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Introduction: This study evaluated whether Schwann cells (SCs) from different nerve sources transplanted into cold-preserved acellular nerve grafts (CP-ANGs) would improve functional regeneration compared with nerve isografts. Methods: SCs isolated and expanded from motor and sensory branches of rat femoral and sciatic nerves were seeded into 14mm CP-ANGs. Growth factor expression, axonal regenera- tion, and functional recovery were evaluated in a 14-mm rat sci- atic injury model and compared with isografts. Results: At 14 days, motor or sensory-derived SCs increased expression of growth factors in CP-ANGs versus isografts. After 42 days, his- tomorphometric analysis found CP-ANGs with SCs and iso- grafts had similar numbers of regenerating nerve fibers. At 84 days, muscle force generation was similar for CP-ANGs with SCs and isografts. SC source did not affect nerve fiber counts or muscle force generation. Conclusions: SCs transplanted into CP-ANGs increase functional regeneration to isograft levels; however SC nerve source did not have an effect. Muscle Nerve 000:000-000, 2013

Objective Probable migraine is a common, disabling migraine subtype fulfilling all but one of the diagnostic criteria for migraine. This study was conducted to evaluate the efficacy and tolerability of sumatriptan/naproxen sodium for the acute treatment of probable migraine without aura. Methods Patients treated a headache of probable migraine without aura when pain was moderate or severe with sumatriptan/naproxen sodium ( n = 222 intent-to-treat (ITT)) or placebo ( n = 221 ITT/complete case analysis a ) in this randomized, double-blind, parallel-group study. Results Sumatriptan/naproxen sodium was more effective than placebo with respect to the co-primary efficacy endpoints two-hour pain-free response (29% sumatriptan/naproxen sodium vs 11% placebo, p Conclusion Sumatriptan/naproxen sodium is effective in the acute treatment of probable migraine as demonstrated by higher rates of freedom from pain and restoration of function.

Benefits of a direct anterior approach (DAA) versus a posterior-lateral (PA) approach to THA were assessed in a single-surgeon, IRB-approved, prospective, randomized clinical study. Subjects (43 DAA and 44 PA) were evaluated at 6 weeks, and 3, 6 and 12 months. The primary end point was ability to climb stairs normally and walk unlimited at each time point. Secondary end points included assessment by several outcome instruments. DAA subjects performed better during the immediate post-operative period; they had lower VAS pain scores on the first post-operative day, more subjects climbing stairs normally and walking unlimited at 6 weeks, and higher HOOS Symptoms scores at 3 months. There were no significant differences between groups at later time points. Findings confirm previous reports of benefits of DAA versus PA in early post-operative phases.

Bioactive glasses have recently been shown to promote regeneration of soft tissues by positively influencing tissue remodeling during wound healing. We were interested to determine whether bioactive glasses have the potential for use in the treatment of peripheral nerve injury. In these experiments, degradable bioactive borate glass was fabricated into rods and microfibers. To study the compatibility with neurons, embryonic chick dorsal root ganglia (DRG) were cultured with different forms of bioactive borate glass. Cell viability was measured with no media exchange (static condition) or routine media exchange (transient condition). Neurite extension was measured within fibrin scaffolds with embedded glass microfibers or aligned rod sheets. Mixed cultures of neurons, glia, and fibroblasts growing in static conditions with glass rods and microfibers resulted in decreased cell viability. However, the percentage of neurons compared with all cell types increased by the end of the culture protocol compared with culture without glass. Furthermore, bioactive glass and fibrin composite scaffolds promoted neurite extension similar to that of control fibrin scaffolds, suggesting that glass does not have a significant detrimental effect on neuronal health. Aligned glass scaffolds guided neurite extension in an oriented manner. Together these findings suggest that bioactive glass can provide alignment to support directed axon growth.

Outcomes after intrasynovial tendon repair are highly variable. An intense inflammatory cascade followed by a delayed healing response can cause adhesion formation and repair-site failure that severely impair the function of repaired digits. No effective remedies exist to fully address these issues. Cell- and growth factor-based therapies have been shown to modulate inflammation and improve cell proliferation and matrix synthesis and therefore are promising treatment approaches for intrasynovial tendon repair. (1) Can autologous adipose-derived mesenchymal stromal cells (ASCs) and recombinant bone morphogenetic protein-12 (rBMP-12) be effectively delivered to an intrasynovial flexor tendon repair without adverse effects? (2) Do autologous ASCs modulate the inflammatory response after intrasynovial tendon injury and repair? (3) Does the combined application of autologous ASCs and rBMP-12 modulate the proliferative and remodeling responses after intrasynovial tendon injury and repair? Sixteen 1- to 2-year-old female canines were used in this study. Autologous ASC sheets, with and without rBMP-12, were applied to the surface of sutured flexor tendons. Fourteen days after repair, the effects of treatment were determined using quantitative PCR (six per group) for the expression of genes related to macrophage phenotype or inflammation (IL-4, CD163, VEGF, NOS2, IL-1B, and IFNG), cell proliferation (CCND1), and tendon formation (SCX, TNMD, COL1A1 and COL3A1). Proteomics analysis (four per group) was performed to examine changes in tendon protein abundances. CD146 immunostaining and hematoxylin and eosin staining (four per group) were used to detect tendon stem or progenitor cells and to semiquantitatively evaluate cellularity at the tendon repair; analyses were done blinded to group. Gross inspection and cell tracing showed that autologous ASCs and rBMP-12 were delivered to the flexor tendon repair site without the deleterious effects of adhesion and repair-site gap formation. Quantitative assessment of gene and protein expression showed effects of treatment: ASC-sheet treatment modulated the postrepair inflammatory response and facilitated healing by increasing regenerative M2 macrophages (M2 marker CD204, twofold of normal, p = 0.030), inflammatory inhibitor (prostaglandin reductase 1 [PTRG1], 1.6-fold of normal, p = 0.026), and proteins involved in tendon formation (periostin [POSTN], 1.9-fold of normal, p = 0.035). Consistently, semiquantitative and qualitative evaluations of repaired tissue showed that ASC-sheet treatment reduced mononuclear cell infiltration (12% less than nontreated tendons, p = 0.021) and introduced CD146+ stem or progenitor cells to the repair site. The combined administration of ASCs and rBMP-12 further stimulated M2 macrophages by increasing IL-4 (116-fold of normal, p = 0.002) and led to the increase of M2 effector matrix metalloproteinase-12 involved in matrix remodeling (twofold of normal, p = 0.016) and reduction of a negative regulator of angiogenesis and cell migration (StAR-related lipid transfer domain protein13 [STARD13]; 84% of normal, p = 0.000), thus facilitating the proliferative stage of tendon repair. ASCs and BMP-12 accelerated the progression of healing in the proliferative stage of tendon repair. The effects of ASCs and BMP-12 on tendon functional recovery should be evaluated in future studies. The cell sheet approach is an effective, biocompatible, and surgeon-friendly approach for cell and growth factor delivery during tendon repair. Combined application of ASCs and BMP-12 may accelerate intrasynovial tendon healing while suppressing the adverse inflammatory response.

