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Competing Interests: The authors declare no funding or conflicts of interest.

Background: Regeneration of functional bone substrate remains a priority in reconstructive surgery especially for patients suffering from complex skeletal defects. Efforts to develop implantable osteoinductive constructs and novel osteoconductive materials remain at the forefront of industry forces and product line development. Despite advancement in clinical practice and bone biology, cancellous autograft remains the gold standard for procedures requiring osteogenic mechanisms of healing. This study investigates the utility of muscle-derived stem cells as a cellular therapy for definitive bone regeneration through a form of neo-osteogenesis., Methods: Adipose-derived stem cell, bone marrow-derived mesenchymal stem cell, and muscle-derived stem cell populations were isolated separately from C57BL/6 murine tissues and supplemented with collagen scaffolding with or without bone morphogenetic protein-2 to compare relative osteogenic potency and ultrastructure organization in both two- and three-dimensional systems. Parallel populations were bound to a deployable collagen implant within a syngeneic murine cranial defect model., Results: Although all populations provided and maintained mesenchymal stem cell multilineage capacity, adipose-derived stem cell- and bone marrow-derived mesenchymal stem cell-enriched constructs were capable of forming small bone aggregates. Defects receiving muscle-derived stem cells self-assembled a form of organized corticocancellous structures within two- and three-dimensional in vitro systems and within the in vivo model. Muscle-derived stem cells also augmented healing, implant angiogenesis, and diploic space formation., Conclusion: Muscle-derived stem cell-enriched implants appear to provide an autologous response to current industry-derived products and an attractive alternative to mesenchymal stem cells for the regeneration of corticocancellous bone and a vascularized diploic space.

Background: Recent literature has shown that full-thickness wounds, devoid of the stem cell niche, can subsequently be reconstructed with functional skin elements following migration of the LGR6 epithelial stem cell into the wound bed. In this study, the authors use a variety of LGR6 epithelial stem cell-seeded scaffolds to determine therapeutic utility and regenerative potential in the immediate reconstruction of full-thickness wounds., Methods: Isolated LGR6 epithelial stem cells were seeded onto a spectrum of acellular matrices and monitored in both in vitro and in vivo settings to determine their relative capacity to regenerate tissues and heal wounds., Results: Wound beds containing LGR6 stem cell-seeded scaffolds showed significantly augmented rates of healing, epithelialization, and hair growth compared with controls. Gene and proteomic expression studies indicate that LGR6 stem cell-seeded constructs up-regulate WNT, epidermal growth factor, and angiogenesis pathways. Finally, the addition of stromal vascular fraction to LGR6 stem cell-seeded constructs induces polarized tissue formation, nascent hair growth, and angiogenesis within wounds., Conclusions: LGR6 stem cells are able to undergo proliferation, differentiation, and migration following seeding onto a variety of collagen-based scaffolding. In addition, deployment of these constructs induces epithelialization, hair growth, and angiogenesis within wound beds. The addition of stromal vascular fraction to LGR6 stem cell-containing scaffolds initiated an early form of tissue polarization, providing for the first time a clinically applicable stem cell-based construct that is capable of the repair of full-thickness wounds and hair regeneration., Clinical Question/level of Evidence: Therapeutic, V.

