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For use in regenerative medicine, large-scale manufacturing of human pluripotent stem cells (hPSCs) under current good manufacturing practice (cGMPs) is required. Much progress has been made since culturing under static two-dimensional (2D) conditions on feeders, including feeder-free cultures, conditioned and xeno-free media, and three-dimensional (3D) dynamic suspension expansion. With the advent of horizontal-blade and vertical-wheel bioreactors, scale-out for large-scale production of differentiated hPSCs became possible; control of aggregate size, shear stress, fluid hydrodynamics, batch-feeding strategies, and other process parameters became a reality. Moving from substantially manipulated processes (i.e., 2D) to more automated ones allows easer compliance to current good manufacturing practices (cGMPs), and thus easier regulatory approval. Here, we review the current advances in the field of hPSC culturing, advantages, and challenges in bioreactor use, and regulatory areas of concern with respect to these advances. Manufacturing trends to reduce risk and streamline large-scale manufacturing will bring about easier, faster regulatory approval for clinical applications.

Spinal interneurons (INs) relay sensory and motor control information between the brain and body. When this relay circuitry is disrupted from injury or disease, it is devastating to patients due to the lack of native recovery in central nervous system (CNS) tissues. Obtaining a purified population of INs is necessary to better understand their role in normal function and as potential therapies in CNS. The ventral V0 (V0The transgenic Evx1-PAC mESC line was created by CRISPR-Cas9-mediated insertion of puromycin-N-acetyltransferase (PAC) into the locus of V0V0Evx1-PAC mESCs can be used to purify V0

Our nationwide network of BME women faculty collectively argue that racial funding disparity by the National Institutes of Health (NIH) remains the most insidious barrier to success of Black faculty in our profession. We thus refocus attention on this critical barrier and suggest solutions on how it can be dismantled.

Background Because early‐stage breast cancer can be treated successfully by a variety of breast‐conservation approaches, long‐term quality of life (QoL) is an important consideration in assessing treatment outcomes for these patients. This study compares patient‐reported QoL outcomes among women with stage 0‐2 disease treated via lumpectomy followed by whole breast irradiation (WBI) or partial breast proton irradiation (PBPT). Methods In this cross‐sectional study, 129 participants evaluated QoL several years post‐treatment by responding to subjective instruments, including established scalar questionnaires and self‐report measures. Responses were averaged between the two groups. Results At 6.5 years (median) postdiagnosis, participants’ demographic, and clinical characteristics were similar. Patient‐reported outcomes were reported as mean scale scores for the two groups, all displaying significant differences favoring PBPT, including: cosmetic breast cancer treatment outcome scale (BCTOS) (PBPT mean 1.45, WBI mean 1.88, P

The central nervous system is not a static, hard-wired organ. Examples of neuroplasticity, whether at the level of the synapse, the cell, or within and between circuits, can be found during development, throughout the progression of disease, or after injury. One essential component of the molecular, anatomical, and functional changes associated with neuroplasticity is the spinal interneuron (SpIN). Here, we draw on recent multidisciplinary studies to identify and interrogate subsets of SpINs and their roles in locomotor and respiratory circuits. We highlight some of the recent progress that elucidates the importance of SpINs in circuits affected by spinal cord injury (SCI), especially those within respiratory networks; we also discuss potential ways that spinal neuroplasticity can be therapeutically harnessed for recovery.

V2a interneurons are located in the hindbrain and spinal cord, where they provide rhythmic input to major motor control centers. Many of the phenotypic properties and functions of excitatory V2a interneurons have yet to be fully defined. Definition of these properties could lead to novel regenerative therapies for traumatic injuries and drug targets for chronic degenerative diseases. Here we describe how to produce V2a interneurons from mouse and human pluripotent stem cells (PSCs), as well as strategies to characterize and mature the cells for further analysis. The described protocols are based on a sequence of small-molecule treatments that induce differentiation of PSCs into V2a interneurons. We also include a detailed description of how to phenotypically characterize, mature, and freeze the cells. The mouse and human protocols are similar in regard to the sequence of small molecules used but differ slightly in the concentrations and durations necessary for induction. With the protocols described, scientists can expect to obtain V2a interneurons with purities of ~75% (mouse) in 7 d and ~50% (human) in 20 d. V2a interneurons are differentiated from mouse and human pluripotent stem cells following culture in the presence of a sequence of small-molecule treatments.

