Biologic therapies for foot and ankle injuries.

Introduction: The use of orthobiologics as supplemental treatment for foot and ankle pathologies have increased in the past decades. They have been used to improve the healing of bone and soft tissue injuries. There have been several studies that examined the use of biologics for knee and hip pathologies but the foot and ankle construct has unique features that must be considered.Areas covered: The biologics for foot and ankle injuries that are covered in this review are platelet-rich plasma (PRP), stem cells, growth factors, hyaluronic acid, bone grafts, bone substitutes, and scaffolds. These modalities are used in the treatment of pathologies related to tendon and soft tissue as well as cartilage.Expert opinion: The utilization of biological adjuncts for improved repair and regeneration of ankle injuries represents a promising future in our efforts to address difficult clinical problems. The application of concentrated bone marrow and PRP each represents the most widely studied and commonly used injection therapies with early clinical studies demonstrating promising results, research is also being done using other potential therapies such as stem cells and growth factors; further investigation and outcome data are still needed.

Sudden Aggravated Radicular Pain Caused by Hemorrhagic Spinal Angiolipomas After Back Massage.

BACKGROUND: Spinal angiolipomas (SALs) are benign tumors that usually present a slow progressive spinal cord or radicular compression. Acute myelopathy or acute aggravated radicular syndrome are exceedingly rare. CASE DESCRIPTION: The authors report an original case with sudden aggravated radicular pain caused by hemorrhagic SALs. A 54-year-old woman presented with a 2-month history of mild back pain, and the pain was significantly aggravated after a therapeutic back massage. Neurologic examination showed pain and hyperalgesia between T4 and T7 dermatome, from back to front, just like a band. Spinal magnetic resonance imaging (MRI) showed a dorsally located epidural lesion (T4-T6) and a small intratumoral hemorrhage at the lower part of the tumor. A bilateral T4-T6 laminectomy was performed to achieve total excision of the tumors. Histologic examination showed that the tumors were composed of mature adipose tissue and vascular tissue as angiolipomas. The postoperative course was uneventful with complete neurologic recovery 4 days after the surgery. MRI at 1-year follow-up indicated no recurrence. CONCLUSIONS: SALs are unusual benign tumors that are composed of mature fatty tissue and abnormal blood vessels; sudden aggravated spinal cord or radicular compression syndrome is rare. MRI is the best choice in the diagnosis of SALs. Surgery may be performed in different ways depending on the type of SALs, and the prognosis is generally good.

Conjugation of a Small-Molecule TLR7 Agonist to Silica Nanoshells Enhances Adjuvant Activity.

Stimulation of Toll-like receptors (TLRs) and/or NOD-like receptors on immune cells initiates and directs immune responses that are essential for vaccine adjuvants. The small-molecule TLR7 agonist, imiquimod, has been approved by the FDA as an immune response modifier but is limited to topical application due to its poor pharmacokinetics that causes undesired adverse effects. Nanoparticles are increasingly used with innate immune stimulators to mitigate side effects and enhance adjuvant efficacy. In this study, a potent small-molecule TLR7 agonist, 2-methoxyethoxy-8-oxo-9-(4-carboxybenzyl)adenine (1V209), was conjugated to hollow silica nanoshells (NS). Proinflammatory cytokine (IL-6, IL-12) release by mouse bone-marrow-derived dendritic cells and human peripheral blood mononuclear cells revealed that the potency of silica nanoshells-TLR7 conjugates (NS-TLR) depends on nanoshell size and ligand coating density. Silica nanoshells of 100 nm diameter coated with a minimum of ∼6000 1V209 ligands/particle displayed 3-fold higher potency with no observed cytotoxicity when compared to an unconjugated TLR7 agonist. NS-TLR activated the TLR7-signaling pathway, triggered caspase activity, and stimulated IL-1ß release, while neither unconjugated TLR7 ligands nor silica shells alone produced IL-1ß. An in vivo murine immunization study, using the model antigen ovalbumin, demonstrated that NS-TLR increased antigen-specific IgG antibody induction by 1000× with a Th1-biased immune response, compared to unconjugated TLR7 agonists. The results show that the TLR7 ligand conjugated to silica nanoshells is capable of activating an inflammasome pathway to enhance both innate immune-stimulatory and adjuvant potencies of the TLR7 agonist, thereby broadening applications of innate immune stimulators.

Thickness and Sphericity Control of Hollow Hard Silica Shells through Iron (III) Doping: Low Threshold Ultrasound Contrast Agents.

