Prior Patellectomy: A Systematic Review and Meta-Analysis Comparing Cruciate-Retaining and Posterior-Stabilized Total Knee Arthroplasty Survivorship and Reported Outcomes.

BACKGROUND: In the setting of total knee arthroplasty (TKA), prior patellectomy historically prompted the use of increased constraint implants, specifically posterior-stabilized (PS) designs. However, modern case series have reported similar outcomes utilizing cruciate-retaining (CR) implants. The primary outcome of this study was to compare implant retention rates between these 2 implant designs in prior patellectomy patients. Secondary outcomes included a comparison of patient-reported outcome scores and cause for revision. METHODS: A comprehensive systematic review was performed using Web of Science, PubMed, and Scopus databases per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Boolean operator search terms included "patellectomy AND (arthroplasty) OR (replacement)." Case reports, review articles, < 2 years of follow-up, and studies in which the implant design could not be ascertained were excluded. An initial screening of titles and abstracts for inclusion was performed, followed by a full manuscript review of eligible articles. Single-data extraction was performed, followed by subsequent statistical analysis. RESULTS: A total of 9 studies (209 knees) met the inclusion criteria. The average time from patellectomy to TKA was 16.1 years. While all patients had significant improvement in functional outcomes, CR implants displayed proportionally greater improvement in Knee Society Scores compared to PS implants (+108 versus +98%, P ≤ .001). However, there was a significantly greater rate of revision in the CR cohort compared to PS (18.6 versus 2.6%, P = .002). CONCLUSIONS: Prior patellectomy patients undergoing TKA have significant improvements in patient-reported functional outcomes and high midterm retention rates. While CR implant designs portend a potentially greater improvement in functional outcomes, they also have a greater risk for revision than their PS implant counterparts. However, contemporary implant designs and operative techniques likely render revision rates equivocal between CR and PS implants in postpatellectomy patients.

Bone Ongrowth of Contemporary Cementless Tibial Components: A Retrieval Analysis.

BACKGROUND: Cementless total knee arthroplasty is gaining interest as total knee arthroplasty patients become younger, more active, and interested in long-term biologic fixation. New porous coatings have altered mechanical properties to improve bone osseointegration, although limited data exist on this topic. We measured the bone ongrowth on retrieved tibial trays to determine how demographic, radiographic, or implant design factors correlate with ongrowth. MATERIAL AND METHODS: Twenty retrieved trays were assessed from 3 designs: Zimmer NexGen Trabecular Metal (n = 9), Stryker Triathlon Tritanium (n = 6), and Biomet Vanguard Regenerex (n = 5). Exclusion criteria included revision for aseptic loosening or early postoperative infection. Ongrowth on the tibial components and on corresponding pegs (if accessible) was assessed. The amount of osseointegration was reported as the bone directly opposed to the surface divided by the available area for ongrowth. Radiographs were reviewed for alignment and regions of biologic fixation. RESULTS: Bone ongrowth covered 65% ± 19% of the tibial tray surface and did not differ among manufacturers (P = .27). Medial pegs had less ongrowth than lateral pegs (39% vs 64%, P = .02). Vanguard medial pegs had less ongrowth than NexGen medial pegs (15% vs 61%, P = .03). Length of implantation was different between the NexGen (55 months) and Triathlon (24 months, P < .05) design only. Patient and radiographic data demonstrated no correlation with ongrowth. CONCLUSION: An average 65% of the porous tibial tray surface had ongrowth at revision. These values are consistent with manufacturing claims for excellent bone ongrowth for newer porous coatings.

Wartime Military Orthopaedics.

