaFET3) were found to be differentially expressed in the resistant isolates. Furthermore, among these differentially expressed genes, some co-regulated with CaCDR1, CaCDR2 and CaIFU5, such as CaPDR16 and CaIFD6, have a DRE-like element and may interact with TAC1 in the promoter region. These findings may shed light on mechanisms of azole resistance in C. albicans and clinical antifungal therapy.