Silica particles are convenient ultrasound imaging contrast agents because of their long imaging time and ease of modification; however, they require a relatively high insonation power for imaging and have low biodegradability. In this study, 2 µm ultrathin asymmetric hollow silica particles doped with iron (III) (Fe(III)-SiO2) are synthesized to produce biodegradable hard shelled particles with a low acoustic power threshold comparable with commercial soft microbubble contrast agents (Definity) yet with much longer in vivo ultrasound imaging time. Furthermore, high intensity focused ultrasound ablation enhancement with these particles shows a 2.5-fold higher temperature elevation than with Definity at the same applied power. The low power visualization improves utilization of the silica shells as an adjuvant in localized immunotherapy. The data are consistent with asymmetric engineering of hard particle properties that improve functionality of hard versus soft particles.

Myths and Facts of In-Office Regenerative Procedures for Tendinopathy.

Tendinopathy carries a large burden of musculoskeletal disorders seen in both athletes and aging population. Treatment is often challenging, and progression to chronic tendinopathy is common. Physical therapy, nonsteroidal anti-inflammatory drugs, and corticosteroid injections have been the mainstay of treatment but are not optimal given that most tendon disorders seem to involve degenerative changes in addition to inflammation. The field of regenerative medicine has taken the forefront, and various treatments have been developed and explored including prolotherapy, platelet rich plasma, stem cells, and percutaneous ultrasonic tenotomy. However, high-quality research with standardized protocols and consistent controls for proper evaluation of treatment efficacy is currently needed. This will make it possible to provide recommendations on appropriate treatment options for tendinopathy.

A Case Report of Supplement-Induced Hepatitis in an Active Duty Service Member.

The incidence of drug-induced hepatic injury has been increasing as a result of more widespread use of workout supplements containing anabolic steroids to increase muscle mass. Synthetic androgenic steroids are shown to cause cholestatic liver injury, but the exact mechanism of injury is not completely understood. We present a case of a healthy, young, active duty Army male soldier who developed pruritis and jaundice shortly after starting to take a body-building supplement containing anabolic steroids, and was subsequently found to have significant biopsy proven drug-induced liver injury.

Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors.

A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2.

Strategies to prevent biofilm-based tympanostomy tube infections.

OBJECTIVE: To review the potential contributory role of biofilms to post-tympanstomy tube otorrhea and plugging as well as the available interventions currently utilized to prevent biofilm formation on tympanostomy tubes. DATA SOURCES: A literature review was performed utilizing the MEDLINE/Pubmed database from 1980 to 2013. REVIEW METHODS: Electronic database was searched with combinations of keywords "biofilm", "tympanostomy tube", "ventilation tube", and "post-tympanostomy tube otorrhea". RESULTS: Two of the most common sequelae that occur after tympanostomy tube insertion are otorrhea and tube occlusion. There is an increased evidence supporting a role for biofilms in the pathogenesis of otitis media. In this review, we have shown a multitude of novel approaches for prevention of biofilm associated sequelae of otitis media with effusion. These interventions include (i) changing the inherent composition of the tube itself, (ii) coating the tubes with antibiotics, polymers, plant extracts, or other biofilm-resistant materials, (iii) tubal impregnation with antimicrobial compounds, and (iv) surface alterations of the tube by ion-bombardment or surface ionization. CONCLUSION: Currently, there is not one type of tympanostomy tube in which bacteria will not adhere. The challenges of treating chronic post-tympanostomy tube otorrhea and tube occlusion indicate the need for further research in optimization of tympanostomy tube design in addition to development of novel therapies.

Use of gold nanoshells to constrain and enhance laser thermal therapy of metastatic liver tumours.

PURPOSE: To investigate the impact of intravenously injected gold nanoparticles on interstitially delivered laser induced thermal therapy (LITT) in the liver. METHODS: 3D finite element modelling, ex vivo canine liver tissue containing gold nanoparticles absorbing at 800 nm, and agar gel phantoms were used to simulate the presence of nanoparticles in the liver during LITT. Real-time magnetic resonance temperature imaging (MRTI) based on the temperature sensitivity of the proton resonance frequency shift (PRFS) was used to map the spatiotemporal distribution of heating in the experiments and validate the predictions of 3D finite element simulations of heating. RESULTS: Experimental results show good agreement with both the simulation and the ex vivo experiments. Average discrepancy between simulation and experiment was shown to be 1.6 degrees C or less with the maximum difference being 3.8 degrees C due to a small offset in laser positioning. CONCLUSION: A high nanoshell concentration in the surrounding liver parenchyma, such as that which would be expected from an intravenous injection of gold nanoshells ( approximately 120 nm) acts as both a beam stop for the laser and secondary heat source for the treatment, helping to better heat the lesions and confine the treatment to the lesion. This indicates a potential to use nanoparticles to enhance both the safety and efficacy of LITT procedures in the liver.