Military orthopaedic surgeons are faced with hardship and decreased morale. Surgeons have frequent deployments and practice inefficiencies resulting in poor retention rates. The purpose of this analysis is to report demographics and factors effecting military retention. A survey was sent to all members of the Society of Military Orthopedic Surgeons. The survey obtained demographic information, as well as factors affecting retention and termination of service. Data was compared between subset groups within the total respondent population. Of active-duty personnel, 38.5% plan on staying in the military until retirement. Most surgeons entered into the military due to a desire to serve their country, while most people leave service due to higher pay as a civilian. A minority of military orthopaedic surgeons achieve military retirement; however, increased pay, increased control over practice, and decreased frequency of deployments are factors that could improve retention rates. (Journal of Surgical Orthopaedic Advances 30(2):116-119, 2021).

Definitive External Fixation for Anterior Stabilization of Combat-related Pelvic Ring Injuries, With or Without Sacroiliac Fixation.

BACKGROUND: Combat-related pelvic ring injuries frequently lead to placement of a temporizing external fixation device for early resuscitation and transport. These injuries are commonly complicated by concomitant polytrauma and extensive soft-tissue injuries, which may preclude early internal fixation and lead to prolonged use of external fixation. To date, few studies have reported on the outcomes of definitive external fixation for combat-related pelvic ring injuries. QUESTIONS/PURPOSES: (1) In patients treated with definitive external fixation after combat-related pelvic ring injuries, how often is the quality of reduction within radiographically acceptable parameters at the end of treatment? (2) What proportion of patients demonstrate local heterotopic ossification after these injuries? (3) What patient- and treatment-related factors are associated with increased complications and pain? METHODS: We retrospectively studied all patients with pelvic ring injuries treated at a tertiary military referral center from January 2003 to December 2012. In total, 114 patients were identified, 55 of whom maintained an external fixation frame throughout their treatment. During that time, the general indications for definitive external fixation were an open, contaminated pelvic ring injury with a high risk of infection or open urologic injury; confluent abdominal, perineal, and thigh wounds; or comminution of the pubic ramus that would necessitate plate fixation extending up the anterior column in patients with open abdomen or exposure-compromising abdominal wounds. Posterior fixation, either sacroiliac or lumbopelvic, was applied in patients with sacroiliac instability. Of the 55 patients with pelvic ring injuries treated with definitive external fixation (27 open and 28 closed), four underwent hemipelvectomy and construct removal for massive ascending infections and four were lost to follow-up, leaving 47 patients (85%) who were available at a minimum follow-up of 12 months (median 29 months, interquartile range 17-43 months). All 47 patients underwent serial imaging to assess their injury and reduction during treatment. External fixators were typically removed after 12 weeks, except in patients in whom pin-site irritation or infection prompted earlier removal, and all were confirmed to be grossly stable during an examination under anesthesia. Clinical union was defined as the absence of radiographically present fracture lines and stable examination findings under anesthesia when the external fixator was removed. Data on demographics, injury pattern, associated injuries, revision procedures, complications, and final functional outcomes including ambulation status, sexual function, and pain were collected. Pelvic radiographs were reviewed for the initial injury pattern, type of pelvic fixation construct, residual displacement after removal of the frame, and evidence of formation of heterotopic ossification in the pelvis or bilateral hips. Pelvic displacement and diastasis were determined by digital caliper measurement on plain images; malunion was defined as anterior diastasis of the pelvis or vertical incongruity of the hemipelvis greater than 10 mm. RESULTS: Radiographic malunion after construct removal occurred in eight of 24 patients with open injuries and in five of 23 patients with closed injuries. Heterotopic ossification developed in the pelvis or hips of all 24 patients with open injuries and in two of the 23 patients with closed injuries. In patients with open pelvic ring injuries, concomitant acetabular fractures were associated with pelvic pain at the final follow-up examination (risk ratio 1.9; 95% confidence interval, 1.0-3.5; p = 0.017). No treatment factor resulted in superior functional outcomes. In the closed-injury group, concomitant lower-extremity amputation was associated with improved radiographic final reduction (RR 0.4; 95% CI, 0.2-0.7; p = 0.02). There was no association between radiographic malunion and increased pain (RR 1.9; 95% CI, 0.5-7.0; p = 0.54 for the open group; RR 0.8; 95% CI, 0.7-1.0; p = 0.86 for the closed group). CONCLUSION: In this series of patients with severe combat-related pelvic ring injuries who were treated anteriorly with definitive external fixation because of a severe soft-tissue injury, high infection risk, or unacceptable physiologic cost of internal fixation, malunion and chronic pelvic pain were less common than previously observed. Prior studies primarily differ in their lack of sacroiliac or lumbopelvic stabilization for posteriorly unstable fracture patterns, likely accounting for much of these differences. There may have been important between-study differences such as extremely severe injuries, concomitant injuries, and study population. Our study also differs because we specifically analyzed a large cohort of patients who sustained open pelvic ring injuries. Future studies should prospectively investigate the ideal construct type and pin material, optimize the length of treatment and assessment of healing, and improve radiographic measures to predict long-term functional outcomes. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Fascia Iliaca Blockade With the Addition of Liposomal Bupivacaine Versus Plain Bupivacaine for Perioperative Pain Management During Hip Arthroscopy: A Double-Blinded Prospective Randomized Control Trial.

