Salvage of Infected Orthopedic Hardware With Intraoperative and Postoperative Hypochlorous Acid Instillations.

Background: Orthopedic hardware infections often require hardware removal or replacement. In some situations, hardware removal is not possible or would require amputation. Thus, a method of in-situ hardware salvage could significantly improve patient outcomes. Hypochlorous acid is a broad-spectrum antimicrobial solution with rapid effectiveness in biofilm impairment. Methods: This article presents 2 patients with orthopedic hardware infection. Patient A had recurrent draining sinuses from an intramedullary nail in the femur. The orthopedic surgery team recommended above-knee amputation if hardware salvage was not possible. Patient B had a degloving injury of the right upper extremity with radius and ulna fractures that required revascularization and free flap coverage; when hardware infection developed, hardware removal would have required external fixator placement. In both patients, hypochlorous acid was used intraoperatively during debridement to soak the hardware for 5 minutes. Closed suction drains were placed along the hardware, and postoperative instillations of hypochlorous acid were placed through the drains for 5 minutes 1 to 2 times a day for 4 days for Patient A and 7 days for Patient B. Results: On follow-up at 10 months for Patient A and at 9 months for Patient B, there was no evidence of recurrent hardware infection. Hardware was successfully salvaged in both patients. Conclusions: Hypochlorous acid is an effective and safe topical antimicrobial agent for recurrent infections due to hardware-associated biofilm. Postoperative instillations of 0.025% hypochlorous acid through closed suctions drains may improve hardware salvage rates and optimize outcomes.

Full-thickness Pediatric Burn following Reaction between Cyanoacrylate Nail Adhesive and Cotton Shirt.

Cyanoacrylate is an acrylic resin that is used as an adhesive in acrylic nail glues and various other strong, rapidly acting adhesives, such as "Dermabond" and "Super Glue." This adhesive is very effective in a variety of settings; however, when cyanoacrylate comes into contact with cotton fibers, an exothermic reaction occurs that is severe enough to cause a full-thickness burn to the underlying skin. Full-thickness burns requiring excision and skin grafting can be psychologically devastating for patients, especially the pediatric population and their parents, who may believe they are to blame for their child's burn. We present the case of a 2-year-old boy who developed a full-thickness burn after spilling acrylic nail glue onto his cotton shirt. Fortunately, his burn was small enough that excision with primary closure was able to be performed. However, he unfortunately developed hypertrophic scarring postoperatively. Owing to the widespread use of cyanoacrylate adhesives in the general population, it is important to spread awareness of the potential dangers associated with these adhesives to prevent potential physical and psychological injuries related to improper use of these adhesives.

The Impact of Perioperative Hormonal Therapy for Breast Cancer on Transverse Rectus Abdominis Myocutaneous Flap Abdominal Complications.

BACKGROUND: The pedicled transverse rectus abdominis myocutaneous (TRAM) flap is a reliable reconstructive option in breast cancer patients; however, it carries known risk of donor site hernia formation. Some hormonal therapy drugs have been associated with hernia formation in animal models. Minimal data exist concerning impact of hormonal therapy for breast cancer on abdominal donor site complications after breast reconstruction. METHODS: Patients who underwent TRAM flap for breast cancer or high-risk status at a single institution by the senior author from 2003 to 2015 were identified. Charts were reviewed. Patient demographics, comorbidities, treatments, and abdominal complications were recorded. Patients were divided into groups based on use of hormonal therapy as well as exposure to specific drugs. Statistical analyses were performed. RESULTS: A total of 358 patients were included. Overall hernia rate was 5.9%. About 231 (64.5%) patients had hormonal therapy, whereas 127 (35.5%) did not. Difference in hernia formation was not statistically significant between the hormonal therapy group (6.9%) and the no hormonal therapy group (3.9%; P = 0.359). Patients exposed to tamoxifen and those exposed to anastrozole had no significant difference in complication rates compared with the no hormonal therapy group, whereas patients exposed to letrozole had increased rate of hernia (13.5%; P = 0.037) and infection (21.6%; P = 0.013) compared with the no hormonal therapy group (3.9% and 7.1%, respectively). CONCLUSIONS: Hormonal therapy is a useful adjunct for chemoprevention in breast cancer; however, use of letrozole in patients undergoing reconstruction with pedicled TRAM can lead to increase in certain complication rates.