Background: Military pediatric plastic surgery humanitarian missions in the Western Hemisphere have been initiated and developed since the early 1990 s using the Medical Readiness Education and Training Exercise (MEDRETE) concept. Despite its initial training mission status, the MEDRETE has developed into the most common and advanced low level medical mission platform currently in use. The objective of this study is to report cleft- and craniofacial-related patient outcomes after initiation and evolution of a standardized treatment protocol highlighting lessons learned which apply to civilian plastic surgery missions., Methods: A review of the MEDRETE database for pediatric plastic surgery/cleft and craniofacial missions to the Dominican Republic from 2005 to 2009 was performed. A multidisciplinary team including a craniofacial surgeon evaluated all patients with a cleft/craniofacial and/or pediatric plastic condition. A standardized mission time line included predeployment site survey and predeployment checklist, operational brief, and postdeployment after action report. Deployment data collection, remote patient follow-up, and coordination with larger land/amphibious military operations was used to increase patient follow-up data. Data collected included sex, age, diagnosis, date and type of procedure, surgical outcomes including speech scores, surgical morbidity, and mortality., Results: Five hundred ninety-four patients with cleft/craniofacial abnormalities were screened by a multidisciplinary team including craniofacial surgeons over 4 years. Two hundred twenty-three patients underwent 330 surgical procedures (cleft lip, 53; cleft palate, 73; revision cleft lip/nose, 73; rhinoplasty, 15; speech surgery, 24; orthognathic/distraction, 21; general pediatric plastic surgery, 58; fistula repair, 12). Average follow-up was 30 months (range, 1-60). The complication rate was 6% (n = 13) (palate fistula, lip revision, dental/alveolar loss, revision speech surgery rate). The average pre-surgical (Pittsburgh Weighted Speech Score) speech score was 12 (range, 6-24). The average postsurgical speech score was 6 (range, 0-21). Average hospital stay was 3 days for cleft surgery. There were no major complications or mortality, 1 reoperation for bleeding or infection, and 12 patients required secondary operations for palatal fistula, unsatisfactory aesthetic result, malocclusion, or velopharygeal dysfunction., Conclusions: Military pediatric plastic surgery humanitarian missions can be executed with similar home institution results after the initiation and evolution of a standardized approach to humanitarian missions. The incorporation of a dedicated logistics support unit, a dedicated operational specialist (senior noncommissioned officer), a speech language pathologist, remote internet follow up, an liaison officer (host nation liaison physician participation), host nation surgical resident participation, and support from the embassy, Military Advisory Attachment Group, and United States Aid and International Development facilitated patient accurate patient evaluation and posttreatment follow-up. Movement of the mission site from a remote more austere environment to a centralized better equipped facility with host nation support to transport patients to the site facilitated improved patient safety and outcomes despite increasing the complexity of surgery performed.

Background: The benefits of routine perioperative steroid use to decrease facial edema, ecchymosis, pain, and reduced length of hospitalization have been reported for many procedures. The role of perioperative steroids after open craniosynostosis surgery remains understudied. The purpose of our study was to assess the safety and efficacy of perioperative steroid administration in open repair of craniosynostosis based on current published clinical evidence., Methods: A systematic review of PubMed, EMBASE, ClinicalTrials.gov, and the Cochrane library databases using inclusion and exclusion criteria was performed for articles that studied the efficacy of perioperative steroid use in craniosynostosis patients receiving open cranial repair surgery., Results: Our review yielded 149 unique citations. One hundred thirty-nine titles were excluded based on predefined criteria. Ten abstracts and 4 articles (n = 14) qualified for full-text screening. Two additional relevant articles were identified using references. Three observational studies were eligible for data abstraction. A Cohen κ coefficient score of 0.88 demonstrated high interrater agreement throughout the screening process. Clinical benefits in this specific population observed were improved control of postoperative edema, earlier time to eye opening, and reduced length of hospital stay. The timing, method, and technique of steroid administration varied between studies., Conclusions: The reviewed literature supports a clinical benefit following administration of perioperative steroids for open repair surgery of craniosynostosis. However, the current level of evidence on safety and efficacy remains limited in rigor and volume. Further randomized trials are necessary prior to recommending routine steroid use in our study population., Clinical Question/level of Evidence: therapeutic, level III.