PURPOSE: To determine in a prospective, randomized fashion whether liposomal bupivacaine extends the effectiveness of decreased pain scores and reduces narcotic requirements following hip arthroscopy when used in addition to a fascia iliaca blockade with plain bupivacaine alone. METHODS: Double-blinded prospective randomized controlled trial of participants undergoing hip arthroscopy. Randomized to receive a fascia iliaca blockade with 40 mL 0.25% plain bupivacaine (100 mg; control group) or 20 mL 0.5% plain bupivacaine (100 mg) plus 20 mL liposomal bupivacaine (266 mg; study group). The primary outcome was Defense and Veterans Pain Rating Scale (DVPRS) scores in the postanesthesia care unit and on postoperative days (POD) 1, 2, 3, and 14. Secondary outcomes included postoperative opioid consumption and subjective loss of anterior thigh sensation. RESULTS: Seventy-four patients were enrolled, and 70 completed the study; 37 were randomized to the control group and 33 to the study group. There was no significant difference in postoperative DVPRS scores at any time point. There was no significant difference in total postoperative opioid use during any postoperative time points. While most patients reported anterior thigh numbness at discharge, significantly more patients in the study group reported anterior thigh numbness at POD2 (control, 19/37 numb vs study, 32/33 numb; P < .0001) and at POD3 (control, 8/37 numb vs study, 26/33 numb; P < .0001). CONCLUSIONS: In this prospective evaluation comparing plain bupivacaine versus the liposomal formulation administered via a fascia iliaca blockade there were no significant differences in postoperative pain scores and narcotic pill usage. Given the highly significant findings of prolonged anterior thigh numbness out to POD3 in patients who received liposomal bupivacaine, this formulation did exhibit prolonged effects; however, it did not provide improved pain control when used in this surgical population, likely due to the innervation of the hip capsule from differential nerve plexi. Given the 6-fold increased cost of using the liposomal formulation, we are unable to recommend its use via a fascia iliaca blockade for hip arthroscopy. LEVEL OF EVIDENCE: Level I, therapeutic study.

Effects of chronic systemic low-impact ampakine treatment on neurotrophin expression in rat brain.

Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive allosteric modulators of AMPA-type glutamate receptors. Currently, they are being developed to prevent opioid-induced respiratory depression without sacrificing the analgesic properties of the opioids. In addition, these molecules increase neuronal activity and have been shown to restore age-related deficits in LTP in aged rats. In the current study, we examined whether two different ampakines could increase levels of BDNF and NGF at doses that are active in behavioral measures of cognition. Results demonstrate that ampakines CX516 and CX691 induce differential increases in neurotrophins across several brain regions. Notable increases in NGF were observed in the dentate gyrus and piriform cortex while notable BDNF increases were observed in basolateral and lateral nuclei of the amygdala. Taken together, our data demonstrates that chronic administration of clinically relevant doses of ampakines have the ability to elevate neurotrophin expression in different brain regions, and may have therapeutic benefit in multiple neurodegenerative and/or neuropsychiatric disorders.

