State-of-the-Art Techniques in Treating Peripheral Nerve Injury.

BACKGROUND: Peripheral nerve injuries remain a major clinical concern, as they often lead to chronic disability and significant health care expenditures. Despite advancements in microsurgical techniques to enhance nerve repair, biological approaches are needed to augment nerve regeneration and improve functional outcomes after injury. METHODS: Presented herein is a review of the current literature on state-of-the-art techniques to enhance functional recovery for patients with nerve injury. Four categories are considered: (1) electroceuticals, (2) nerve guidance conduits, (3) fat grafting, and (4) optogenetics. Significant study results are highlighted, focusing on histologic and functional outcome measures. RESULTS: This review documents the current state of the literature. Advancements in neuronal stimulation, tissue engineering, and cell-based therapies demonstrate promise with regard to augmenting nerve regeneration and appropriate rehabilitation. CONCLUSIONS: The future of treating peripheral nerve injury will include multimodality use of electroconductive conduits, fat grafting, neuronal stimulation, and optogenetics. Further clinical investigation is needed to confirm the efficacy of these technologies on peripheral nerve recovery in humans, and how best to implement this treatment for a diverse population of nerve-injured patients.

Treatment of Keloids With Excision and Adjuvant Radiation: A Single Center Experience and Review of the Literature.

BACKGROUND: Management of keloids has remained a conundrum, because an optimum treatment regimen has yet to be elucidated. Currently, treatment varies widely between more conservative measures, such as steroid injections, topical medications, and silicone sheeting, to more aggressive options, such as surgery and postoperative radiation. The latter combination has been touted to have superior results, with the lowest rates of pathologic scar recurrence. METHODS: We performed a retrospective review to critically evaluate the effectiveness of surgical excision and radiation treatment in patients with keloids. Surgical resection of surgeon-selected keloids, combined with state-of-the-art postoperative cutaneous radiation therapy, was used at a major tertiary referral center. For patients with poor follow-up, phone calls were made to determine recurrence. In addition, we present a review of the current literature to provide a comprehensive synopsis of current keloid treatment. RESULTS: A total of 69 patients' records were reviewed. There were a total of 84 keloids upon pathology review. The overall recurrence rate for all keloids was 27%, and in those followed greater than 1 year, recurrence for keloids was 74%. About half the patients with more than 1 year of follow-up experienced recurrence more than 1 year after treatment. CONCLUSIONS: At this time, the evidence supporting surgery and radiation for the treatment of keloids remains equivocal, and randomized controlled studies are needed to determine the efficacy of this treatment protocol. Most importantly, our data reinforce the need for long-term follow-up in this patient population.

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy.

UNLABELLED: Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. IMPORTANCE: The emergence and spread of multidrug-resistant M. tuberculosis are a major threat to global public health. Linezolid is an oxazolidinone that is licensed for human use and has demonstrated potent activity against multidrug-resistant M. tuberculosis. However, long-term use of linezolid has shown to be toxic in patients, often resulting in thrombocytopenia. We examined therapeutic linezolid regimens in an in vitro model to characterize the exposure-toxicity relationship. The antibacterial activity against M. tuberculosis was also assessed for these regimens, including the amplification or suppression of resistant mutant subpopulations by the chosen regimen. Higher exposures of linezolid resulted in greater antibacterial activity, but with more toxicity and, for some regimens, increased resistant mutant subpopulation amplification, illustrating the trade-off between activity and toxicity. These findings can provide valuable insight for designing optimal dosage regimens for linezolid that are part of the long combination courses used to treat multidrug-resistant M. tuberculosis.

Impact of spores on the comparative efficacies of five antibiotics for treatment of Bacillus anthracis in an in vitro hollow fiber pharmacodynamic model.

Bacillus anthracis, the bacterium that causes anthrax, is an agent of bioterrorism. The most effective antimicrobial therapy for B. anthracis infections is unknown. An in vitro pharmacodynamic model of B. anthracis was used to compare the efficacies of simulated clinically prescribed regimens of moxifloxacin, linezolid, and meropenem with the "gold standards," doxycycline and ciprofloxacin. Treatment outcomes for isogenic spore-forming and non-spore-forming strains of B. anthracis were compared. Against spore-forming B. anthracis, ciprofloxacin, moxifloxacin, linezolid, and meropenem reduced the B. anthracis population by 4 log(10) CFU/ml over 10 days. Doxycycline reduced the population of this B. anthracis strain by 5 log(10) CFU/ml (analysis of variance [ANOVA] P = 0.01 versus other drugs). Against an isogenic non-spore-forming strain, meropenem killed the vegetative B. anthracis the fastest, followed by moxifloxacin and ciprofloxacin and then doxycycline. Linezolid offered the lowest bacterial kill rate. Heat shock studies using the spore-producing B. anthracis strain showed that with moxifloxacin, ciprofloxacin, and meropenem therapies the total population was mostly spores, while the population was primarily vegetative bacteria with linezolid and doxycycline therapies. Spores have a profound impact on the rate and extent of killing of B. anthracis. Against spore-forming B. anthracis, the five antibiotics killed the total (spore and vegetative) bacterial population at similar rates (within 1 log(10) CFU/ml of each other). However, bactericidal antibiotics killed vegetative B. anthracis faster than bacteriostatic drugs. Since only vegetative-phase B. anthracis produces the toxins that may kill the infected host, the rate and mechanism of killing of an antibiotic may determine its overall in vivo efficacy. Further studies are needed to examine this important observation.

