Paul S. Cederna

Prospective analysis of psychosocial outcomes in breast reconstruction: one-year postoperative results from the Michigan Breast Reconstruction Outcome Study.

In the past decade, changing attitudes toward breast reconstruction among both patients and providers have led a growing number of women to seek breast reconstruction after mastectomy. Although investigators have documented the psychological, social, emotional, and functional benefits of breast reconstruction, little research has evaluated the effects of procedure choice on these outcomes. The current study prospectively evaluated and compared psychosocial outcomes for three common options for mastectomy reconstruction: tissue expander/implant, pedicle TRAM, and free TRAM techniques. In a prospective cohort design, patients undergoing postmastectomy reconstruction for the first time with expander/implant, pedicle TRAM, or free TRAM procedures were recruited from 12 centers and 23 plastic surgeons in the United States and Canada. Before reconstruction and at 1 year after reconstruction, patients were evaluated by a battery of questionnaires consisting of both generic and condition-specific surveys. Outcomes assessed included emotional well-being, vitality, general mental health, social functioning, functional well-being, social well-being, and body image. Baseline (preoperative) scores and the change in scores (the difference between postoperative and preoperative scores) were compared across procedure types using t tests and analysis of covariance. Preoperative and 1-year postoperative surveys were obtained from 273 patients. Procedure type was reported in 250 patients, of whom 56 received implant reconstructions, 128 pedicle TRAM flaps, and 66 free TRAM flaps. A total of 161 immediate and 89 delayed reconstructions were performed. Among women receiving immediate reconstruction, significant improvements were observed in all psychosocial variables except body image. However, no significant effects of procedure type on these changes over time existed. Similarly, delayed reconstruction patients had significant increases in emotional well-being, vitality, general mental health, functional well-being, and body image. Although the choice of reconstructive technique did not significantly impact most of these outcomes, significant differences existed among procedure types for three psychosocial subscales. Patients undergoing delayed expander/implant reconstructions reported greater improvements in vitality and social well-being relative to women receiving delayed TRAM procedures. By contrast, delayed TRAM patients noted significantly greater gains in body image compared with women choosing delayed expander-implant reconstruction. The authors conclude that both immediate and delayed breast reconstructions provide substantial psychosocial benefits for mastectomy patients. Although the choice of reconstructive procedure does not seem to significantly affect improvements in psychosocial status with immediate reconstruction, our data suggest that procedure type does have a significant effect on gains in vitality and body image for women undergoing delayed reconstruction.

Number of contractions to maintain mass and force of a denervated rat muscle

Within 5 weeks, denervated extensor digitorum longus (EDL) muscles of rats lose 66% of mass, 91% of force, and 76% of fiber cross‐sectional area (CSA). We previously determined the parameters of electrical stimulation for denervated rat EDL muscles to generate tetanic contractions sufficient to maintain mass and force close to control values. Using these parameters, we tested the hypothesis that a range exists for number of contractions per day, below and above which values for mass, maximum force, and fiber CSA are lower than values for innervated control muscles. For 5 weeks, denervated EDL muscles were stimulated to generate between 25 and 5000 contractions daily with contractions separated by constant intervals of rest, repeated 24 h per day. Force was not maintained with fewer than 200 or more than 800 contractions daily, whereas mass and fiber CSA were not maintained with fewer than 50 contractions daily. Protocols of stimulation that maintain muscle mass and force during prolonged periods of denervation may minimize problems clinically associated with denervation atrophy. Muscle Nerve 30: 77–86, 2004

Aging increases the susceptibility of skeletal muscle derived satellite cells to apoptosis.

The mechanisms causing the impaired regenerative response to injury observed in skeletal muscle of old animals are unknown. Satellite cells, stem cell descendants within adult skeletal muscle, are the primary source of regenerating muscle fibers. Apoptosis may be a mechanism responsible for the depletion of satellite cells in old animals. This work tested the hypothesis that aging increases the susceptibility of satellite cells to apoptosis. Satellite cells were cultured from the extensor digitorum longus muscles of young (3-month-old), adult (9-month-old), and old (31-month-old) Brown Norway rats. Satellite cells were treated for 24h with the pro-apoptotic agents TNF-alpha (20 ng/mL) and Actinomycin D (250 ng/mL). Immunostaining for activated caspases and terminal deoxynucleotydil transferase-mediated dutp nick-end labeling (TUNEL) was performed to identify apoptotic satellite cells. Quantity of the anti-apoptotic protein bcl-2 was determined by Western blot analysis. Satellite cells from old animals demonstrated significantly higher percentages of cells with activated caspases and TUNEL-positive cells, and significantly lower amounts of bcl-2 compared to young and adult animals. These data support the hypothesis that aging increases satellite cell susceptibility to apoptosis. In old muscle, apoptosis may play a causative role in the depletion of satellite cells, impairing the regenerative response to injury.