Ampakines Attenuate Staurosporine-induced Cell Death in Primary Cortical Neurons: Implications in the 'Chemo-Brain' Phenomenon.

BACKGROUND/AIM: Mounting evidence suggests that trophic cell signaling can be mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation. It has been demonstrated that exogenous application of brain-derived neurotrophic factor (BDNF) is highly neuroprotective in vitro against neurotoxic insults such as standard chemotherapies. MATERIALS AND METHODS: Because positive allosteric modulation of AMPARs with ampakines can increase both BDNF mRNA and protein in vitro and in vivo, we examined whether application of the ampakines CX614 and CX729 promoted neuroprotection against staurosporine-induced cell death in rat primary cortical neurons using propidium iodide to stain for dead cells. RESULTS: A transient 2-h pretreatment with CX614 or CX729 performed 24 h prior to staurosporine produced significant, time-dependent neuroprotection that was resistant to the AMPAR antagonists NBQX or GYKI 52466, suggesting that this effect may be independent of ion flow. Furthermore, the pretreatment time requirements of CX729 matched the time course for increased BDNF expression previously reported to occur in hippocampal slices, suggesting that increased neurotrophin expression might be associated with the neuroprotective effects conferred by ampakines. CONCLUSION: Our data demonstrate that ampakines may be able to perturb neuronal toxicity and peripheral neuropathy of front-line chemotherapies.

Tarps differentially affect the pharmacology of ampakines.

Transmembrane AMPA receptor regulatory proteins (TARPs) govern AMPA receptor cell surface expression and distinct physiological properties including agonist affinity, desensitization and deactivation kinetics. The prototypical TARP, STG or γ2 and TARPs γ3, γ4, γ7 and γ8 are all expressed to varying degrees in the mammalian brain and differentially regulate AMPAR gating parameters. Positive allosteric AMPA receptor modulators or ampakines alter receptor rates of agonist binding/unbinding, channel opening and can offset receptor desensitization and deactivation. The effects of the two ampakines, CX614 and cyclothiazide (CTZ) were evaluated on homomeric GluR1-flip receptors and GluR2-flop receptors expressed on HEK293 cells by transient transfection with or without different TARPs γ2, γ3, γ4 or γ8 genes. γ4 was the most robust TARP in increasing the affinities of CX614 and CTZ on GluR1-flip receptors, but had no such effect on GluR2-flop receptors. However, γ8 gave the most significant increases in affinities of CX614 and CTZ on GluR2-flop. These data show that TARPs differentially affect the surface expression and kinetics of the AMPA receptor, as well as the pharmacology of ampakines for the AMPA receptor. The modulatory effects of TARPs on ampakine pharmacology are complex, being dependent on both the TARP subtype and the AMPA receptor subtypes/isoforms.

Clinical Outcomes After Extracorporeal Shock Wave Therapy for Chronic Plantar Fasciitis in a Predominantly Active Duty Population.

Chronic plantar fasciitis is a common cause of foot pain, with conservative treatment providing relief for most patients. However, because of the common occurrence of this pathology, this leaves many patients dissatisfied. The purpose of the present study was to determine the effectiveness of extracorporeal shock wave therapy (ESWT) to treat chronic plantar fasciitis (PF) in a largely active duty population. A review of 82 patients (115 heels) who had undergone ESWT for chronic PF was performed. Outcome data were obtained by patient telephone interviews. All ESWT was conducted at 24 kV for 2000 shocks. Of the 82 patients (115 heels), 76 (93%; 111 heels) agreed to participate. Their mean age was 42 ± 10 years, with 41 males (54%) and 35 females (46%). The mean follow-up period was 42 ± 22 months. Of the patients, 73.6% were active duty military personnel. The mean preoperative pain score of 7.8 ± 2 had improved to 2.5 ± 2 at the last follow-up visit (p <.0001). Active duty patients reported a mean improvement in pain of 4.8 ± 3 compared with 6.8 ± 3 in non-active duty patients (p = .005). Of the 76 patients, 75 (98%) underwent 1 ESWT session, and 1 (2%) requiring 2 sessions. Overall, 74% of patients rated the outcome of their procedure as either good or excellent, with 87% stating that ESWT was successful. Ten patients (18%) left the military because of continued foot pain, with 76% able to return to running. For patients with chronic PF, these results support the use of ESWT to relieve pain in >85% of patients, with a preponderance for better pain relief in patients who are not active duty military personnel.