Photothermal therapy in a murine colon cancer model using near-infrared absorbing gold nanorods.

The photothermal ablation of solid tumors using exogenous, near-infrared (NIR)-absorbing nanoparticles has been previously investigated using various preclinical models and is currently being evaluated in the clinic. Here, we evaluate the circulation kinetics, preliminary toxicity, and efficacy of photothermal ablation of solid tumors using gold nanorods systemically delivered and passively accumulated in a murine subcutaneous colon cancer model. Tumored animals were infused with nanorods followed by the percutaneous illumination of the tumor with an 808-nm laser. Control groups consisted of laser-only, nanorod-only, and untreated tumored animals. The survival of the treated and control groups were monitored for 60 days post-treatment. The survival of the photothermally treated group was statistically longer than the control groups, with approximately 44% tumor free through the evaluation period. Histopathology of the major organs of animals infused with nanorods did not indicate any significant toxicity at 60 days post-treatment. Particle biodistribution was evaluated by elemental analysis of the major organs of untumored mice at 1, 7, and 30 days after infusion with nanorods. Elemental analysis indicates nanorod clearance from the blood and retention by the reticuloendothelial system. This study indicates that gold nanorods are promising agents for photothermal ablation of solid tumors.

Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study.

BACKGROUND AND PURPOSE: Restless Legs Syndrome (RLS) is a primary disorder of sensation that affects sleep and has been associated with iron deficiency. The purpose of this study was to determine if symptomatic RLS patients with low-normal serum ferritin levels benefit from oral iron replacement. PATIENTS AND METHODS: This was a randomized, placebo-controlled, double-blinded study. Eligible patients were randomized to oral iron therapy vs. appearance-matched placebo and followed over a 12 week period. RESULTS: Baseline International Restless Leg Scale (IRLS) scores for the treatment (24.8+/-5.72) and placebo (23.0+/-5.03) groups were similar. Baseline ferritin levels for the treatment (40.6+/-15.3ng/ml) and placebo (36.7+/-20.8ng/ml) groups were also similar. After 12 weeks, IRLS scores decreased more in the treatment arm (10.3+/-7.40) than in the placebo arm (1.14+/-5.64), (p=0.01). Ferritin levels increased more in the treatment arm (25.1+/-20.3ng/ml) than in the placebo arm (7.5+/-13.7ng/ml), (p=0.04). We observed a nonsignificant trend toward improved quality of life in the treated patients, (p=0.07). CONCLUSIONS: This is the first double-blinded, placebo-controlled study to demonstrate statistically significant improvement in RLS symptoms using oral iron therapy in patients with low-normal ferritin. The findings from this study suggest that additional larger randomized placebo-controlled trials of iron as treatment for patients with low-normal ferritin are warranted.

Modulation of in vivo tumor radiation response via gold nanoshell-mediated vascular-focused hyperthermia: characterizing an integrated antihypoxic and localized vascular disrupting targeting strategy.

We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies.

Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform.

We report here the results of a chemical genetic screen using small molecules with known pharmacologies coupled with a cortical brain slice-based model for ischemic stroke. We identified a small-molecule compound not previously appreciated to have neuroprotective action in ischemic stroke, the cardiac glycoside neriifolin, and demonstrated that its properties in the brain slice assay included delayed therapeutic potential exceeding 6 h. Neriifolin is structurally related to the digitalis class of cardiac glycosides, and its putative target is the Na(+)/K(+)-ATPase. Other cardiac glycoside compounds tested also showed neuroprotective activity, although with lower apparent potencies. In subsequent whole-animal studies, we found that neriifolin provided significant neuroprotection in a neonatal model of hypoxia/ischemia and in a middle cerebral artery occlusion model of transient focal ischemia. The neuroprotective potential of Na(+)/K(+)-ATPase is of particular interest because of its known "druggability"; indeed, Food and Drug Administration-approved, small-molecule compounds such as digitoxin and digoxin have been in clinical usage for congestive heart failure and arrhythmias for several decades. Thus, an existing cardiac glycoside or closely related compound could provide an accelerated path toward clinical trial testing for ischemic stroke. Our findings underscore the important role that hypothesis-neutral, high-content, tissue-based screens can play in the identification of new candidate drugs and drug targets for the treatment of diseases for which validated therapeutic pathways are not currently available.