Identifying patients at high risk for venous thromboembolism requiring treatment after outpatient surgery.

Objective:To identify independent predictors of 30-day venous thromboembolism (VTE) events requiring treatment after outpatient surgery. Background:An increasing proportion of surgical procedures are performed in the outpatient setting. The incidence of VTE requiring treatment after outpatient surgery is unknown. Methods:Prospective observational cohort study using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2005 to 2009. Adult patients who had outpatient surgery or surgery with subsequent 23-hour observation were included. The main outcome measure was 30-day VTE requiring treatment. Patients were randomly assigned to derivation (N = 173,501) or validation (N = 85,730) cohorts. Logistic regression examined independent risk factors for 30-day VTE. A weighted risk index was created and applied to the validation cohort. Stratified analyses examined 30-day VTE by risk level. Results:Thirty-day incidence of VTE for the overall cohort was 0.15%. Independent risk factors included current pregnancy (adjusted odds ratio [OR] = 7.80, P = 0.044), active cancer (OR = 3.66, P = 0.005), age 41 to 59 years (OR = 1.72, P = 0.008), age 60 years or more (OR = 2.48, P < 0.001), body mass index 40 kg/m2 or higher (OR = 1.81, P = 0.015), operative time 120 minutes or more (OR = 1.69, P = 0.027), arthroscopic surgery (OR = 5.16, P < 0.001), saphenofemoral junction surgery (OR = 13.20, P < 0.001), and venous surgery not involving the great saphenous vein (OR = 15.61, P < 0.001). The weighted risk index identified a 20-fold variation in 30-day VTE between low (0.06%) and highest risk (1.18%) patients. Conclusions:Thirty-day VTE risk after outpatient surgery can be quantified using a weighted risk index. The risk index identifies a high-risk subgroup of patients with 30-day VTE rates of 1.18%.

Effects of high- and low-velocity resistance training on the contractile properties of skeletal muscle fibers from young and older humans

A two-arm, prospective, randomized, controlled trial study was conducted to investigate the effects of movement velocity during progressive resistance training (PRT) on the size and contractile properties of individual fibers from human vastus lateralis muscles. The effects of age and sex were examined by a design that included 63 subjects organized into four groups: young (20-30 yr) men and women, and older (65-80 yr) men and women. In each group, one-half of the subjects underwent a traditional PRT protocol that involved shortening contractions at low velocities against high loads, while the other half performed a modified PRT protocol that involved contractions at 3.5 times higher velocity against reduced loads. Muscles were sampled by needle biopsy before and after the 14-wk PRT program, and functional tests were performed on permeabilized individual fiber segments isolated from the biopsies. We tested the hypothesis that, compared with low-velocity PRT, high-velocity PRT results in a greater increase in the cross-sectional area, force, and power of type 2 fibers. Both types of PRT increased the cross-sectional area, force, and power of type 2 fibers by 8-12%, independent of the sex or age of the subject. Contrary to our hypothesis, the velocity at which the PRT was performed did not affect the fiber-level outcomes substantially. We conclude that, compared with low-velocity PRT, resistance training performed at velocities up to 3.5 times higher against reduced loads is equally effective for eliciting an adaptive response in type 2 fibers from human skeletal muscle.

Hybrid Conducting Polymer–Hydrogel Conduits for Axonal Growth and Neural Tissue Engineering

Successfully and efficiently bridging peripheral nerve gaps without the use of autografts is a substantial clinical advance for peripheral nerve reconstructions. Novel templating methods for the fabrication of conductive hydrogel guidance channels for axonal regeneration are designed and developed. PEDOT is electrodeposited inside the lumen to create fully coated-PEDOT agarose conduits and partially coated-PEDOT agarose conduits.

The Current State of Fat Grafting: A Review of Harvesting, Processing, and Injection Techniques.

Background: Interest in and acceptance of autologous fat grafting for use in contour abnormalities, breast reconstruction, and cosmetic procedures have increased. However, there are many procedural variations that alter the effectiveness of the procedure and may account for the unpredictable resorption rates observed. Methods: The authors highlighted studies investigating the effects of harvesting procedures, processing techniques, and reinjection methods on the survival of fat grafts. This review focused on the impact different techniques have on outcomes observed in the following: in vitro analyses, in vivo animal experiments, and human studies. Results: This systemic review revealed the current state of the literature. There was no significant difference in the outcomes of grafted fat obtained from different donor sites, different donor-site preparations, harvest technique, fat harvesting cannula size, or centrifugation speed, when tumescent solution was used. Gauze rolling was found to enhance the volume of grafted fat, and no significant difference in retention was observed following centrifugation, filtration, or sedimentation in animal experiments. In contrast, clinical studies in patients found more favorable outcomes with fat processed by centrifugation compared with sedimentation. In addition, higher retention was observed with slower reinjection speed and when introduced into less mobile areas. Conclusions: There has been a substantial increase in research interest to identify methodologies for optimizing fat graft survival. Despite some differences in harvest and implantation technique in the laboratory, these findings have not translated into a universal protocol for fat grafting. Therefore, additional human studies are necessary to aid in the development of a universal protocol for clinical practice.