Phenotypic Knockout of CXCR4 Expression by a Novel Intrakine Mutant hSDF-1α/54/KDEL Inhibits Breast Cancer Metastasis.

Many malignant tumors express high levels of the chemokine receptor CXCR4, and the interaction between CXCR4 and its ligand, SDF-1, promotes migration, invasion, and metastasis of breast cancer cells. Therefore, blocking the interaction between CXCR4 and SDF-1 could alter the tumor's metastatic phenotype and control the development and progression of cancers. We used a cellular phenotypic knockout strategy and developed a novel recombinant gene, AdSDF-1α/54/KDEL, which contains an adenovirus vector, a mutant form of SDF-1 that lacks a C-terminal α-helix, and a KDEL tetrapeptide sequence that promotes retention at the endoplasmic reticulum (ER). We hypothesized that SDF-1α/54/KDEL could efficiently block metastasis of breast cancer cells with less inflammatory side effects than SDF-1α/KDEL. Using the MCF-7 cell line, which expresses a stable, high level of CXCR4, we found that SDF-1α/54/KDEL efficiently becomes localized at the ER of tumor cells, where it specifically binds to newly synthesized CXCR4 and prevents it from reaching the cell surface. Chemotaxis and invasion assays revealed that the cells treated with SDF-1α/54/KDEL failed to migrate toward SDF-1. We also found that SDF-1α/54/KDEL impaired lung metastasis of metastatic breast cancer by decreasing CXCR4 on the cell surface. The novel recombinant gene, SDF-1α/54/KDEL, played an instrumental role in blocking SDF-1/CXCR4-mediated cell migration, and we found that this gene-based strategy for targeting the SDF-1/CXCR4 axis offers a very effective alternative method for preventing metastasis of breast cancer and other cancers expressing high levels of CXCR4.

Synthesis and Evaluation of a CBZ-AAN-Dox Prodrug and its in vitro Effects on SiHa Cervical Cancer Cells Under Hypoxic Conditions.

Although doxorubicin (Dox) is widely used in clinical treatment for solid tumors, it causes many side-effects such as heart and kidney damage, bone marrow suppression, and drug resistance. Legumain is a lysosomal protease that is elevated and associated with an invasive and metastatic phenotype in a number of solid tumors. In this study, we designed and synthesized a Dox prodrug, N-benzyloxycarbonyl-Ala-Ala-Asn-Doxorubicin (CBZ-AAN-Dox), with 94% purity. Single substrate kinetic assays demonstrated hLegumain-specific enzymatic cleavage and activation of the prodrug in vitro, and this enzymatic cleavage of the prodrug substrate was more sensitive in acidic conditions, releasing more than 70% of Dox after 24 h. Treatment of tumor cells with our prodrug demonstrated a much higher IC50 value, significantly enhanced uptake of the prodrug, and considerably less cellular toxicity compared to Dox treatment alone. Our study presents a novel prodrug, CBZ-AAN-Dox, to potentially increase both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain.

Presence and utility of intrinsically disordered regions in kinases.