Elimination of Preoperative Flexion Contracture as a Contraindication for Unicompartmental Knee Arthroplasty.

INTRODUCTION: Unicompartmental knee arthroplasty (UKA) is an effective alternative to total knee arthroplasty (TKA) for the management of unicondylar osteoarthritis. Historical contraindications limit patients' eligibility for UKA. However, recent reports have suggested that some contraindications may not be absolute. This study evaluates preoperative flexion contracture with regard to UKA. METHODS: This study was a retrospective review of 53 patients with preoperative flexion contracture between 11° and 20° who underwent fixed-bearing UKA and a matched cohort of 53 patients who underwent cruciate-retaining TKA. RESULTS: Preoperatively, the average flexion contracture was 13.8° in the UKA group and 14.1° in the TKA group (P = 0.42). Mean preoperative motion was greater in the patients treated with UKA (106°) than in those treated with TKA (97°; P < 0.001). Postoperatively, patients who underwent UKA had greater motion than patients who underwent TKA had (121° versus 113°; P < 0.01). Residual flexion contracture was greater in the UKA group (4.1°) than in the TKA group (2.1°; P = 0.02). The two groups demonstrated similar improvements in Knee Society clinical scores (P = 0.32). However, patients treated with UKA demonstrated higher Knee Society functional scores, compared with patients treated with TKA (86 versus 75; P = 0.03). DISCUSSION: Although residual flexion contracture was worse after UKA, this group had similar clinical improvement, greater postoperative motion, and greater function scores, compared with the matched TKA group. Preoperative flexion contracture >5° may not be an absolute contraindication to UKA. CONCLUSION: The contraindications to UKA regarding flexion contracture may not be as absolute as previously thought. Larger, prospective studies are needed to generalize these findings to a wider population.

Fascia iliaca blockade with the addition of liposomal bupivacaine vs. plain bupivacaine for perioperative pain management following hip arthroscopy.

PURPOSE: A newer formulation of bupivacaine, encapsulated within carrier molecules, has garnered attention for its role in providing extended post-operative analgesia. The purpose was to evaluate the addition of liposomal bupivacaine to fascia iliaca blockade during hip arthroscopy. METHODS: Retrospective cohort study of patients undergoing hip arthroscopy with a pre-operative fascia iliaca blockade with either liposomal bupivacaine (Group 1; 266mg + 20 cc 0.5% plain bupivacaine) or bupivacaine (Group 2; 40 cc 0.25% plain bupivacaine). All patients received standardized pre-operative oral pain medications. The primary outcome was the defense veteran pain rating scale (DVPRS). Secondary outcomes included duration of hospital admission, PACU opioid use, PACU pain scores, and duration of nerve blockade. RESULTS: Thirty-eight males and 30 females, mean age of 33 years (range 14-56). There was no difference in pre-operative DVPRS between the groups (n.s.). There was no difference in post-operative DVPRS pain scores at POD0 (3.7 vs. 3.9, n.s.), POD1 (4.2 vs. 3.8, n.s.), POD2 (4.2 vs. 3.7, n.s.), POD3 (3.9 vs. 3.7, n.s.) or POD14 (2.2 vs. 2.4, n.s.). Group 1 trended towards longer mean total hospital admission time (872 vs. 822 min, n.s.), and greater mean morphine equivalents administered in the PACU (33 vs. 29 mg, n.s.). 68% of patients in group 1 reported continued anterior thigh numbness at POD3, compared to 34% in group 2 (p = 0.008). CONCLUSIONS: Despite the advertised benefits of prolonged post-operative analgesia using liposomal bupivacaine, there were no significant differences in post-operative pain scores or PACU opioid consumption. Our results support that acceptable pain scores are successfully achieved at all time periods with the use of multimodal analgesia including fascia iliaca blockade despite the type of pain medication administered. LEVEL OF EVIDENCE: III.