The complex pathology of spinal cord injury (SCI), involving a cascade of secondary events and the formation of inhibitory barriers, hampers regeneration across the lesion site and often results in irreversible loss of motor function. The limited regenerative capacity of endogenous cells after SCI has led to a focus on the development of cell therapies that can confer both neuroprotective and neuroregenerative benefits. Stem cells have emerged as a candidate cell source because of their ability to self-renew and differentiate into a multitude of specialized cell types. While ethical and safety concerns impeded the use of stem cells in the past, advances in isolation and differentiation methods have largely mitigated these issues. A confluence of work in stem cell biology, genetics, and developmental neurobiology has informed the directed differentiation of specific spinal cell types. After transplantation, these stem cell-derived populations can replace lost cells, provide trophic support, remyelinate surviving axons, and form relay circuits that contribute to functional recovery. Further refinement of stem cell differentiation and transplantation methods, including combinatorial strategies that involve biomaterial scaffolds and drug delivery, is critical as stem cell-based treatments enter clinical trials. Biotechnol. Bioeng. 2017;114: 245-259. © 2016 Wiley Periodicals, Inc.

Background The clinical outcomes following intrasynovial flexor tendon repair are highly variable. Excessive inflammation is a principal factor underlying the formation of adhesions at the repair surface and affecting matrix regeneration at the repair center that limit tendon excursion and impair tendon healing. A previous in-vitro study revealed that adipose-derived mesenchymal stromal cells (ASCs) modulate tendon fibroblast response to macrophage-induced inflammation. The goal of the current study was therefore to explore the effectiveness of autologous ASCs on the inflammatory stage of intrasynovial tendon healing in vivo using a clinically relevant animal model. Methods Zone II flexor tendon transections and suture repairs were performed in a canine model. Autologous ASC sheets were delivered to the surface of repaired tendons. Seven days after repair, the effects of ASCs on tendon healing, with a focus on the inflammatory response, were evaluated using gene expression assays, immunostaining, and histological assessments. Results ASCs delivered via the cell sheet infiltrated the host tendon, including the repair surface and the space between the tendon ends, as viewed histologically by tracking GFP-expressing ASCs. Gene expression results demonstrated that ASCs promoted a regenerative/anti-inflammatory M2 macrophage phenotype and regulated tendon matrix remodeling. Specifically, there were significant increases in M2-stimulator (IL-4), marker (CD163 and MRC1), and effector (VEGF) gene expression in ASC-sheet treated tendons compared with nontreated tendons. When examining changes in extracellular matrix expression, tendon injury caused a significant increase in scar-associated COL3A1 expression and reductions in COL2A1 and ACAN expression. The ASC treatment effectively counteracted these changes, returning the expression levels of these genes closer to normal. Immunostaining further confirmed that ASC treatment increased CD163+ M2 cells in the repaired tendons and suppressed cell apoptosis at the repair site. Conclusions This study provides a novel approach for delivering ASCs with outcomes indicating potential for substantial modulation of the inflammatory environment and enhancement of tendon healing after flexor tendon repair.

RGD peptides have been incorporated into several gene delivery vehicles to enhance specific interactions of nonviral vehicles with the cell surface. However, there are contradictory results regarding the effect of linear RGD peptides on specific cell surface binding of polyethylene glycol (PEG)-conjugated gene delivery vehicles. This study sought to understand how coupling RGD peptides to PEG vehicles affects cell binding and internalization using a novel four arm PEG backbone. Coupling multiple RGD peptides to the PEG backbone increased the affinity of the vehicle for the cell surface, and that the PEG backbone did not reduce the affinity of RGD peptides for integrin receptors in both kinetic and equilibrium studies. Kinetic studies suggest that cellular internalization of PEG-based vehicles is not regulated by the RGD peptides on the vehicle, but rather by nonspecific interactions with heparan sulfate proteoglycans either alone or in combination with integrins. These results suggest that while increasing the number of RGD peptides per vehicle increases cell binding, but it does not contribute to increased internalization or transfection efficiency.

Phenotypic differences in Schwann cells (SCs) may help to guide axonal regeneration down motor or sensory specific pathways following peripheral nerve injury. The goal of this study was to identify phenotypic markers for SCs harvested from the cutaneous (sensory) and quadriceps (motor) branches of the rat femoral nerve and to study the effects of expansion culture on the expression patterns of these motor or sensory phenotypic markers. RNA was extracted from SCs harvested from the motor and sensory branches of the rat femoral nerve and analyzed using Affymetrix Gene Chips (Rat Genome 230 v2.0 Array A). Genes that were upregulated in motor SCs compared with the sensory SCs or vice versa were identified, and the results were verified for a subset of genes using quantitative real-time polymerase chain reaction (qRT-PCR). The expression levels of the "phenotype-specific" genes were then evaluated in SC expansion cultures at various time points over 30 days by qRT-PCR to determine the effect of expansion on SC phenotype. Expression levels of the phenotype-specific genes were significantly altered after expansion culture for both the motor and the sensory markers compared with fresh nerve tissue. These results indicate that both motor and sensory SC gene expression patterns are disrupted during expansion in vitro and may affect the ability of SCs to express phenotype-specific genes after transplantation.