The combination of rifampin plus moxifloxacin is synergistic for suppression of resistance but antagonistic for cell kill of Mycobacterium tuberculosis as determined in a hollow-fiber infection model.

Moxifloxacin is under development for expanded use against Mycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber infection model, in which organisms are exposed to clinically relevant drug concentration-time profiles and the impact on bacterial cell kill and resistant subpopulation amplification is determined. In log phase, resistance emergence was observed in all monotherapy regimens and in no combination therapy regimen. No difference was seen in time to a 3-log reduction in the bacterial burden; there was a significant difference in time to resistance emergence (P = 0.0006). In the NRP experiment, no resistance emergence was seen. There was a significant difference between the monotherapy and combination therapy regimens in time to a 3-log reduction in the bacterial burden (P = 0.042). The combination is efficacious for suppressing resistant organisms but is antagonistic for cell kill.

Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition).

The actual incidence of neurologic dysfunction resulting from hemorrhagic complications associated with neuraxial blockade is unknown. Although the incidence cited in the literature is estimated to be less than 1 in 150,000 epidural and less than 1 in 220,000 spinal anesthetics, recent epidemiologic surveys suggest that the frequency is increasing and may be as high as 1 in 3000 in some patient populations.Overall, the risk of clinically significant bleeding increase with age,associated abnormalities of the spinal cord or vertebral column, the presence of an underlying coagulopathy, difficulty during needle placement,and an indwelling neuraxial catheter during sustained anticoagulation( particularly with standard heparin or low-molecular weight heparin). The need for prompt diagnosis and intervention to optimize neurologic outcome is also consistently reported. In response to these patient safety issues, the American Society of Regional Anesthesia and Pain Medicine (ASRA) convened its Third Consensus Conference on Regional Anesthesia and Anticoagulation. Practice guidelines or recommendations summarize evidence-based reviews. However, the rarity of spinal hematoma defies a prospective randomized study, and there is no current laboratory model. As a result,the ASRA consensus statements represent the collective experience of recognized experts in the field of neuraxial anesthesia and anticoagulation. These are based on case reports, clinical series, pharmacology,hematology, and risk factors for surgical bleeding. An understanding of the complexity of this issue is essential to patient management.

Neurotization improves contractile forces of tissue-engineered skeletal muscle.

Engineered functional skeletal muscle would be beneficial in reconstructive surgery. Our previous work successfully generated 3-dimensional vascularized skeletal muscle in vivo. Because neural signals direct muscle maturation, we hypothesized that neurotization of these constructs would increase their contractile force. Additionally, should neuromuscular junctions (NMJs) develop, indirect stimulation (via the nerve) would be possible, allowing for directed control. Rat myoblasts were cultured, suspended in fibrin gel, and implanted within silicone chambers around the femoral vessels and transected femoral nerve of syngeneic rats for 4 weeks. Neurotized constructs generated contractile forces 5 times as high as the non-neurotized controls. Indirect stimulation via the nerve elicited contractions of neurotized constructs. Curare administration ceased contraction in these constructs, providing physiologic evidence of NMJ formation. Histology demonstrated intact muscle fibers, and immunostaining positively identified NMJs. These results indicate that neurotization of engineered skeletal muscle significantly increases force generation and causes NMJs to develop, allowing indirect muscle stimulation.

Cardiovascular effects of ephedra alkaloids: a comprehensive review.

The Ephedra alkaloids have received much press lately secondary to reported adverse events in those using whole extracts as "dietary supplements" for weight loss or athletic performance enhancement. These reports are troubling given the increasing use of these supplements by the general public. We reviewed the available literature as well as online material on these compounds, including information on their pharmacology, regulation, effects on weight loss and athletic performance, and adverse events. Extracts of Ephedra shrubs contain highly active alpha- and beta-adrenergic agonists that have profound effects on the heart and vasculature. Evidence for their effectiveness is limited. Adverse cardiovascular and cerebrovascular effects, including stroke, myocardial infarction, and sudden death, temporally related to their use are well described. The recent Food and Drug Administration ban on these compounds is not broad enough. Ephedra supplements contain a highly bioactive class of compounds that pose a significant risk to the public under the current regulatory framework. More stringent oversight by regulatory authorities is required to minimize the incidence of adverse events.

Vitamin B12 deficiency.

Vitamin B12 (cobalamin) deficiency is a common cause of macrocytic anemia and has been implicated in a spectrum of neuropsychiatric disorders. The role of B12 deficiency in hyperhomocysteinemia and the promotion of atherosclerosis is only now being explored. Diagnosis of vitamin B12 deficiency is typically based on measurement of serum vitamin B12 levels; however, about 50 percent of patients with subclinical disease have normal B12 levels. A more sensitive method of screening for vitamin B12 deficiency is measurement of serum methylmalonic acid and homocysteine levels, which are increased early in vitamin B12 deficiency. Use of the Schilling test for detection of pernicious anemia has been supplanted for the most part by serologic testing for parietal cell and intrinsic factor antibodies. Contrary to prevailing medical practice, studies show that supplementation with oral vitamin B12 is a safe and effective treatment for the B12 deficiency state. Even when intrinsic factor is not present to aid in the absorption of vitamin B12 (pernicious anemia) or in other diseases that affect the usual absorption sites in the terminal ileum, oral therapy remains effective.