Background: A role for natural killer (NK) cells in cardiac allograft vasculopathy (CAV) was suggested by our earlier observation that CAV arises even in the absence of detectable antidonor T-cell or B-cell reactivity in parental to F1 mouse heart grafts. However, prevention of CAV in this setting required the depletion of both NK and CD4 T cells., Methods: To clarify the interrelationship between NK and CD4 cells, we analyzed early events and selective depletion of T regulatory cells (Tregs). Hearts from C57BL/6 (B6) donors were transplanted heterotopically into BALB/c x C57BL/6 (CB6F1) recipients and NK cells, CD4 T cells, and Tregs were depleted with anti-NK1.1 (PK136), anti-CD4 (GK1.5), or anti-CD25 (PC61), respectively., Results: In contrast to prior studies in which the prevention of CAV at 8 weeks required the codepletion of NK and CD4 T cells, NK cells depletion alone eliminated CAV at 3 weeks. Furthermore, depletion of CD25 cells accelerated the onset and maturation of CAV at both 2 and 3 weeks (P<0.02 and P<0.001, respectively). However, anti-NK1.1 treatment prevented lesions in CD25-depleted recipients. Finally, CD4 T cell depletion alone did not prevent or accelerate development of CAV but inhibited the effect of CD25 T cell depletion., Conclusion: These data suggest that NK cells can play an important role in the early pathogenesis of CAV but that their ability to mediate early CAV can be modulated by Tregs.

Background and Purpose: Data on long-term outcome after intravenous tissue-type plasminogen activator (tPA) in ischemic stroke are limited. We examined the risk of long-term mortality, recurrent ischemic stroke, and major bleeding, including intracranial and gastrointestinal bleeding, in intravenous tPA-treated patients when compared with intravenous tPA eligible but nontreated patients with ischemic stroke., Methods: We conducted a register-based nationwide propensity score-matched follow-up study among patients with ischemic stroke in Denmark (2004-2011). Cox regression analysis was used to compute adjusted hazard ratios for all outcomes., Results: Among 4292 ischemic strokes (2146 intravenous tPA-treated and 2146 propensity score-matched nonintravenous tPA-treated patients), with a follow-up for a median of 1.4 years, treatment with intravenous tPA was associated with a lower risk of long-term mortality (adjusted hazard ratio, 0.66; 95% confidence interval, 0.49-0.88). The long-term risk of recurrent ischemic stroke (adjusted hazard ratio, 1.05; 95% confidence interval, 0.68-1.64) and major bleeding (adjusted hazard ratio, 0.59; 95% confidence interval, 0.24-1.47) did not differ significantly between the intravenous tPA-treated and nontreated patients., Conclusions: Treatment with intravenous tPA in patients with ischemic stroke was associated with improved long-term survival., (© 2014 American Heart Association, Inc.)

Background: Normal myocardial perfusion imaging (MPI) indicates a low risk for cardiac death and new ischaemic events. However, the impact of normal MPI combined with a high coronary artery calcium score (CACS) is not clear. The aims of this study were to evaluate the risk of severely elevated CACS and to identify other risk factors in patients with normal MPI., Methods: The study included 318 consecutive patients who underwent a Tc-sestamibi MPI protocol along with either the ergometer bicycle test or the pharmacological stress test. Acquisition of CACS was performed immediately before MPI. Patient history and events were retrieved from hospital files. The median follow-up time was 989 days. End points were myocardial infarction, need for revascularization of coronary arteries and/or death., Results: CACS was less than 400 in 256 patients (81%) and at least 400 in 62 patients with normal MPI. Cox regression analysis showed that CACS was a predictor of cardiovascular events or death [relative risk (RR) 3.4, P=0.008]. Inability to perform the ergometer stress test (RR 5.6, P=0.02) was also included in the model. CACS (RR 4.2, P=0.01) and diabetes (RR 3.7, P=0.03) were the strongest predictors of cardiac events without death., Conclusion: CACS is the single most important predictor of cardiac events and/or death in patients with normal MPI. If possible, CACS could be included when performing MPI to identify patients with an increased risk for cardiac events and/or death.