Peripheral nerve regeneration after injury depends on environmental cues and trophic support. Schwann cells (SCs) secrete trophic factors that promote neuronal survival and help guide axons during regeneration. The addition of SCs to acellular nerve grafts is a promising strategy for enhancing peripheral nerve regeneration; however, inconsistencies in seeding parameters have led to varying results. The current work sought to establish a systematic approach to seeding SCs in cold-preserved acellular nerve grafts. Studies were undertaken to (1) determine the needle gauge for optimal cell survival and minimal epineurial disruption during injection, (2) track the seeded SCs using a commercially available dye, and (3) evaluate the seeding efficiency of SCs in nerve grafts. It was determined that seeding with a 27-gauge needle resulted in the highest viability of SCs with the least damage to the epineurium. In addition, Qtracker(®) dye, a commercially available quantum dot nanocrystal, was used to label SCs prior to transplantation, which allowed visualization of the seeded SCs in nerve grafts. Finally, stereological methods were used to evaluate the seeding efficiency of SCs in nerve grafts immediately after injection and following a 1- or 3-day in vitro incubation in SC growth media. Using a systematic approach, the best needle gauge and a suitable dye for SC visualization in acellular nerve grafts were identified. Seeding efficiency in these grafts was also determined. The findings will lead to improvements ability to assess injection of cells (including SCs) for use with acellular nerve grafts to promote nerve regeneration.

Despite advances in surgical technique, rotator cuff repairs are plagued by a high rate of failure. This failure rate is in part due to poor tendon-to-bone healing; rather than regeneration of a fibrocartilaginous attachment, the repair is filled with disorganized fibrovascular (scar) tissue. Transforming growth factor beta 3 (TGF-β3) has been implicated in fetal development and scarless fetal healing and, thus, exogenous addition of TGF-β3 may enhance tendon-to-bone healing. We hypothesized that: TGF-β3 could be released in a controlled manner using a heparin/fibrin-based delivery system (HBDS); and delivery of TGF-β3 at the healing tendon-to-bone insertion would lead to improvements in biomechanical properties compared to untreated controls. After demonstrating that the release kinetics of TGF-β3 could be controlled using a HBDS in vitro, matrices were incorporated at the repaired supraspinatus tendon-to-bone insertions of rats. Animals were sacrificed at 14-56 days. Repaired insertions were assessed using histology (for inflammation, vascularity, and cell proliferation) and biomechanics (for structural and mechanical properties). TGF-β3 treatment in vivo accelerated the healing process, with increases in inflammation, cellularity, vascularity, and cell proliferation at the early timepoints. Moreover, sustained delivery of TGF-β3 to the healing tendon-to-bone insertion led to significant improvements in structural properties at 28 days and in material properties at 56 days compared to controls. We concluded that TGF-β3 delivered at a sustained rate using a HBDS enhanced tendon-to-bone healing in a rat model.

Parvovirus B19 is a small single-stranded DNA virus of the Parvoviridae family. Depending on host factors, it may produce a wide array of clinical disease states. Disease severity can range from self-limited to severe, requiring significant supportive care. Immunocompromised patients are generally affected more severely but rarely develop prolonged and persistent infections. Here, we describe a patient who was diagnosed with parvovirus during maintenance therapy for acute lymphoblastic leukemia and required therapy with intravenous immunoglobulin; the patient remained parvovirus positive according to a polymerase chain reaction testing but had no clinical symptoms for 27 months off chemotherapy.

Histiocytic sarcoma (HS) is a malignant tumor composed of proliferating cells of histiocytic origin. True HS is exceedingly rare, particularly in pediatric patients. These tumors are frequently aggressive, and outcome for patients with HS has traditionally been poor. There is currently no consensus on the optimal management of these tumors, with the literature consisting largely of case reports and small case series utilizing a wide variety of therapies. We describe a case of HS in an 8-year-old female who was successfully treated with an abbreviated leukemia chemotherapy regimen.

Immediate stone-free rates of ureteroscopy are rarely reported. To establish accurate stone-free rates after ureteroscopy we assessed the safety and success of ureteroscopy for patients undergoing the procedure at contralateral percutaneous nephrolithotomy.From our prospectively collected, institutional review board approved, percutaneous nephrolithotomy database we identified patients who underwent contralateral ureteroscopy for urolithiasis at percutaneous nephrolithotomy from December 2001 to December 2008. Stone-free status was assessed with noncontrast computerized tomography on postoperative day 1.A total of 65 patients underwent ureteroscopy for urolithiasis at contralateral percutaneous nephrolithotomy. There were 63 patients available for review who had noncontrast computerized tomography on postoperative day 1. Immediate stone-free status was achieved after ureteroscopy in 37 of 63 patients (58.7%). The remaining 26 patients (41.3%) demonstrated a residual stone burden. Of these patients with residual stones after ureteroscopy 65.4% (17 of 26) had residual fragments of 1 to 3 mm and 34.6% (9 of 26) had residual stones larger than 3 mm. Three patients (4.8%) underwent repeat ureteroscopy at secondary percutaneous nephrolithotomy. There was no association of stone composition, patient age, stone location, gender or surgical complications with residual fragments (p0.05).Based on noncontrast computerized tomography 58.7% of patients who underwent ureteroscopy were rendered immediately stone-free. When residual passable stone fragments less than 3 mm were included the success rate increased to 85.7%. We found no association between characteristics of patients, stones or procedures and residual fragments.

Nephrocalcinosis generally refers to the presence of calcium salts within renal tissue, but this term is also used radiologically in diagnostic imaging in disease states that also produce renal stones, so that it is not always clear whether it is tissue calcifications or urinary calculi that give rise to the characteristic appearance of the kidney on x-ray or computed tomography (CT). Recent advances in endoscopic imaging now allow the visual distinction between stones and papillary nephrocalcinosis, and intrarenal endoscopy can also verify the complete removal of urinary stones, so that subsequent radiographic appearance can be confidently attributed to nephrocalcinosis. This report shows exemplary cases of primary hyperparathyroidism, type I distal renal tubular acidosis, medullary sponge kidney, and common calcium oxalate stone formation. In the first three cases--all being conditions commonly associated with nephrocalcinosis--it is shown that the majority of calcifications seen by radiograph may actually be stones. In common calcium oxalate stones formers, it is shown that Randall's plaque can appear as a small calculus on CT scan, even when calyces are known to be completely clear of stones. In the current era with the use of non-contrast CT for the diagnosis of nephrolithiasis, the finding of calcifications in close association with the renal papillae is common. Distinguishing nephrolithiasis from nephrocalcinosis requires direct visual inspection of the papillae and so the diagnosis of nephrocalcinosis is essentially an endoscopic, not radiologic, diagnosis.