Since aberrant cell signaling pathways underlie majority of pathophysiological morbidities, kinase inhibitors are routinely used for pharmacotherapy. However, most kinase inhibitors suffer from adverse off-target effects. Inhibition of one kinase in a pathogenic signaling pathway elicits multiple compensatory feedback signaling loops, reinforcing the pathway rather than inhibiting it, leading to chemoresistance. Thus, development of novel computational strategies providing predictive evidence to inhibit a specific set of kinases to mitigate an aberrant signaling pathway with minimum side-effects is imperative. First, our analyses reveal that many kinases contain intrinsically disordered regions, which may participate in facilitating protein-protein interactions at the kinome level. Second, we employ a kinome-wide approach to identify intrinsic disorder and streamline a methodology that adds to the knowledge of therapeutically targeting kinase cascades to treat diseases. Furthermore, we find that within the kinome network, some kinases with intrinsically disordered regions have a high topological score, likely acting as kinome modulators. Third, using network analysis, we demonstrate that 5 kinases emerge as topologically most significant, forming kinome sub-networks, comprising of other kinases and transcription factors that are known to serve as drivers of disease pathogenesis. To support these findings, we have biologically validated the interplay between kinome modulators SRC and AKT kinases and uncovered their novel function in regulating transcription factors of the SMAD family. Taken together, we identify novel kinome modulators driven by intrinsic disorder, and biologically validate the thesis that therapeutic disruption of the function of kinome modulators engaged in regulatory cross-talk between disparate pathways can lead to reduced oncogenic potential in cancer cells.

Protective effect of neutralization of the extracellular high-mobility group box 1 on renal ischemia-reperfusion injury in miniature swine.

BACKGROUND: Strategies that reduce ischemia-reperfusion injury (IRI) have the potential to expand the numbers of available organs for transplantation. Recent reports in rodent models have demonstrated that high-mobility group box 1 (HMGB1) acts as an alarm in initiating the inflammatory response resulting from ischemic injury. The aim of this study was to evaluate the cytoprotective effects of anti-HMGB1 antibodies on renal IRI in preclinical large animals. METHODS: One hundred twenty minutes of warm and 60 min of cold renal ischemia were induced in 8 CLAWN miniature swine. Three of eight animals received intravenous anti-HMGB1 antibody at 1 mg/kg just before the reperfusion of renal blood flow. Renal function was assessed by serum creatinine and renal biopsy. Serum levels of interleukin (IL)-1ß, IL-6, and HMGB1 were measured. RESULTS: The concentration of HMGB1 increased as early as 30 min after reperfusion and before the elevation of IL-1ß and IL-6. Serum creatinine levels were markedly elevated, peaking at a median of 5 days (peak creatinine levels: 11.6 ± 1.6 mg/dL) and recovering by day 14. Anti-HMGB1 antibody injection dramatically decreased renal damage as well as serum levels of HMGB1 associated with IRI. Renal function returned to near normal by day 9, and peak creatinine levels were markedly lower (7.4 ± 0.2 mg/dL), and biopsies possessed fewer pathologic changes when compared to the control group. CONCLUSION: In this study, we demonstrated the beneficial effects of perioperative administration of anti-HMGB1 antibody in reducing renal IRI in a clinically relevant, large animal model.

The pathophysiology of venous thromboembolism: implications with compression garments.

The highest risk of venous thromboembolism lies with abdominoplasty and liposuction and deaths increase when combined with other procedures. The objective of this study was to evaluate physiologic changes in the deep venous system with compression-garments and asses whether there is a correlation between these procedures, rectus plication, and garments. Part 1 of this article is a retrospective review of all office surgical incidents that resulted in an abdominoplasty and/or liposuction death in the state of Florida over the past 8 years. Part 2 is a clinical study, evaluating the effect compression garments have on the pathophysiology of venous thromboembolism. Duplex ultrasounds were performed with and without garments to evaluate venous changes. Literature was reviewed related to intraabdominal pressure and high-tension abdominal closures and surgeons were polled about their use of rectus plication and garments/binders. In 8 years, 13 patients died related to abdominoplasty, liposuction, or the combination of the 2. In 100% of subjects, ultrasounds showed a decrease in venous flow, proximal vessel dilation, and loss of normal biphasic flow within the popliteal vein. Multiple publications have reported an increased morbidity and mortality related to liposuction and abdominoplasty procedures. The most frequent cause of death with these types of procedures was thromboembolism, and we discuss possible reasons for this increased rate. The exact cause of deep venous thrombosis in these procedures remains unknown, but postoperative garments may affect the physiology of venous flow, and may be involved in the formation of deep venous thrombosis and should be considered along with other patient safety procedures.