Operating room traffic in total joint arthroplasty: Identifying patterns and training the team to keep the door shut.

BACKGROUND: Surgical site infections after joint arthroplasty are devastating complications and are influenced by patient, surgical, and operating room environmental factors. METHODS: In an effort to reduce the incidence of door openings (DOs) during total joint arthroplasty cases, this prospective observational study consisted of 3 phases. Phase 1 determined the baseline incidence of DOs, followed by installation of a mechanical door counter (phase 2). Finally, an educational seminar was presented to all personnel (phase 3) regarding the implications frequent DOs have on patient and surgical outcomes. RESULTS: The average openings per case (OPC) for each of the 3 phases were 33.5, 34.2, and 27.7, respectively. There was a 17% reduction in OPC between phases 1 and 3 (P= .02). There were no significant differences between knee and hip arthroplasty cases during the 3 phases (P= .21, P= .46, and P= .81, respectively). There was a strong correlation between length of surgery and OPC, with a Pearson coefficient of r = 0.87 during phase 3. To account for differences in average operative time between phases, data were normalized for the length of surgery with the ratio of door openings per minute determined (0.36, 0.34, and 0.32 for each phase, respectively). CONCLUSIONS: We were able to show that simply monitoring door openings during joint arthroplasty was not effective in reducing the occurrences. However, after a novel educational seminar given to all personnel, we were able to significantly reduce the incidence of operating room door openings, reducing a potential risk factor for surgical site infections.

Stargazin differentially modulates ampakine gating kinetics and pharmacology.

It was previously reported that Stargazin (STG) enhances the surface expression of AMPA receptors, controls receptor gating and slows channel desensitization as an auxiliary subunit of the receptors. Ampakines are a class of AMPA receptor positive allosteric modulators that modify rates of transmitter binding, channel activity and desensitization parameters. As such, they have shown efficacy in animal models of neurodegenerative diseases, where excitatory synaptic transmission is compromised. Given the functional similarities between STG and ampakines, the current study sought to probe interactions between STG and ampakine gating properties. The effects of the high impact ampakines, CX614 and cyclothiazide (CTZ), were compared with homomeric GluR1-flip (Glur1i) and GluR2-flop (Glur2o) receptors expressed in HEK293 cells by transient transfection with or without STG gene. STG dramatically enhanced the surface expression of AMPA receptors and increased glutamate-induced steady-state currents during desensitization. STG also increased ratios of 500 µM kainate and 500 µM glutamate activated steady-state currents. STG reduced association rates of ampakines and differentially affected the dissociation rates for both CX614 and CTZ on desensitized receptors. The estimated Kd value for CX614 was lowered from 340 µM to 70 µM, whereas that for CTZ was lowered from 170 µM to 6 µM by STG. The data suggest that Stargazin can dramatically alter the conformation of the receptor dimer interface where CX614 and CTZ are known to bind. This work also demonstrates the importance of considering STG interactions when developing ampakines to treat neurodegenerative diseases in which AMPAergic signaling is compromised.

Comparison of Wound Complications and Deep Infections With Direct Anterior and Posterior Approaches in Obese Hip Arthroplasty Patients.