Background: Studies have demonstrated thatflexor tendon repair strength fails to increase in thefirstthree weeks following suturing ofthetendon,afindingthatcorrelatescloselywiththetimingofmanyclinical failures.Theapplicationofgrowthfactorsholdspromisefor improving the tendon-repair response and obviating failure in the initial three weeks. Methods: The effects of basic fibroblast growth factor on flexor tendon healing were evaluated with use of a canine model. Operative repair followed by the sustained delivery of basic fibroblast growth factor, at two different doses, was compared with operative repair alone. Histological, biochemical, and biomechanical methods were used to evaluate the tendons twenty-one days after repair. Results: Vascularity, cellularity, and adhesion formation were increased in the tendons that received basic fibroblast growth factor as comparedwiththe tendons that received operative repair alone. DNA concentration was increased in the tendons that received 1000 ng of basicfibroblast growthfactor(meanand standarddeviation,5.7±0.7 mg/mg)ascompared with the tendonsthat received 500 ngofbasic fibroblast growth factor (3.8 ± 0.7 mg/mg) and the matched control tendons that received operative repair alone (4.5 ± 0.9 mg/mg). Tendonsthatweretreatedwithbasicfibroblastgrowthfactorhadalowerratiooftype-Icollagentotype-IIIcollagen,indicatingincreasedscar formation compared with that seen in tendons that received operative repair alone (3.0 ± 1.6 in the group that received 500-ng basic fibroblast growth factor compared with 4.3 ± 1.0 in the paired control group that received operative repair alone, and 3.4± 0.6 in the group that received 1000-ng basic fibroblast growth factor compared with 4.5 ± 1.9 in the paired control group that received operative repair alone).Consistentwith the increasesinadhesion formation thatwereseen intendonstreated with basicfibroblastgrowthfactor,the range of motionwasreducedinthegroup thatreceivedthehigherdose of basicfibroblast growthfactorthanitwasinthepairedcontrolgroupthat received operative repair alone (16.6� ± 9.4� in the group that received 500 ng basic fibroblast growth factor, 13.4� ± 6.1� in the paired controlgroup that received operativerepairalone,and29.2� ± 5.8� inthe normalgroup [i.e.,the groupof corresponding,uninjured tendons from the contralateral forelimb]; and 15.0� ± 3.8� in the group that received 1000 ng basic fibroblast growth factor, 19.3� ± 5.5� in the paired control group that received operative repair alone, and 29.0� ± 8.8� in the normal group). There were no significant differences in tendon excursion or tensile mechanical properties between the groups that were treated with basic fibroblast growth factor and the groups that received operative repair alone. Conclusions: Although basic fibroblast growth factor accelerated the cell-proliferation phase of tendon healing, it also promoted neovascularization and inflammation in the earliest stages following the suturing ofthe tendon. Despite a substantial biologic response, the administration of basic fibroblast growth factor failed to produce improvements in either the mechanical or functional properties of the repair. Rather, increased cellular activity resulted in peritendinous scar formation and diminished range of motion. Clinical Relevance: Despite success in stimulating cellular proliferation and matrix synthesis in flexor tendons through the application of a growth factor in a clinically relevant animal model, no significant improvements were noted in either functional or structural properties. Therefore, as applied in this model, basic fibroblast growth factor is not recommended for intrasynovial flexor tendon repair.

OBJECTIVES • To compare the Cyberwand (Gyrus/ACMI, Southborough, MA, USA), a dual-probe ultrasonic lithotrite, with a single-probe ultrasonic lithotrite. • The Cyberwand incorporates coaxial high-and low-frequency ultrasonic probes that work synergistically. PATIENTS AND METHODS • An institutional review board-approved, multicentre, randomized controlled trial to compare the Cyberwand to the Olympus LUS-II (Olympus America, Inc., Melville, NY, USA) single-probe lithotrite was performed. • Patients undergoing a percutaneous nephrolithotomy (PCNL) with a target stone >2 cm in diameter were eligible for the study. • The primary outcome was the time to removal of the targeted stone. RESULTS • A total of 57 PCNLs were performed after randomization: 25 Cyberwand and 32 LUS-II. • There was no difference (P> 0.05) observed between the two devices for target stone surface area (Cyberwand 526.6 cm 3 vs LUS-II 540.1 cm 3 ), time to clearance of target stone (Cyberwand 15.8 min vs LUS-II 14.2 min) and target stone clearance rate (Cyberwand 61.9 mm 2 /min vs LUS-II 75.8 mm 2 /min). • Of the patients with stone analysis, hard stones (calcium oxalate monohydrate, brushite and cystine) were noted in 14 (56.0%) of the 25 Cyberwand and 18 (62.1%) of the 29 LUS-II patients. • Fifteen of the 25 (60.0%) Cyberwand and 20 of the 32 (62.5%) LUS-II patients were stone-free after the initial PCNL. • Those patients not rendered stone-free went on to receive a secondary PCNL. • Device malfunction occurred in eight of 25(32.0%) Cyberwand and five of 32 (15.6%) LUS II patients. • Complications were similar in both treatment groups. CONCLUSION • No appreciable difference between the dual-probe Cyberwand and the standard ultrasonic Olympus LUS-II lithotrites can be identified.

Glial-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) have both been shown to enhance peripheral nerve regeneration following injury and target different neuronal populations. The delivery of either growth factor at the site of injury may, therefore, result in quantitative differences in motor nerve regeneration and functional recovery. In this study we evaluated the effect of affinity-based delivery of GDNF or NGF from fibrin-filled nerve guidance conduits (NGCs) on motor nerve regeneration and functional recovery in a 13 mm rat sciatic nerve defect. Seven experimental groups were evaluated consisting of GDNF or NGF and the affinity-based delivery system (DS) within NGCs, control groups excluding the DS and/or growth factor, and nerve isografts. Groups with growth factor in the conduit demonstrated equivalent or superior performance in behavioral tests and relative muscle mass measurements compared to isografts at 12 weeks. Additionally, groups with GDNF demonstrated greater specific twitch and tetanic force production in extensor digitorum longus (EDL) muscle than the isograft control, while groups with NGF produced demonstrated similar force production compared to the isograft control. Assessment of motor axon regeneration by retrograde labeling further revealed that the number of ventral horn neurons regenerating across NGCs containing GDNF and NGF DS was similar to the isograft group and these counts were greater than the groups without growth factor. Overall, the GDNF DS group demonstrated superior functional recovery and equivalent motor nerve regeneration compared to the isograft control, suggesting it has potential as a treatment for motor nerve injury.