The Hadassah hESC Research Center's aim is to be a supplier of clinical and research-grade human embryonic stem cell (hESC) lines. In 2012, we derived the first three entirely GMP-compliant and xeno-free, fully-characterised, feeder-dependent (human umbilical cord) hESC lines developed under cleanroom conditions. In 2018, we established four new GMP and xeno-free, feeder-independent MCB hESCs under GMP conditions using commercially available reagents, media and matrix. All cell lines were derived under Israeli Ministry of Health's National Ethics Committee for Genetic Research in Humans and the ethical considerations that guided the development of the hESCs strictly followed Israeli law. Hadassah has provided its clinical-grade hESC lines to commercial entities of which two are already in clinical trials, establishing Hadassah as a key provider of clinical-grade hESC lines. Keywords: Transplantation therapy, Xeno-free, Clinical-grade hESC lines, Disease-affected hESC lines, Biosafety testing, QC testing, Certificate of analysis

Background Interest in direct anterior approach (DAA) has increased over the last decade. In our previously published study comparing DAA to posterolateral approach (PA), early 3-month benefits were noted in terms of pain and function. There was no difference noted at 6 or 12 months. This study reports average 5-year follow-up of our original study. Methods Originally there were 43 DAA patients and 44 PA patients. At an average 5-year follow-up, patients were evaluated clinically with a University of California at Los Angeles activity score, Harris hip score, and Hip Disability and Osteoarthritis Outcome Score Jr Survivorship analysis was calculated. Radiographs were evaluated for loosening and evidence of radiolucent lines. Results There were 2 deaths 1 in each group, neither was related to the implant or procedure. Four patients were lost to follow-up: 2 in the DAA group and 2 in the PA group. There was no statistical difference between surgical approaches in terms of Harris hip score, University of California at Los Angeles activity score, and Hip Disability and Osteoarthritis Outcome Score Jr. The 7-year survivorship was not significantly different. There were no loose implants at average 5-year follow-up. Conclusion Both DAA and PA yield good results at an average 5-year follow-up in terms of survivorship, function, rate of complications, and radiographic analysis.

Due to the nature of the biological response to traumatic spinal cord injury, there are very limited therapeutic options available to patients. Recent advances in cell transplantation have demonstrated the therapeutic potential of transplanting supportive cell types following spinal cord injury. In particular, pluripotent stem cell derived neural cells are of interest for future investigation. Use of pluripotent stem cells as the source allows many cell types to be produced from a population that can be expanded in vitro. In this review, we will discuss the signaling pathways that have been used to differentiate spinal neural phenotypes from pluripotent stem cells. Additionally, we will highlight methods that have been developed to direct the differentiation of pluripotent stem cells to specific neural fates. Further refinement and elaboration of these techniques might aid in elucidating the multitude of neuronal subtypes endogenous to the spinal cord, as well as produce further therapeutic options for spinal cord injury recovery. Developmental Dynamics 248:78-87, 2019. © 2018 Wiley Periodicals, Inc.

Nerve injuries can be life-long debilitating traumas that severely impact patients' quality of life. While many acellular neural scaffolds have been developed to aid the process of nerve regeneration, complete functional recovery is still very difficult to achieve, especially for long-gap peripheral nerve injury and most cases of spinal cord injury. Cell-based therapies have shown many promising results for improving nerve regeneration. With recent advances in neural tissue engineering, the integration of biomaterial scaffolds and cell transplantation are emerging as a more promising approach to enhance nerve regeneration. This review provides an overview of important considerations for designing cell-carrier biomaterial scaffolds. It also discusses current biomaterials used for scaffolds that provide permissive and instructive microenvironments for improved cell transplantation.

Recent developments in genome engineering methods have advanced our knowledge of central nervous system (CNS) function in both normal health and following disease or injury. This review discusses current literature using gene editing tools in CNS disease and injury research, such as improving viral-mediated targeting of cell populations, generating new methods for genome editing, reprogramming cells into CNS cell types, and using organoids as models of development and disease. Readers may gain inspiration for continuing research into new genome engineering methods and for therapies for CNS applications.

Trauma to either the central or peripheral nervous system often leads to significant loss of function and disability in patients. This high rate of long-term disability is due to the overall limited regenerative potential of nervous tissue, even though the peripheral nervous system (PNS) has more regenerative potential than the central nervous system (CNS). The supporting glial cells in the periphery, Schwann cells, are part of the reason for the improved recovery observed in the PNS. In the CNS, the glial populations, astrocytes and oligodendrocytes, do not have as much potential to promote regeneration and are at times inhibitory to neuronal growth. In particular, the inhibitory roles astrocytes play following trauma has led to a historical focus on neurons and oligodendrocytes instead of astrocytes. Recently, this focus has shifted as new, regenerative astrocyte phenotypes have been described. From these observations, glial cells clearly play critical roles in native recovery pathways in both the CNS and PNS. This makes the ability to manipulate both transplanted and native glial cell phenotypes a potentially successful strategy to improve nerve injury outcomes. This review focuses on factors that cause glial cells to adopt repair phenotypes and biomaterials that manipulate and/or harness these glial phenotypes.