Background: Long-term exposure to outdoor air pollution has typically been estimated on the aggregate level, and more individual measures of exposure are needed. We investigated the associations with lung function of residential outdoor air pollution in early life, total lifetime, and days before lung function test., Methods: In 2001-2002, spirometry was performed in 2307 9- and 10-year-old children who had lived in Oslo, Norway, since birth. Outdoor air pollution exposure for each child was assessed by the EPISODE dispersion model, calculating hourly concentrations of nitrogen dioxide (NO2), particulate matter (PM) with aerodynamic diameter less than 10 microm (PM10) and 2.5 microm (PM2.5). We applied linear regression analysis stratified by sex., Results: Early and lifetime exposures to outdoor air pollution were associated with reduced peak expiratory flow and reduced forced expiratory flow at 25% and 50% of forced vital capacity, especially in girls. One interquartile increase of lifetime exposure to NO2, PM10, and PM2.5 was associated with change in adjusted peak respiratory flow of, respectively, -79 mL/s (95% confidence interval = -128 to -31), -66 mL/s (-110 to -23), and -58 mL/s (-94 to -21). We also found short-term effects of NO2 that became stronger with increasing time lags, but no short-term effects of PM. When we included short- and long-term NO2 exposures simultaneously, only the long-term effect remained. We found no effect on forced volumes. Adjusting for a contextual socioeconomic factor diminished the associations., Conclusions: Short- and long-term residential exposures to traffic-related pollutants in Oslo were associated with reduced peak expiratory flow and forced expiratory flow at 25% and 50% in 9- to 10-year-old children, especially in girls, with weaker associations after adjusting for a contextual socioeconomic factor.

Objective: To investigate the cognitive functioning of migraineurs vs nonmigraineurs in a large population-based sample of middle-aged twins where headache diagnoses were established by neurologists., Methods: Twins identified through the population-based Danish Twin Registry participated in face-to-face structured interviews, which included cognitive tests and two previously validated questions screening for migraine. Twins who screened positive for migraine and their co-twins were invited to participate in a telephone-based interview conducted by neurologists, who established headache diagnoses according to the International Headache Society criteria. Cognitive scores on fluency, digit span, delayed word recall, and symbol digit substitution test were compared between migraineurs and nonmigraineurs. Comparisons within monozygotic and dizygotic same sex twin pairs discordant for migraine were also performed., Results: Of the 1,789 twins who were eligible for inclusion in the present study, 1,393 (77.8%) were interviewed. A diagnosis of migraine was established in 536 twins (migraine without aura n = 347; migraine with aura n = 157). Average scores on cognitive tests in twins with migraine or one of the migraine subtypes did not differ from those of nonmigraineurs in any of the tests. Comparisons within twin pairs discordant for migraine produced highly comparable results. Adjustment for possible confounders and stratification by cumulated number of lifetime attacks did not influence the results., Conclusions: A lifetime diagnosis of migraine was not associated with cognitive deficits in middle-aged subjects.

Background: Tricyclic antidepressants (TCA) are often used in the treatment of painful polyneuropathy. Venlafaxine is a serotonin and weak noradrenaline reuptake inhibitor antidepressant with a different profile of other pharmacologic actions from those of TCA., Objective: To test if venlafaxine would relieve painful polyneuropathy and compare its possible efficacy with that of the TCA imipramine., Methods: The study design was randomized, double blind, and placebo controlled, with a three-way crossover. Forty patients were assigned to one of the treatment sequences, and 29 completed all three study periods. The daily doses were venlafaxine 225 mg and imipramine 150 mg. During the three treatment periods, each of 4 weeks' duration, patients rated pain paroxysms, constant pain, and touch- and pressure-evoked pain by use of 0- to 10-point numeric rating scales., Results: The sum of the individual pain scores during treatment week 4 was lower on venlafaxine (80% of baseline score; p = 0.006) and imipramine (77%; p = 0.001) than on placebo (100%) and did not show any statistical difference between venlafaxine and imipramine (p = 0.44). The individual pain scores for pain paroxysms, constant pain, and pressure-evoked pain showed a similar pattern, whereas touch-evoked pain was uncommon and was not altered by any of the drugs. Numbers needed to treat to obtain one patient with moderate or better pain relief were 5.2 for venlafaxine and 2.7 for imipramine., Conclusion: Venlafaxine relieves pain in polyneuropathy and may be as effective as imipramine.