As controllers and CFOs try to improve the quality of information they provide to decision makers, the one key challenge often is getting the technology support for their needs. This can be particularly true as they develop more strategic information. This article describes the processes that accounting professionals commonly experience as they work to capture more strategic information. It also gives tips for effective technology enablement in the accounting and finance function. © 2010 Wiley Periodicals, Inc.

Holmium laser prostate enucleation is a contemporary treatment for benign prostatic hyperplasia. We report our experience with more than 1,000 procedures.From June 1998 to March 2009 we performed 1,065 holmium laser prostate enucleations. After receiving institutional review board approval we retrospectively reviewed the database. Reported short-term, intermediate term and long-term results are 0 to 6, 6 to 12 and greater than 12 months, respectively.Bladder stones were present in 50 patients (4.7%) and 87 of the 717 (12.1%) with laboratory studies available had renal insufficiency. Preoperative urinary retention was present in 411 cases (38.7%). Significant preoperative stress and urge incontinence was noted in 8 and 16 patients, respectively. Mean transrectal ultrasound prostate volume was 99.3 gm (range 9 to 391). Mean preoperative American Urological Association symptom score was 20.3 (range 1 to 35) and maximum urinary flow was 8.4 cc per second (range 1.1 to 39.3). Intraoperative or postoperative complications occurred in 24 cases (2.3%). Mean followup was 287 days (range 6 to 3,571). At short-term, intermediate term and long-term followup the mean symptom score was 8.7, 5.9 and 5.3, and maximum urinary flow was 17.9, 19.5 and 22.7 cc per second, respectively. At the most recent followup 3 patients (0.3%) were in urinary retention. One patient with maximum urinary flow 20 cc per second required a second procedure for bleeding prostatic regrowth. Urethral stricture was noted in 9 (0.9%), 11 (1.3%), 4 (1.3%) and 0 patients, and bladder neck contracture was found in 0, 7 (0.8%), 4 (1.3%) and 5 (6.0%) at short-term, intermediate term, long-term and greater than 5-year followup, respectively. At the most recent followup significant stress and urge incontinence was noted in 9 and 6 patients, respectively.Holmium laser prostate enucleation is safe and effective for benign prostatic hyperplasia. The complication rate is low, and incontinence and the need for ancillary procedures are rare for holmium laser prostate enucleation with durable long-term results.

Open simple prostatectomy has been considered the treatment of choice for symptomatic benign prostatic hyperplasia (BPH) of large prostates because traditional endoscopic techniques have not proven either effective or feasible. We present our experience with holmium laser enucleation of the prostate (HoLEP) for glands175 cc.An Institutional Review Board approved prospective database has been maintained since January 1999 for all HoLEP procedures. The database was reviewed retrospectively for patients who underwent HoLEP for BPH with a preoperative transrectal ultrasonography (TRUS) volume of175 cc.From January 1999 to November 2008, we identified 57 patients with a mean pretreatment TRUS volume of 217.8 cc (range 175-391 cc). Preoperative retention was present in 30 patients. Preoperative mean prostate-specific antigen level was 14.6 ng/mL, mean American Urological Association (AUA) symptom index was 19.0, and mean peak flow (Qmax) was 8.2 mL/sec. Mean hospital stay was 26 hours, and postoperative catheterization was 18.5 hours (range 6-96 hrs). All patients were able to void after catheter removal. Mean enucleated tissue weight was 176.4 g (range 48-532.2 g). At 6-month follow-up, AUA symptom index was 6.5, mean PSA level was 0.78 ng/mL, and Qmax was 18.5. During the follow-up period, no patient needed catheterization or had persistent incontinence.Even in the large prostate gland, HoLEP provides a satisfactory outcome with low morbidity. HoLEP is the only endoscopic technique that allows for tissue removal comparable to that of open prostatectomy for such patients.

(Headache 2010;50:357-373) Objective.— To describe the pharmacokinetic and safety profiles of sumatriptan 85 mg formulated with RT Technology (RT) and naproxen sodium 500 mg in a fixed-dose combination tablet (sumatriptan/naproxen sodium) that targets both serotonergic dysmodulation and inflammation in migraine. Methods.— Six open-label, crossover studies were conducted in healthy volunteers (Studies 1, 2, 3, 4, 5) or patients with migraine (Study 6). Results.— Consistently across studies, naproxen administered as a component of sumatriptan/naproxen sodium demonstrated a delayed-release profile similar to that of an enteric-coated product. Naproxen from the combination tablet showed a delayed time to peak plasma concentration and lower peak plasma concentration while exposures (area under the plasma concentration–time curve) were similar. The peak plasma concentration for naproxen was approximately 36% lower and the time to peak plasma concentration approximately 4 hours later when naproxen was administered as sumatriptan/naproxen sodium compared with a single naproxen sodium 550 mg tablet. Sumatriptan peak plasma concentration and area under the plasma concentration–time curve after administration of sumatriptan/naproxen sodium (containing sumatriptan 85 mg) were comparable to those after administration of a commercially available sumatriptan 100 mg (RT) tablet. Sumatriptan time to peak plasma concentration occurred, on average, 30 minutes earlier with sumatriptan/naproxen sodium compared with sumatriptan 100 mg (RT). No clinically significant differences between sumatriptan/naproxen sodium and sumatriptan tablets 100 mg (RT) were identified with respect to electrocardiograms, blood pressure, or heart rate. In addition, food had no significant effect on the bioavailability of naproxen or sumatriptan after administration of sumatriptan/naproxen sodium but slightly delayed the time to peak plasma concentration of sumatriptan by approximately 40 minutes. The pharmacokinetics of sumatriptan and naproxen did not differ according to whether sumatriptan/naproxen sodium was administered during a migraine attack or a migraine-free period. The pharmacokinetics of 2 sumatriptan/naproxen sodium tablets administered 2 hours apart were consistent with the pharmacokinetic predictions from a single dose of the combination tablet. The adverse-event profile of the sumatriptan/naproxen sodium combination tablet did not appear to differ from that of the individual components of the same or similar dosage strengths administered alone or in combination. In addition, the incidence of adverse events with 2 sumatriptan/naproxen sodium tablets administered 2 hours apart was lower than that with the single dose. Conclusion.— The combination tablet of sumatriptan/naproxen sodium has unique pharmacokinetic properties. The rapid absorption of sumatriptan with the delayed-release properties of naproxen sodium from sumatriptan/naproxen sodium might contribute to its therapeutic advantage over monotherapy with either component. No clinically meaningful effects of food, administration during a migraine attack, or administration of a second tablet (2 hours after initial dose) on the pharmacokinetics or safety of sumatriptan/naproxen sodium were observed.