Prophylaxis with posaconazole, an extended-spectrum triazole antifungal, has been shown to increase overall survival in adults with acute myeloid leukemia receiving intensive remission induction chemotherapy. A paucity of data exists evaluating therapeutic drug monitoring and subsequent dose adjustment based on serum concentrations in humans.An observational study was performed in 29 adult patients with acute myeloid leukemia who initially received posaconazole oral suspension 200 mg 3 times daily and required ≥1 dose adjustment because of steady-state posaconazole serum concentration0.7 mcg/mL. Four dosing schemas were compared simultaneously. Patient records were reviewed to collect patient-related and medication-related factors that may affect serum concentrations.Thirty-five percent of patients experienced subtherapeutic posaconazole serum concentrations with prophylactic dosing of posaconazole oral suspension. Increasing the dose and/or schedule of posaconazole oral suspension led to attainment of goal posaconazole serum concentrations in all groups. However, patients who received 400 mg orally 3 times daily experienced the least significant increase in serum concentration and remained subtherapeutic, despite doubling the posaconazole daily dose. Toxicities were similar to baseline within all groups. Increasing the dose and/or frequency of posaconazole oral suspension led to an increase in systemic exposure and did not appreciably increase incidence of toxicities.Patients receiving posaconazole oral suspension that experience subtherapeutic posaconazole serum concentrations may benefit from increasing the frequency to 200 mg orally 4 times daily or dose to 300 mg orally 3 times daily.

Dysmenorrhea and menstrual migraine may share a common pathogenic pathway. Both appear to be mediated, in part, by an excess of prostaglandin production that occurs during menstruation.Data were pooled from two replicate randomized controlled trials of 621 adult menstrual migraineurs with dysmenorrhea who treated migraine with sumatriptan-naproxen or placebo. Along with headache symptoms, nonpain menstrual symptoms (bloating, fatigue, and irritability) and menstrual pain symptoms (abdominal and back pain) were recorded at the time periods of 30 minutes and 1, 2, 4, and 4-24 hours. Relief of menstrual symptoms was compared using a Cochran-Mantel-Haenszel test. Logistic regression was used to determine the odds of a headache response with increasing numbers of moderate to severe dymenorrheic symptoms.Sumatriptan-naproxen was superior to placebo for relief of tiredness, irritability, and abdominal pain at the time periods of 2, 4, and 4-24 hours (p≤0.023); back pain at the time periods of 4 and 4-24 hours (p≤0.023); and bloating at 4-24 hours endpoint (p=0.01). The odds ratios (ORs) of attaining migraine pain freedom for 2 hours and for sustained 2-24 hours decreased as moderate to severe dysmenorrhea symptoms increased with sumatriptan-naproxen versus placebo.Treatment with sumatriptan-naproxen may provide relief of menstrual symptoms and migraine in female migraineurs with dysmenorrhea. The presence of moderate to severe dysmenorrhea symptoms is associated with decreased response rates for menstrual migraine, suggesting that the co-occurrence of these disorders may negatively impact the results of migraine-abortive therapy.

This review provides an overview on the incorporation of heparin into biomaterials with a focus on drug delivery and the use of heparin-based biomaterials for self-assembly of polymer networks. Heparin conjugation to biomaterials was originally explored to reduce the thrombogenicity of materials in contact with blood. Many of the conjugation strategies that were developed for these applications are still popular today for other applications. More recently heparin has been conjugated to biomaterials for drug delivery applications. Many of the delivery approaches have taken advantage of the ability of heparin to bind to a wide variety of growth factors, protect them from degradation and to potentiate their interactions with cell surface receptors. More recently, the use of heparin as a base polymer for scaffold fabrication has also been explored, often utilizing non-covalent binding of heparin with peptides or proteins to promote self-assembly of hydrogel networks. This review will highlight recent advances in each of these areas.

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.

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.

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.

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.

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.

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.

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

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.