BACKGROUND: The purpose of this study was to compare the posterior approach (PA) with the direct anterior approach (DAA) among obese and nonobese total hip arthroplasty patients to determine if obese DAA patients have a higher risk of infection or wound complications compared with obese PA patients. METHODS: We retrospectively evaluated 4651 primary total hip cases performed via anterior approach or PA between 2009 and 2015. Patients were divided into 4 study groups based on approach and body mass index (BMI): (1) DAA <35 kg/m2, (2) DAA ≥35 kg/m2, (3) PA <35 kg/m2, and (4) PA ≥35 kg/m2. Infection rates and wound complications were compared. RESULTS: The rate of deep infection in groups 1 and 3 (nonobese anterior vs posterior) was 0.28% and 0.36%, respectively (P = .783); and in groups 2 and 4 (obese anterior vs posterior) was 2.35% and 2.7%, respectively (P = .80). The rate of wound complications between groups 1 and 3 (nonobese) was 1.0% and 0.3%, respectively (P = .005). Between groups 2 and 4 (obese), the rates of complications were 1.7% and 1.4%, respectively (P = 1.0). There was no difference in reoperation rates for wounds between groups 1 and 3 or between groups 2 and 4 (P = .217, P = .449). CONCLUSION: In the largest available series, there was no difference in deep infection rates between the 2 approaches. In the subset of obese patients with BMI ≥35 kg/m2, there was no increased risk of deep infection or wound complications in DAA patients compared with PA patients. However, anterior hip cases experienced higher rates of superficial wound complications compared with posterior cases across all BMIs.

Oncolytic Properties of Ampakines In Vitro.

BACKGROUND/AIM: The 5-year survival rate of glioblastoma (GBM) is ~10%, demonstrating that a new therapeutic modality for this cancer is desperately needed. Complicating the search for such a modality is that most large molecules cannot pass through the blood brain barrier, so molecules demonstrating efficacy in vitro may not be useful in vivo because they never reach the brain. Recently, the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) was identified as an effective agent in targeting GBM in vitro and in vivo by agonizing AMPA-glutamate receptors (AMPARs), eliciting massive calcium influx and mitochondrial calcium overload and apoptosis. MATERIALS AND METHODS: In the current study, we used a colorimetric cell viability assay to determine if we could enhance the oncolytic effect of FLX in vitro by pre-treating cells with an AMPAR-positive allosteric modulator (Ampakine). RESULTS: Our results demonstrated for the first time that concentrations of the Class I ampakine CX614, which increase AMPAR agonist binding affinity, possess oncolytic activity as a sole agent and synergistically reduce GBM viability when paired with FLX. FLX also demonstrates a dose-dependent induction of apoptosis in cancer cells originating outside the CNS that overexpress calcium-permeable AMPARs. Likewise, CX614 inhibits cancer cell viability in a dose-dependent fashion and its combination with FLX synergistically reduces cell viability. These effects of CX614 were not seen with the Class II ampakines, CX717 and CX1739. CONCLUSION: CX614 inhibits the growth of multiple cancers in vitro and bolsters the oncolytic activity of FLX in several cancers.

Combat-related acetabular fractures: Outcomes of open versus closed injuries.