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b OBJECTIVE To analyse the structure and composition of unattached stones in idiopathic calcium oxalate (CaOx) stone-formers (ICSF) and compare them to attached stones from the same cohort, to investigate whether there is more than one pathogenic mechanism for stone formation in ICSF. PATIENTS AND METHODS ICSF undergoing percutaneous nephrolithotomy or ureteroscopy for the treatment of nephrolithiasis gave consent to participate in this study. All accessible renal papillae were endoscopically imaged using a digital endoscope. All stones were removed and determined by the operating surgeon to be attached or unattached to the underlying papilla. Micro-computed tomography (micro-CT), which provides three-dimensional analysis of entire stones, was used to compare the structure and composition of attached and unattached stones. RESULTS Of 115 stones collected from nine patients (12 renal units), only 25 stones were found not to be attached to renal papillae. Of these 25 stones, four were lost and 12 showed definite morphological evidence of having been attached to tissue, probably having been displaced from papillae during access. For the remaining nine stones, micro-CT analysis showed at least one internal region of calcium phosphate within each of these unattached CaOx stones, i.e. the internal structure of the unattached stones is consistent with their having originated attached to Randall’s plaque, and then having become detached but retained in the kidney, with new layers of CaOx eventually covering the original attachment site. CONCLUSIONS Micro-CT analysis supports the hypothesis that in ICSF, both attached and unattached stones occur as a result of a common pathogenic mechanism, i.e. in this type of stone former, CaOx stones, even those not showing morphology that betrays attachment, all originate attached to interstitial plaque on the renal papilla.

The controlled delivery of nerve growth factor (NGF) to the peripheral nervous system has been shown to enhance nerve regeneration following injury, although the effect of release rate has not been previously studied with an affinity-based delivery system (DS). The goal of this research was to determine if the binding site affinity of the DS affected nerve regeneration in vivo using nerve guidance conduits (NGCs) in a 13-mm rat sciatic nerve defect. These DSs consisted of bi-domain peptides that varied in heparin-binding affinity, heparin and NGF, which binds to heparin with moderate affinity. Eight experimental groups were evaluated consisting of NGF with DS, control groups excluding one or more components of the DS within silicone conduits and nerve isografts. Nerves were harvested 6 weeks after treatment for analysis by histomorphometry. These DSs with NGF resulted in a higher frequency of nerve regeneration compared to control groups and were similar to the nerve isograft group in measures of nerve fiber density and percent neural tissue, but not in total nerve fiber count. In addition, these DSs with NGF contained a significantly greater percentage of larger diameter nerve fibers, suggesting more mature regenerating nerve content. While there were no differences in nerve regeneration due to varying peptide affinity with these DSs, their use with NGF enhanced peripheral nerve regeneration through a NGC across a critical nerve gap.

This study investigated whether delayed treatment of spinal cord injury with controlled release of neurotrophin-3 (NT-3) from fibrin scaffolds can stimulate enhanced neural fiber sprouting. Long Evans rats received a T9 dorsal hemisection spinal cord injury. Two weeks later, the injury site was re-exposed, and either a fibrin scaffold alone, a fibrin scaffold containing a heparin-based delivery system with different concentrations of NT-3 (500 and 1,000 ng/mL), or a fibrin scaffold containing 1,000 ng/mL of NT-3 (no delivery system) was implanted into the injury site. The injured spinal cords were evaluated for morphological differences using markers for neurons, astrocytes, and chondroitin sulfate proteoglycans 2 weeks after treatment. The addition of 500 ng/mL of NT-3 with the delivery system resulted in an increase in neural fiber density compared to fibrin alone. These results demonstrate that the controlled release of NT-3 from fibrin scaffolds can enhance neural fiber sprouting even when treatment is delayed 2 weeks following injury.

Percutaneous nephrolithotomy (PCNL) can involve establishing more than one access into the urinary collecting system. The present study examined whether multiple percutaneous accesses results in a more severe reduction in renal function than that after single-percutaneous access.Adult female pigs were anesthetized, and percutaneous access to the left urinary collecting system was achieved by puncturing the lower pole calyx (single-tract access, n = 16) or serially puncturing the lower pole, interpolar region, and upper pole calyces [multiple (three)-tract access, n = 11]. Renal function measurements included glomerular filtration rate and effective renal plasma flow, and were taken immediately before and 1.5 and 4.5 hours after percutaneous access. We also examined glomerular function in a group of adult patients with normal preoperative serum creatinine (Cr) levels (or=1.4 mg/dL) who underwent either unilateral single-tract PCNL (23 patients) or unilateral multiple (two)-tract PCNL (10 patients). Access tracts were dilated to 30F with a NephroMax balloon dilator system in animal and human patients.Single- and multiple-tract percutaneous access procedures in pigs resulted in a similar renal functional response; both glomerular filtration rate and effective renal plasma flow significantly declined by approximately 60% immediately after access and remained depressed throughout the experimental observation period. A retrospective analysis of patients with normal serum Crs (or=1.4 mg/dL) who underwent single- or multiple-tract PCNL demonstrated that the procedures produced similar and significant increases in serum Cr on postoperative day 1 (0.33 +/- 0.09 [standard error of mean] mg/dL and 0.39 +/- 0.11 mg/dL, respectively) and day 2 (0.33 +/- 0.09 mg/dL and 0.25 +/- 0.09 mg/dL, respectively).Multiple-tract access does not lead to a more severe reduction in renal function than single-tract access; that is, the acute renal hemodynamic response to PCNL appears independent of the number of access tracts.