Background With recent progress in gene therapy clinical trials, there is an even greater demand to advance the development of nonviral gene delivery vehicles. We have previously developed poly(ethylene glycol) (PEG)-based vehicles with transfection efficiency similar to polyethyleneimine and low cytotoxicity. It was hypothesized that conjugating endosomal escape peptides (EEPs) to PEG-based vehicles would further increase their transfection efficiency. The present study aimed to determine how two different EEPs, INF7 and H5WYG, which destabilize the endosomal membrane at different pHs, affect the efficiency of PEG-based vehicles. Methods INF7 and H5WYG were conjugated to PEG-tetraacrylate (PEG-TA) via a Michael-type addition at the desired molar ratios. The pH-dependent membrane lytic activity, transfection efficiency, particle size, zeta potential, and endosomal escape kinetic rate constants were determined. Results Fusogenic peptides, INF7 and H5WYG, showed pH-dependent membrane lytic activity when conjugated to PEG-TA. The highest membrane lytic activity of PEG-INF7 and PEG-H5WYG conjugates occurred at pH 5 and 5.5, respectively. Coupling one INF7 peptide to PEG-DNA binding peptide (DBP) vehicles increased the transfection efficiency ten-fold and showed greater transfection efficiency than PEG-DBP vehicles coupled with H5WYG peptide. Fitting a first-order kinetic model to the average intracellular pH of the vehicle/DNA particles over time determined that coupling EEPs to PEG-DBP vehicles increased the endosomal escape rate constant by two orders of magnitude. Conclusions Endosomal escape is a key step in nonviral cellular trafficking and thus the transfection efficiency of nonviral vehicles can be increased by targeting release of DNA from the endosome with EEPs. Copyright © 2008 John Wiley & Sons, Ltd.

Large or complex calculi within a horseshoe kidney can present a challenge because many cases are associated with other aberrant anatomy. We performed a study to define the outcome of patients with a horseshoe kidney who were treated with percutaneous nephrolithotomy (PNL).From August 1999 to February 2007, 44 PNLs were performed in 35 patients for calculi within a horseshoe kidney. Mean age was 55.4 years. Parameters evaluated to assess the outcomes of PNL included presenting symptoms, stone burden, location of access, stone-free rate, need for secondary intervention, length of stay (LOS), complication rate, stone analysis, and metabolic data.The average stone burden per kidney was 2.59 cm (range 1-6.2 cm). Single percutaneous access was used in 97.7%. Location of the access tract was upper pole (82.2%), interpolar (13.4%), and lower pole (4.4 %). Flexible nephroscopy was performed in all patients. The stone-free rate after primary PNL was 84.1%. Second-look nephroscopy was performed in five kidneys. Overall stone-free rate was 93.2%. Average LOS was 1.92 days (range 1-4 d). Overall complication rate was 14.3%. Stone analysis revealed predominantly calcium stones, and metabolic abnormalities were demonstrated in all patients with 24-hour urine studies.PNL is the treatment of choice for large and/or complex stones. The presence of a horseshoe kidney does not affect the outcome of PNL. Upper pole access is usually preferred, and flexible nephroscopy is essential to maximize stone-free rates. SA and metabolic data support the premise that calculus formation is a metabolic event.

The goal of this study was to develop a gene delivery vehicle that can specifically target cell surface receptors with low nonspecific protein adsorption and low cytotoxicity. Toward this goal, four-arm poly(ethylene glycol) vehicles were functionalized with DNA-binding peptides (DBPs) and integrin-binding (RGD) peptides. We have previously described a novel PEG-based gene delivery vehicle functionalized with DBPs that successfully transfected Chinese hamster ovary (CHO) cells with low toxicity and low protein adsorption. This work investigated whether incorporating RGD peptides onto PEG-DBP vehicles could target specific cell surface receptors and increase transfection efficiency of HEPG2 cells. DBP and RGD peptides were coupled onto PEG-tetraacrylate (PEG-TA) in three combinations (molar ratios of DBP:RGD of 1:3, 2:2, and 3:1) and characterized by measuring particle size, zeta potential, and transfection efficiency as a function of charge ratio (peptide amine groups:DNA phosphate). Nonspecific protein adsorption and cytotoxicity of PEG-DBP-RGD vehicles were also measured. Dynamic light scattering showed that PEG-DBP-RGD vehicles condensed DNA into particles having mean diameters of 250-300 nm and zeta potentials ranging from -10 to 7 mV. It was found that coupling two RGD peptides to the PEG-DBP 2 vehicle increased the transfection efficiency at a polymer/DNA charge ratio of 5:1 (+/-) and 6:1 (+/-) and that these vehicles had transfection efficiencies similar to those of polyethylenimine (PEI)/DNA particles. However, coupling one or three RGD peptides to PEG-DBP vehicles did not increase the transfection efficiency. Additionally, the PEG-DBP-RGD/DNA particles adsorbed less protein than PEI particles and were less toxic to HEPG2 cells.