Treatment of heterotopic ossification through remote ATP hydrolysis.

Heterotopic ossification induced by injuries and burns is mediated by signaling through the SMAD pathway and can be targeted with topical apyrase. No Bones About It Heterotopic ossification is a painful side effect that can complicate burns, trauma, and some types of surgery. In patients with this condition, small amounts of bone form in abnormal locations throughout the body, causing pain and complicating recovery. Now, Peterson et al. have developed a mouse model of heterotopic ossification, investigated the mechanism of this disorder, and then used their animal model to demonstrate a potential therapeutic intervention: topical application of apyrase. Although apyrase was only applied to the injury site, it decreased the abnormal formation of bone throughout the body. Other therapies, such as celecoxib and a drug called LDN-193189, were effective as well, suggesting the possibility of multiple therapeutic options for preventing heterotopic ossification in injured patients. Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein–mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3′,5′-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury–exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation.

Early detection of burn induced heterotopic ossification using transcutaneous Raman spectroscopy

INTRODUCTION Heterotopic ossification (HO), or the abnormal formation of bone in soft tissue, occurs in over 60% of major burn injuries and blast traumas. A significant need exists to improve the current diagnostic modalities for HO which are inadequate to diagnose and intervene on HO at early time-points. Raman spectroscopy has been used in previous studies to report on changes in bone composition during bone development but has not yet been applied to burn induced HO. In this study, we validate transcutaneous, in-vivo Raman spectroscopy as a methodology for early diagnosis of HO in mice following a burn injury. METHODS An Achilles tenotomy model was used to study HO formation. Following tenotomy, mice were divided into burn and sham groups with exposure of 30% surface area on the dorsum to 60° water or 30° water for 18s respectively. In-vivo, transcutaneous Raman spectroscopy was performed at early time points (5 days, 2 and 3 weeks) and a late time point (3 months) on both the tenotomized and non-injured leg. These same samples were then dissected down to the bone and ex-vivo Raman measurements were performed on the excised tissue. Bone formation was verified with Micro CT and histology at corresponding time-points. RESULTS Our Raman probe allowed non-invasive, transcutaneous evaluation of heterotopic bone formation. Raman data showed significantly increased bone mineral signaling in the tenotomy compared to control leg at 5 days post injury, with the difference increasing over time whereas Micro CT did not demonstrate heterotopic bone until three weeks. Ex-vivo Raman measurements showed significant differences in the amount of HO in the burn compared to sham groups and also showed differences in the spectra of new, ectopic bone compared to pre-existing cortical bone. CONCLUSIONS Burn injury increases the likelihood of developing HO when combined with traumatic injury. In our in-vivo mouse model, Raman spectroscopy allowed for detection of HO formation as early as 5 days post injury. Changes in bone mineral and matrix composition of the new bone were also evidenced in the Raman spectra which could facilitate early identification of HO and allow more timely therapy decisions for HO patients.

Mechanical function of muscle reinnervated by end-to-side neurorrhaphy.

End-to-side neurorrhaphy is a surgical technique for peripheral nerve reconstruction when end-to-end neurorrhaphy is not an option. To define the effectiveness of end-to-side neurorrhaphy as a method of nerve repair, the authors tested the null hypothesis: there is no difference in the mechanical function of skeletal muscle denervated and reinnervated by end-to-side versus end-to-end neurorrhaphy. Adult Lewis rats underwent either transection and end-to-end epineurial repair of the left peroneal nerve (n = 9) or end-to-side repair of the distal stump of the peroneal nerve to the side of the tibial nerve (n = 8). After a 6-month recovery period, isometric force (Fo) was measured, and specific force (sFo) was calculated for the extensor digitorum longus muscle of each animal. Immunohistochemical staining for neural cell adhesion molecule (NCAM) was performed to identify populations of denervated muscle fibers. The mean extensor digitorum longus muscle mass in the end-to-end group (195 +/- 32 g) was significantly greater than that of the end-to-side group (146 +/- 55 g) (p < 0.05). A significantly greater percentage of denervated fibers was identified in the extensor digitorum longus muscles of animals in the end-to-side group (9.4 +/- 3.2 percent) than in those in the end-to-end group (3.8 +/- 1.0 percent) (p < 0.05). Despite a lower muscle mass and a higher percentage of denervated fibers, neither Fo nor sFo was significantly different in the two groups. These data support the null hypothesis that, under appropriate circumstances, there is no difference in the recovery of whole muscle force and specific force production in muscles reinnervated by end-to-side versus end-to-end neurorrhaphy.