INTRODUCTION: Since the onset of the Global War on Terror close to 50,000 United States service members have been injured in combat, many of these injuries would have previously been fatal. Among these injuries, open acetabular fractures are at an increased number due to the high percentage of penetrating injuries such as high velocity gunshot wounds and blast injuries. These injuries lead to a greater degree of contamination, and more severe associated injuries. There is a significantly smaller proportion of the classic blunt trauma mechanism typically seen in civilian trauma. METHODS: We performed a retrospective review of the Department of Defense Trauma Registry into which all US combat-injured patients are enrolled, as well as reviewed local patient medical records, and radiologic studies from March 2003 to April 2012. Eighty seven (87) acetabular fractures were identified with 32 classified as open fractures. Information regarding mechanism of injury, fracture pattern, transfusion requirements, Injury Severity Score (ISS), and presence of lower extremity amputations was analyzed. RESULTS: The mechanism of injury was an explosive device in 59% (n=19) of patients with an open acetabular fracture; the remaining 40% (n=13) were secondary to ballistic injury. In contrast, in the closed acetabular fracture cohort 38% (21/55) of fractures were due to explosive devices, and all remaining (n=34) were secondary to blunt trauma such as falls, motor vehicle collisions, or aircraft crashes. Patients with open acetabular fractures required a median of 17units of PRBC within the first 24h after injury. The mean ISS was 32 in the open group compared with 22 in the closed group (p=0.003). In the open fracture group nine patients (28%) sustained bilateral lower extremity amputations, and 10 patients (31%) ultimately underwent a hip disarticulation or hemi-pelvectomy as their final amputation level. DISCUSSION: Open acetabular fractures represent a significant challenge in the management of combat-related injuries. High ISS and massive transfusion requirements are common in these injuries. This is one of the largest series reported of open acetabular fractures. Open acetabular fractures require immediate damage control surgery and resuscitation as well as prolonged rehabilitation due to their severity. The dramatic number of open acetabular fractures (37%) in this review highlights the challenge in treatment of combat related acetabular fractures.

Brain Vacuolation Resulting From Administration of the Type II Ampakine CX717 Is An Artifact Related to Molecular Structure and Chemical Reaction With Tissue Fixative Agents.

Ampakines are small molecule positive allosteric modulators of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). One class II ("low impact") ampakine, CX717, has been implicated to have a neurotoxic effect based on findings in nonclinical, long-term toxicity studies. The neurotoxicity concerns, which halted the clinical development of the molecule, arose due to a finding of extensive white matter vacuolation in multiple brain regions of animals that were administered high doses of CX717 in several test species (unpublished data). This work characterized the features and a potential mechanism by which ampakines induce vacuoles in brain tissue. Brain sections from adult rats given CX717 (750 mg/kg BID by oral gavage) exhibited no vacuoles with acute or short-term dosing. However, after 14 or more days of treatment, vacuoles were prominent in cerebellum, globus pallidus, and hippocampus. Vacuole margins were lined by glial fibrillary acidic protein (GFAP), and by transmission electron microscopy were shown to be astrocyte processes. CX717-associated vacuoles occurred in formaldehyde-fixed specimens but not flash-frozen samples. Time-course experiments showed that brain tissue slices from CX717-treated animals exhibit no vacuoles until immersed in formaldehyde fixative, whereupon vacuoles form and expand in a time-dependent manner. Chemical interactions in test tube experiments have demonstrated that the combination of CX717 and formalin in an aqueous solution produces an exothermic reaction. Taken together, the data indicate that CX717 does not induce vacuoles in vivo, but rather is associated with astrocyte vacuolation post mortem, likely as the ampakine reacts with formalin to produce gas pockets in brain parenchyma.

Results of Porous-Coated Anatomic Total Hip Arthroplasty without Cement at 25 to 30 Years: A Concise Follow-up of a Previous Report.

The purpose of this study was to update the results of a prospective series of 100 primary cementless total hip arthroplasty (THA) procedures that were performed between 1983 and 1986 with use of the Porous Coated Anatomic (PCA) system. This is one of the first prospective studies of cementless primary THA with a minimum of 25 years of follow-up. Twenty-one patients (22 hips) of the original series were alive and had clinical and radiographic follow-up at a minimum of 25 years postoperatively. Twenty-three percent (23) of all hips and 50% (11) of the hips among the living cohort had undergone revision for loosening and/or osteolysis of the acetabular component, and 7% (7) of all hips and 4.5% (1) of the hips among the living cohort were revised for loosening and/or osteolysis of the femoral component. Only 4 femoral stems were revised for isolated loosening (without osteolysis). The PCA femoral component proved to be durable at a minimum of 25 years postoperatively, while the acetabular component was less durable. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.