This review seeks to give an overview of the current approaches to drug delivery from scaffolds for neural tissue engineering applications. The challenges presented by attempting to replicate the three types of nervous tissue (brain, spinal cord, and peripheral nerve) are summarized. Potential scaffold materials (both synthetic and natural) and target drugs are discussed with the benefits and drawbacks given. Finally, common methods of drug delivery, including degradable/diffusion-based delivery systems, affinity-based delivery systems, immobilized drug delivery systems, and electrically controlled drug delivery systems, are examined and critiqued. Based on the current body of work, suggestions for future directions of research in the field of neural tissue engineering are presented.

OBJECTIVES To evaluate the long-term safety and tolerability of sumatriptan-naproxen sodium for the treatment of moderate to severe acute migraines and to assess the safety of administration of an optional second dose. PATIENTS AND METHODS A 12-month, multicenter, open-label safety study was conducted in adults treated for migraine attacks of moderate to severe intensity from April 14, 2004, to August 18, 2005. Safety evaluations included adverse events and laboratory tests. RESULTS Of 600 patients enrolled, 565 (94%) were treated for at least 1 migraine. Of treated patients, 414 (73%) and 362 (64%) completed 6 and 12 months of treatment, respectively. Of the 24,485 attacks treated, 17,144 (70%) were treated with only 1 dose. On average, patients treated 5 migraine attacks per month, with a median of 6 days between attacks. The most common treatment-related adverse events were nausea, muscle tightness, and dizziness. Fourteen patients reported 1 or more serious adverse event with only 1 judged probably related to treatment. No deaths occurred. Eight percent of patients discontinued participation in the study because of adverse events or pregnancy. The rates of adverse events reported were no higher after treatment with 2 tablets (at least 2 hours apart) compared with 1 tablet. CONCLUSIONS In this 12-month data set of more than 24,000 migraine attacks in 565 patients, sumatriptan-naproxen sodium formulated in a single tablet was well tolerated when used episodically for the treatment of acute migraine. The adverse events did not differ from those expected for the individual components alone, and no new or unexpected findings occurred.

In 2009 the International Stem Cell Banking Initiative (ISCBI) contributors and the Ethics Working Party of the International Stem Cell Forum published a consensus on principles of best practice for the procurement, cell banking, testing and distribution of human embryonic stem cell (hESC) lines for research purposes [1] , which was broadly also applicable to human induced pluripotent stem cell (hiPSC) lines. Here, we revisit this guidance to consider what the requirements would be for delivery of the early seed stocks of stem cell lines intended for clinical applications. The term 'seed stock' is used here to describe those cryopreserved stocks of cells established early in the passage history of a pluripotent stem cell line in the lab that derived the line or a stem cell bank, hereafter called the 'repository'. The seed stocks should provide cells with suitable documentation and provenance that would enable them to be taken forward for development in human therapeutic applications. WHO recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biologicals and for the characterization of cell banks were updated in 2010 and provide a number of definitions and guiding principles that may apply to stem cells. The term 'cell bank' is used to describe a stock of vials or other containers of cells with consistent composition aliquoted from a single pool of cells of the same culture history (for other specific definitions see PAS 84 [2] and WHO [3] ).Three important assumptions have been made in the preparation of this document. First, that seed stocks of hPSCs are used as starting materials to make cell banks for use in clinical trials. The cell banks made within a clinical trial would need to be established according to Good Manufacturing Practice (GMP) in a facility with a relevant product manufacturing license. These banks would need additional risk assessment focused on the new banking process/reagents and the specific intended clinical application. Second, it has been assumed that undifferentiated pluripotent stem cells would not be inoculated into patients. Third, where feeder cells are used to culture hPSC lines, their cellular nature and intimate contact with the therapeutic cells means that they should be subject to similar risk assessment and banking procedures as applied to the hPSC cells.It is important to note that responsibility for establishing and updating national regulations for medicinal products relies on National Regulatory Authorities. Therefore, national requirements for cell therapy may vary considerably. Accordingly, it is not intended that this international consensus provides comprehensive guidance that will ensure compliance with requirements in any given jurisdiction. Rather, it is designed to aid the development of clinical grade materials by providing points to consider in the preparation of seed stocks of stem cell lines for use in cell therapy. It may arise that there are circumstances where it is not reasonably possible to meet specific procedures presented in this document. Where this is the case any alternative procedures should be justified and mitigate against any adverse consequences. Finally, this document could also serve as a useful reference to assist in the evaluation of potential sources of candidate cell lines for the development of cell-based medicines, and provide the links necessary to identify some of the key differences in regulatory requirements between countries.

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.

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.

Current approaches for treating peripheral nerve injury have resulted in promising, yet insufficient functional recovery compared to the clinical standard of care, autologous nerve grafts. In order to design a construct that can match the regenerative potential of the autograft, all facets of nerve tissue must be incorporated in a combinatorial therapy. Engineered biomaterial scaffolds in the future will have to promote enhanced regeneration and appropriate reinnervation by targeting the highly sensitive response of regenerating nerves to their surrounding microenvironment.