Flexor tendon injuries are often encountered clinically and typically require surgical repair. Return of function after repair is limited due to adhesion formation, which leads to reduced tendon gliding, and due to a lack of repair site strength, which leads to repair site gap formation or rupture. The application of the growth factors basic fibroblastic growth factor (bFGF) and platelet derived growth factor BB (PDGF-BB) has been shown to have the potential to enhance tendon healing. The objectives of this study were to examine: (1) the conditions over which delivery of bFGF can be controlled from a heparin-binding delivery system (HBDS) and (2) the effect of bFGF and PDGF-BB released from this system on tendon fibroblast proliferation and matrix gene expression in vitro over a 10-day interval. Delivery of bFGF was controlled using a HBDS. Fibrin matrices containing the HBDS retained bFGF better than did matrices lacking the delivery system over the 10-day period studied. Delivery of bFGF and PDGF-BB using the HBDS stimulated tendon fibroblast proliferation and promoted changes in the expression of matrix genes related to tendon gliding, strength, and remodeling. Both growth factors may be effective in enhancing tendon healing in vivo.

A fibrin/heparin-based delivery system was used to provide controlled delivery of platelet derived growth factor BB (PDGF-BB) in an animal model of intrasynovial flexor tendon repair. We hypothesized that PDGF-BB, administered in this manner, would stimulate cell proliferation and matrix remodeling, leading to improvements in the sutured tendon's functional and structural properties. Fifty-six flexor digitorum profundus tendons were injured and repaired in 28 dogs. Three groups were compared: (1) controlled delivery of PDGF-BB using a fibrin/heparin-based delivery system; (2) delivery system carrier control; and (3) repair- only control. The operated forelimbs were treated with controlled passive motion rehabilitation. The animals were euthanized at 7, 14, and 42 days, at which time the tendons were assessed using histologic (hyaluronic acid content, cellularity, and inflammation), biochemical (total DNA and reducible collagen crosslink levels), and biomechanical (gliding and tensile properties) assays. We found that cell activity (as determined by total DNA, collagen crosslink analyses, and hyaluronic acid content) was accelerated due to PDGF-BB at 14 days. Proximal interphalangeal joint rotation and tendon excursion (i.e., tendon gliding properties) were significantly higher for the PDGF-BB-treated tendons compared to the repair-alone tendons at 42 days. Improvements in tensile properties were not achieved, possibly due to suboptimal release kinetics or other factors. In conclusion, PDGF-BB treatment consistently improved the functional but not the structural properties of sutured intrasynovial tendons through 42 days following repair.

The anisotropic mechanical properties of magnetically aligned fibrin gels were measured by magnetic resonance elastography (MRE) and by a standard mechanical test: unconfined compression. Soft anisotropic biomaterials are notoriously difficult to characterize, especially in vivo. MRE is well-suited for efficient, non-invasive, and non-destructive assessment of shear modulus. Direction-dependent differences in shear modulus were found to be statistically significant for gels polymerized at magnetic fields of 11.7 and 4.7 T compared to control gels. Mechanical anisotropy was greater in the gels polymerized at the higher magnetic field. These observations were consistent with results from unconfined compression tests. Analysis of confocal microscopy images of gels showed measurable alignment of fibrils in gels polymerized at 11.7 T. This study provides direct, quantitative measurements of the anisotropy in mechanical properties that accompanies fibril alignment in fibrin gels.

Two identical randomized, placebo-controlled, crossover studies were conducted to evaluate consistency of response to sumatriptan/naproxen sodium 85/500 mg (S/NS) over four attacks in adults with migraine. Patients were instructed to treat within 1 h of pain onset while pain was mild. Co-primary end-points were pain-free response at 2 h (2hPF) and 24-h sustained pain-free response (24hSPF) calculated as percentages of all attacks. In Study 1, 570 patients treated 1693 attacks with S/NS and 424 with placebo. In Study 2, 565 patients treated 1678 attacks with S/NS and 422 with placebo. Compared with placebo, S/NS conferred higher 2hPF rates (Study 1: S/NS 52%, placebo 25%; Study 2: S/NS 50%, placebo 20%; both P < 0.001) and higher 24hSPF rates (Study 1: S/NS 37%, placebo 17%; Study 2: S/NS 34%, placebo 12%; both P < 0.001). 2hPF was reported in at least two of the first three S/NS-treated attacks in 55.0% of patients in Study 1 and 52.1% of patients in Study 2. 24hSPF was reported in at least two of the first three S/NS-treated attacks in 35.7% of patients in Study 1 and 32.6% of patients in Study 2. The incidences of any adverse event and of specific adverse events were low and generally similar between S/NS and placebo.

Objective.— To evaluate efficacy and tolerability of a single, fixed-dose tablet of sumatriptan 85 mg/naproxen sodium 500 mg (sumatriptan/naproxen sodium) vs placebo in migraineurs who had discontinued treatment with a short-acting triptan because of poor response or intolerance. Background.— Triptan monotherapy is ineffective or poorly tolerated in 1 of 3 migraineurs and in 2 of 5 migraine attacks. In April, 2008, the Food and Drug Administration approved the combination therapy sumatriptan/naproxen sodium, developed specifically to target multiple migraine mechanisms. This combination product offers an alternative migraine therapy for patients who have reported poor response or intolerance to short-acting triptans. Methods.— Two replicate, randomized, multicenter, double-blind, placebo-controlled, 2-attack crossover trials evaluated migraineurs who had discontinued a short-acting triptan in the past year because of poor response or intolerance. Patients were instructed to treat within 1 hour and while pain was mild. Results.— Patients (n = 144 study 1; n = 139 study 2) had discontinued an average of 3.3 triptans before study entry. Sumatriptan/naproxen sodium was superior (P

Glial-derived neurotrophic factor (GDNF) promotes both sensory and motor neuron survival. The delivery of GDNF to the peripheral nervous system has been shown to enhance regeneration following injury. In this study, we evaluated the effect of affinity-based delivery of GDNF from a fibrin matrix in a nerve guidance conduit on nerve regeneration in a 13 mm rat sciatic nerve defect. Seven experimental groups were evaluated which received GDNF or nerve growth factor (NGF) with the delivery system within the conduit, control groups excluding one or more components of the delivery system, and nerve isografts. Nerves were harvested 6 weeks after treatment for analysis by histomorphometry and electron microscopy. The use of the delivery system (DS) with either GDNF or NGF resulted in a higher frequency of nerve regeneration vs. control groups, as evidenced by a neural structure spanning the 13 mm gap. The GDNF DS and NGF DS groups were also similar to the nerve isograft group in measures of nerve fiber density, percent neural tissue and myelinated area measurements, but not in terms of total fiber counts. In addition, both groups contained a significantly greater percentage of larger diameter fibers, with GDNF DS having the largest in comparison to all groups, suggesting more mature neural content. The delivery of GDNF via the affinity-based delivery system can enhance peripheral nerve regeneration through a silicone conduit across a critical nerve gap and offers insight into potential future alternatives to the treatment of peripheral nerve injuries.