Objectives: The aim of this study was to determine the diagnostic yield and to describe the spectrum of diagnosis encountered by evaluation of patients with symptoms suggestive of chronic polyneuropathy., Methods: We prospectively evaluated 198 patients referred to a department of neurology with symptoms suggestive of polyneuropathy. The evaluation included nerve conduction studies with near-nerve technique, quantitative examination of temperature sensation, blood tests, chest x-rays, and skin biopsies as well as diagnostic tests for differential diagnoses., Results: Polyneuropathy was found in 147 patients, alternative diagnoses in 25, and 26 remained undiagnosed. The etiology of polyneuropathy could not be identified in 25% of the patients with polyneuropathy. In the remaining 75%, the cause of neuropathy was diabetes and/or alcohol abuse (41%), monoclonal gammopathy of undetermined significance (5%), drugs (5%), connective tissue disease (3%), and a number of less frequent conditions. A previously undiagnosed condition was found in 30% of the patients with polyneuropathy., Conclusion: Evaluation of patients with symptoms suggestive of polyneuropathy reveals a high fraction of patients with previously undiagnosed conditions both in patients ending up with a polyneuropathy diagnosis and those without this diagnosis.

Tricyclic antidepressants are the mainstay of treatment of painful polyneuropathy but cannot be used in a substantial number of patients. St. John's wort is a herbal antidepressant, which may act via mechanisms similar to the tricyclics. The aim of this study was to test if St. John's wort would relieve painful polyneuropathy. The study design was randomized, double-blind, placebo-controlled and cross-over. Fifty-four patients were assigned to one of the two treatment sequences. The daily dose of St. John's wort was three tablets each containing 900 microg totalhypericin. During the two treatment periods of 5 weeks duration, patients rated constant pain, lancinating pain paroxysms, touch-evoked pain and pain on pressure by use of 0--10 point numeric rating scales. Forty-seven patients -- 18 diabetics and 29 non-diabetics -- completed the study. There was a trend of lower total pain score (sum of the individual pain scores) on St. John's wort than on placebo (median 14 vs. 15, P=0.05). None of the individual pain ratings were significantly changed by St. John's wort as compared to placebo (P=0.09--0.33). Complete, good or moderate pain relief was experienced by nine patients with St. John's wort and two with placebo (P=0.07). In conclusion, St. John's wort has no significant effect on pain in polyneuropathy.

It is generally believed that opioids relieve neuropathic pain less effectively than nociceptive pain and that they have no effect on some of the key characteristics of neuropathic pain such as touch-evoked pain (allodynia). Tramadol is an analgesic drug acting directly on opioid receptors and indirectly on monoaminergic receptor systems. The aim of this trial was to determine whether tramadol relieved painful polyneuropathy and reduced allodynia. The study design was randomised, double-blind, placebo-controlled and cross-over. After baseline observations, 45 patients were assigned to one of the two treatment sequences. The dose of tramadol slow-release tablets was titrated to at least 200 mg/day and at highest 400 mg/day. During the two treatment periods of 4 weeks duration, patients rated pain, paraesthesia and touch-evoked pain by use of 0-10 point numeric rating scales. Mechanical allodynia induced by stimulation with an electronic toothbrush was rated at the end of each treatment period with a similar scale. Thirty-four patients completed the study. Their ratings for pain (median 4 vs. 6, P=0.001), paraesthesia (4 vs. 6, P=0.001) and touch-evoked pain (3 vs. 5, P<0.001) were lower on tramadol than on placebo, as were their ratings of allodynia (0 vs. 4, P=0.012). The number needed to treat to obtain one patient with >/=50% pain relief was 4.3 (95% confidence interval 2.4-20). It is concluded that tramadol appears to relieve both ongoing pain symptoms and the key neuropathic pain feature allodynia in polyneuropathy.