Clinically compliant human embryonic stem cells (hESCs) should be developed in adherence to ethical standards, without risk of contamination by adventitious agents. Here we developed for the first time animal-component free and good manufacturing practice (GMP)-compliant hESCs. After vendor and raw material qualification, we derived xeno-free, GMP-grade feeders from umbilical cord tissue, and utilized them within a novel, xeno-free hESC culture system. We derived and characterized three hESC lines in adherence to regulations for embryo procurement, and good tissue, manufacturing and laboratory practices. To minimize freezing and thawing, we continuously expanded the lines from initial outgrowths and samples were cryopreserved as early stocks and banks. Batch release criteria included DNA-fingerprinting and HLA-typing for identity, characterization of pluripotency-associated marker expression, proliferation, karyotyping and differentiation in-vitro and in-vivo. These hESCs may be valuable for regenerative therapy. The ethical, scientific and regulatory methodology presented here may serve for development of additional clinical-grade hESCs.

Noncontrast computed tomography (CT) is commonly utilized after percutaneous nephrolithotomy (PNL) to assess stone-free (SF) status. In addition to assessing SF status, CT is useful in the recognition of complications after PNL. We characterized complications demonstrated by postoperative CT scan and compared hospital re-admission rates based on whether or not CT was performed.We retrospectively reviewed records of 1032 consecutive patients from April 1999 to June 2010. Patients were divided into two cohorts based on whether they had a CT within 24 hours of PNL. Demographic data, CT findings, and need for re-admission for complication management were assessed.Nine hundred fifty-seven patients (92.7%) underwent post-PNL CT. CT-diagnosed complications were perinephric hematoma in 41 (4.3%; 2 requiring embolization and 9 necessitating transfusion), pleural effusion in 25 (2.6%; 10 requiring intervention), colon perforation in 2 (0.2%), and splenic injury in 2 (0.2%). Of patients with postoperative complications, 33% required intervention. Among patients with a CT, 6 (0.6%) were readmitted despite negative postoperative CT (four perinephric hematomas, one calyceal-pleural fistula, and one pseudoaneurysm). The sensitivity of CT for diagnosing complications was 92.7%. Seventy-five patients (7.3%) did not undergo CT post-PNL. Of these, four (5.33%) were readmitted: three for perinephric hematomas and one for ureteral clot obstruction. Patients undergoing post-PNL CT were less likely to be readmitted because of missed complications (p=0.02).Serious post-PNL complications are uncommon, but their prompt diagnosis and treatment is imperative. In addition to identifying residual stones, CT is useful in diagnosing postoperative complications. Postoperative CT could potentially be considered for all patients undergoing PNL, particularly in complex cases such as patients with anatomical abnormalities (renal anatomic abnormality or retrorenal colon), patients requiring upper pole access (risk of thoracic, hepatic, and splenic complications), and patients requiring multisite access (higher risk of perinephric hematoma or need for transfusion).

The inhibitory extracellular environment that develops in response to traumatic brain injury and spinal cord injury hinders axon growth thereby limiting restoration of function. Several strategies have been developed to engineer a more permissive central nervous system (CNS) environment to promote regeneration and functional recovery. The multi-faced inhibitory nature of the CNS lesion suggests that therapies used in combination may be more effective. In this mini-review we summarize the most recent attempts to engineer the CNS extracellular environment after injury using combinatorial strategies. The advantages and limits of various combination therapies utilizing neurotrophin delivery, cell transplantation, and biomaterial scaffolds are discussed. Treatments that reduce the inhibition by chondroitin sulfate proteoglycans, myelin-associated inhibitors, and other barriers to axon regeneration are also reviewed. Based on the current state of the field, future directions are suggested for research on combination therapies in the CNS.

This article explores the implementation of evidence-based design elements in the renovation of 1 patient room on a budget of $3500. The functional mock-up was evaluated through survey and focus groups by staff, visitors, and physicians to identify problematic features. Overall, participants perceived that design elements were effective with only minor modification needed before replication. Suggestions are provided for ways to implement evidence-based design with limited funds.