Electrospun nanofibers can be readily assembled into various types of scaffolds for applications in neural tissue engineering. The objective of this study is to examine and understand the unique patterns of neurite outgrowth from primary dorsal root ganglia (DRG) cultured on scaffolds of electrospun nanofibers having different orders, structures, and surface properties. We found that the neurites extended radially outward from the DRG main body without specific directionality when cultured on a nonwoven mat of randomly oriented nanofibers. In contrast, the neurites preferentially extended along the long axis of fiber when cultured on a parallel array of aligned nanofibers. When seeded at the border between regions of aligned and random nanofibers, the same DRG simultaneously expressed aligned and random neurite fields in response to the underlying nanofibers. When cultured on a double-layered scaffold where the nanofibers in each layer were aligned along a different direction, the neurites were found to be dependent on the fiber density in both layers. This bi-axial pattern clearly demonstrates that neurite outgrowth can be influenced by nanofibers in different layers of a scaffold, rather than the topmost layer only. Taken together, these results will provide valuable information pertaining to the design of nanofiber scaffolds for neuroregenerative applications, as well as the effects of topology on neurite outgrowth, growth cone guidance, and axonal regeneration.

Endosomal escape and nuclear localization are two barriers to gene delivery that need to be addressed in the design of new nonviral gene delivery vehicles. We have previously synthesized low-toxicity polyethylene glycol (PEG)-based vehicles with endosomal escape functionalities, but it was determined that the transfection efficiency of PEG-based vehicles that escaped the endosome was still limited by poor nuclear localization. Two different nuclear localization signal (NLS) peptides, SV40 and TAT, were coupled to PEG-based vehicles with DNA-binding peptides (DBPs) to determine the effect of NLS peptides on the transfection efficiency of PEG-based gene delivery vehicles. Coupling one SV40 peptide, a classical NLS, or two TAT peptides, a nonclassical NLS, to PEG-DBP vehicles increased the transfection efficiency of PEG-DBP/DNA particles 15-fold and resulted in similar efficiency to that of a common cationic polymer vehicle, polyethylenimine (PEI). The transfection efficiency of both types of PEG-DBP-NLS particles was further increased 7-fold in the presence of chloroquine, suggesting that the transfection efficiency of PEG-DBP-NLS particles is limited by their ability to escape the endosome. To develop particles that could escape the endosome and target the nucleus, a mixture of PEG-DBP-NLS vehicles and PEG-based vehicles with DBPs and endosomal escape peptides were complexed with plasmid DNA to form multifunctional particles that had a transfection efficiency 2-3 times higher than that of PEI. Additionally, the PEG-based vehicles were less toxic and more resistant to nonspecific protein adsorption than PEI, making them an attractive alternative for nonviral gene delivery.

Numerous factors affect the ability or choice of fishes to breed. For example, studies demonstrate that the appropriate amount of light, temperature, and food must be present before many species will breed. For some species, we are also aware of social factors that affect breeding, such as the size or colour of one's potential mates. Although studies on mate choice (i.e., choice of one potential mate over another) and factors affecting breeding are extensive, there remain significant gaps in our knowledge with regard to scientifically important species. For instance, the fathead minnow (Pimephales promelas), used by numerous researchers as a test subject in reproductive toxicology and behavioural ecology, has well established physical parameters known to facilitate breeding. Conversely, there is very little data describing social factors which may influence breeding. The purpose of the current study was to examine some of the factors affecting mate choice in the fathead minnow. Results indicate a consistent relationship between male and female size length and mass), which can be used to predict the probability of a couple's breeding potential. Specifically, we found that female minnows prefer larger males. In successful pairs there was a greater difference in size between the male and female as compared with unsuccessful pairs. The findings of this study could substantially improve methods for reproductive studies in laboratories or artificial streams by decreasing both the number of pairs tested against baseline performance criteria and the time needed to establish actively breeding individuals. This will decrease the cost and increase the efficiency of future studies, as well as add ecologically interesting knowledge to the literature regarding a scientifically important, ubiquitous, and representative North American fish species.

Purpose Surgically repaired intrasynovial tendons are at greatest risk of failure in the first 3 weeks after surgery. Attempts to improve the strength of repair by modifying rehabilitation parameters have not always been successful. Manipulation of the biological environment of the sutured tendon holds great promise for accelerating the repair process. The goals of this study were to examine (1) the range of conditions (eg, dosage, delivery system formulation, presence of cells) over which delivery of platelet-derived growth factor-BB (PDGF-BB) can be sustained from fibrin matrices using a heparin-binding delivery system (HBDS) and (2) the biological activity of the PDGF-BB released from this system on canine tendon fibroblasts in vitro . Methods We examined in vitro release kinetics from cellular and acellular fibrin matrices using enzyme-linked immunosorbent assays. We examined the biologic activity of the PDGF-BB in vitro by measuring cell proliferation (ie, total DNA) and collagen synthesis (ie, proline incorporation). Results The acellular release kinetics of PDGF-BB was modulated by varying the ratio of PDGF-BB to heparin (PDGF-binding sites) or the dose of PDGF-BB in the presence of the delivery system. In the presence of canine tendon fibroblasts, the delivery system prolonged the duration of PDGF-BB release from fibrin matrices, thus demonstrating that cells are able to liberate PDGF-BB retained by the HBDS. Sustained delivery of PDGF-BB promoted increased cell proliferation at doses of 0.125 μg/mL and 1.25 μg/mL compared to fibrin without delivery system. Collagen synthesis was enhanced by PDGF-BB at doses of 0.125 μg/mL and 1.25 μg/mL; however, there was an enhancement over fibrin without the delivery system only at the lower dose. Conclusions These results demonstrate that the PDGF-BB released from fibrin matrices containing an HBDS is biologically active and can modulate both cell proliferation and extracellular matrix synthesis, both of which are key factors in the process of tendon repair.