Calculi from patients with musculoskeletal (MS) anomalies who are largely immobile and prone to urinary infections have been traditionally composed primarily of struvite and carbonate apatite. Because of substantial improvements in the care of these patients in recent decades, stone etiology may have shifted from infectious to metabolic. We assessed the composition of renal calculi and metabolic characteristics in a contemporary cohort of patients with MS anomalies who underwent percutaneous nephrolithotomy (PCNL).Retrospective analysis of patients who underwent PCNL between April 1999 and June 2009 and had follow-up 24-hour urine studies was performed. Patients with MS anomalies included spinal cord injury, myelomeningocele, muscular dystrophy, multiple sclerosis, cerebral palsy, or other clinical syndromes causing kyphoscoliosis and contractures.Our cohort included 33 patients with MS anomalies and 334 consecutive patients as a control group who underwent PCNL and had metabolic workup. Stones were infectious in etiology in 18.4% and 6.2% in MS and control groups, respectively. Thus, most patients harbored stones of metabolic origin. Metabolic stones in the MS group were composed of 52.7% hydroxyapatite, 10.5% calcium oxalate, 7.9% brushite, 2.6% uric acid, 0% cystine, and 7.9% other. Metabolic stones in the control group were 50.5% calcium oxalate, 16.4% hydroxyapatite, 11.5% brushite, 10.8% uric acid, 4.3% cystine, and 0.3% other. Mean 24-hour urine values for patients with metabolic stones in MS/control groups were volume 2.18/1.87 L/d, pH 6.78/6.05, calcium to creatinine ratio 220/151 mg/g, and oxalate 44.8/39.5 mg/d.Although patients with MS anomalies are traditionally thought to harbor infection-related calculi, most will be found to have calculi of metabolic etiology. The incidence of calcium phosphate stones is high in this group of patients, perhaps reflecting their high urinary pH.

• 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.• 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 stone2 cm in diameter were eligible for the study. • The primary outcome was the time to removal of the targeted stone.• A total of 57 PCNLs were performed after randomization: 25 Cyberwand and 32 LUS-II. • There was no difference (P0.05) observed between the two devices for target stone surface area (Cyberwand 526.6 cm³ vs LUS-II 540.1 cm³), time to clearance of target stone (Cyberwand 15.8 min vs LUS-II 14.2 min) and target stone clearance rate (Cyberwand 61.9 mm²/min vs LUS-II 75.8 mm²/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.• No appreciable difference between the dual-probe Cyberwand and the standard ultrasonic Olympus LUS-II lithotrites can be identified.

The incidence of brushite stones has increased during the last 3 decades and we report our experience with brushite stone formers.From 1996 to 2008 we identified 82 patients with brushite urinary calculi. After institutional review board approval a review of our prospectively collected database was performed.There were 54 (65.9%) male and 28 (34.1%) female stone formers. Mean age was 44 years (range 4 to 84). Prior stone events were reported by 69 (84.1%) patients with 54 (78.3%) having received shock wave lithotripsy. Bilateral calculi were present in 28 (34.1%) patients. Mean stone area was 29.2 mm(2) (range 2 to 130). Surgery was performed in 80 patients including 63 (76.8%) percutaneous nephrolithotomy, 8 (9.8%) ureteroscopy, 3 (3.7%) shock wave lithotripsy, and 6 (7.3%) ureteroscopy and percutaneous nephrolithotomy. After primary and secondary procedures 76 (92.7%) patients were rendered stone-free. Metabolic urine studies were available in 45 patients. All patients demonstrated 1 or more abnormalities, with hypercalciuria (greater than 250 mg daily for women and greater than 275 mg daily for men) in 38 (80.9%), urine pH greater than 6.2 in 29 (61.7%), urine volume less than 2 l in 27 (57.4%), hypocitraturia (less than 320 mg daily) in 22 (46.8%), hyperuricosuria (greater than 750 mg daily in women, greater than 800 mg daily in men) in 8 (17%) and hyperoxaluria (greater than 32 mg daily in women and greater than 43 mg daily in men) in 5 (10.6%). Recurrent stone events occurred in 31 (37.8%) patients at a mean of 33 (range 2 to 118) months from treatment.Brushite stone formers are a treatment challenge. Almost a third will present with bilateral stones and the stone burden is sizeable. Nearly 80% of patients report having prior shock wave lithotripsy and recurrent stone events occurred approximately 3 years after treatment. All patients with brushite stones in this cohort had an underlying metabolic abnormality and specifically brushite stones should be heralded as a marker for hypercalciuria. Based on these data we recommend all brushite stone formers undergo 24-hour urine studies and have close long-term followup.

The incidence of calcium phosphate (CaP) stone disease has increased over the last three decades; specifically, brushite stones are diagnosed and treated more frequently than in previous years. Brushite is a unique form of CaP, which in certain patients can form into large symptomatic stones. Treatment of brushite stones can be difficult since the stones are resistant to shock wave and ultrasonic lithotripsy, and often require ballistic fragmentation. Patients suffering from brushite stone disease are less likely to be rendered stone-free after surgical intervention and often experience stone recurrence despite maximal medical intervention. Studies have demonstrated an association between brushite stone disease and shock wave lithotripsy (SWL) treatment. Some have theorized that many brushite stone formers started as routine calcium oxalate (CaOx) stone formers who sustained an injury to the nephron (such as SWL). The injury to the nephron leads to failure of urine acidification and eventual brushite stone formation. We explore the association between brushite stone disease and iatrogenic induced transformation of CaOx stone disease to brushite by reviewing the current literature.

Background: Rescue medication options that are consistent with the product labeling for sumatriptan/ naproxen sodium (S/N) and that have been permitted in ≥1 clinical trial include the use of a second tablet of S/N, sumatriptan tablets (to a total daily dose of 200 mg), and naproxen sodium tablets (within the maximum limits recommended in the labeling). Sumatriptan subcutaneous (SC) injection might be especially useful as rescue medication mostly because of its rapid onset of activity. Objective: The aim of this study was to assess the pharmacokinetics and tolerability of sumatriptan SC used as rescue medication after the administration of oral S/N for the treatment of migraine. Methods: This randomized, open-label, 3-period crossover study compared the exposure to sumatriptan (Cmax and AUC to 14 hours after the administration of the second dose [AUC 0–14 ]) between 3 treatment regimens: an initial dose of S/N 85/500 mg followed 2 hours later by sumatriptan 4 or 6 mg SC (S/N + S4 and S/N + S6, respectively) (test), or sumatriptan 100 mg PO (2 tablets administered 2 hours apart) (S100 + S100) (reference). Healthy adults aged 18 to 55 years were randomly assigned to receive all 3 regimens in a randomized sequence. On day 1 of each treatment period, continuous cardiovascular monitoring (ECG telemetry), serial 12-lead ECG, and serial blood pressure (BP) measurements were conducted 1 hour before to 10 hours after the administration of the first dose. Blood samples for pharmacokinetic assessment were collected up to 14 hours after the administration of the first dose. Adverse events (AEs) were monitored from the time of consent until study completion. Participants returned to the clinic for pharmacokinetic blood sampling (for S/N + S4 and S/N + S6) and for tolerability assessment at 24, 48, and 72 hours after S/N administration. Results: A total of 30 healthy adults were randomized. Five withdrew prematurely (3, withdrawn consent; 1, AE; and 1, protocol deviation). Half of the subjects were men, the mean age was 27.8 years, and the mean weight was 79.3 kg (range, 54.6–100.8 kg). With S/N + S4, sumatriptan Cmax and AUC 0–14 did not exceed those with S100 + S100. Sumatriptan Cmax was 1.26-fold higher with S/N + S6 than with S100 + S100. Sumatriptan AUC 0–14 with S/N + S6 was not significantly greater than that with S100 + S100. Differences in serial BP measurements between the SC and S100 + S100 regimens were not statistically significant. The numbers of subjects in whom any AE was reported were 10 (37%) with S/N + S4, 14 (54%) with S/N + S6, and 13 (48%) with S100 + S100. Conclusions: Sumatriptan 4 and 6 mg SC administered 2 hours after an S/N tablet yielded sumatriptan exposure that did not exceed that of S100 + S100. Cmax with the S/N + S6 regimen was 1.26-fold higher than reference values. Both regimens were reasonably well tolerated. Randomized controlled trials are needed to test the efficacy and tolerability of these SC regimens. ClinicalTrials.gov identifier: NCT00875784.

The purpose of this study was to evaluate the effects of fibrin scaffolds on subacute rat spinal cord injury (SCI). Long-Evans rats were anesthetized and underwent a dorsal hemisection injury; two weeks later, the injury site was re-exposed, scar tissue was removed, and a fibrin scaffold was implanted into the wound site. An effective method for fibrin scaffold implantation following subacute SCI was investigated based on the presence of fibrin within the lesion site and morphological analysis 1 week after implantation. Prepolymerized fibrin scaffolds were found to be present within the lesion site 1 week after treatment and were used for the remainder of the study. Fibrin scaffolds were then implanted for 2 and 4 weeks, after which spinal cords were harvested and evaluated using markers for neurons, astrocytes, and chondroitin sulfate proteoglycans. Compared with untreated control, the fibrin-treated group had significantly higher levels of neural fiber staining in the lesion site at 2 and 4 weeks after treatment, and the accumulation of glial fibrillary acidic protein (GFAP) positive reactive astrocytes surrounding the lesion was delayed. These results show that fibrin is conducive to regeneration and cellular migration and illustrate the advantage of using fibrin as a scaffold for drug delivery and cell-based therapies for SCI.