BAK Group Research Articles

Discovery of bakuchiol as an AIM2 inflammasome activator and cause of hepatotoxicity

Ethnopharmacological relevancePsoralea corylifolia (P. corylifolia Linn.) is a traditional Chinese medicinal plant that exhibits significant aphrodisiac, diuretic, and anti-rheumatic effects. However, it has been reported to cause hepatic injury, but the precise mechanisms remain unclear. Aim of the studyTo evaluate the safety and risk of P. corylifolia and to elucidate the underlying mechanisms of drug-induced liver injury. Materials and methodsWestern blotting, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, quantitative polymerase chain reaction (Q-PCR), and flow cytometry were used to explore the effect of bakuchiol (Bak), one of the most abundant and biologically active components of P. corylifolia, on the AIM2 inflammasome activation and the underlying mechanism. Furthermore, we used the lipopolysaccharides (LPS)-induced drug-induced liver injury (DILI) susceptible mice model to study the Bak-mediated hepatotoxicity. ResultsBak induced the maturation of caspase-1 P20, and significantly increased the expression of IL-1β and TNF-α (P < 0.0001) compared with the control group. Moreover, compared to the Bak group, knockdown of AIM2 inhibited Bak-induced caspase-1 maturation and significantly decreased the production of IL-1β and TNF-α, but knockout of NLRP3 had no effect. Mechanistically, Bak-induced AIM2 inflammasome activation is involved in mitochondrial damage, mitochondrial DNA (mtDNA) release, and subsequent recognition of cytosolic mtDNA. Our in vivo data showed that co-exposure to LPS and non-hepatotoxic doses of Bak significantly increased the levels of ALT, AST, IL-1β, TNF-α, and IL-18, indicating that Bak can induce severe liver inflammation (P < 0.005). ConclusionsThe result shows that Bak activates the AIM2 inflammasome by inducing mitochondrial damage to release mtDNA, and subsequently binds to the AIM2 receptor, indicating that Bak may be a risk factor for P. corylifolia-induced hepatic injury.

Risk factors for periorbital dermatitis in patients using dorzolamide/timolol eye drops

This study assessed the clinical risk factors for periorbital dermatitis (PD) after using dorzolamide/timolol eye drops in a total of 1282 glaucoma patients. Both the PD(+) group and the PD(−) group were evaluated using clinical data such as age, sex, dosing duration, presence of benzalkonium chloride (BAK) in the formulation, ocular surgery history (e.g. cataract or glaucoma operations), height, weight, personal history of systemic hypertension, smoking, alcohol consumption, intraocular pressure, best-corrected visual acuity (BCVA), central corneal thickness, axial length, and visual field index (VFI). Univariate analyses showed that shorter dosing duration, higher rate of BAK-included cases, worse BCVA, worse VFI, more systemic hypertension history, and more ocular surgery history were more associated with the PD(+) group than the PD(−) group. The BAK(−) group showed a lower PD rate than the BAK-included group, which was supported by the Kaplan–Meier analysis (log-rank test, p = 0.0014). Multivariate analyses revealed that the probability of PD increased by 8 times if they had a history of ocular surgery and increased by 2.3% when the VFI decreased by 1% (Cox’s hazard regression test, p < 0.001). Therefore, a preservative-free dorzolamide/timolol can benefit the subjects for those who had ocular surgery or who have worse VFI.

The Effects of Antiglaucoma Ophthalmic Solutions on the Cornea Revealed by a Corneal Electrical Resistance Device.

Purpose: We sought to evaluate the effect of antiglaucoma ophthalmic solutions on the cornea with a corneal resistance device (CRD), and to compare the results with those by fluorescein staining. Methods: In 6 rabbit groups (n = 7 each), right eyes were administered latanoprost ophthalmic solution containing 0.02% benzalkonium chloride (BAK); dorzolamide/timolol (1%/0.5%) containing 0.005% BAK; dorzolamide/timolol without BAK; dorzolamide/timolol+latanoprost with 0.02% BAK; 0.005% BAK; or 0.02% BAK to the conjunctival sac 3 × at 15-min intervals. Left (control) eyes were administered saline. Baseline and post-treatment corneal resistance (CR) were measured. The CR ratio = CR before versus after treatment. We evaluated superficial punctate keratitis by fluorescein staining using area and density (AD) grades. Results: In the dorzolamide/timolol-without BAK group, there were no significant difference in the CR ratio between the control and treatment eyes at any time point. In the 0.005%-BAK group at 30 min and the other 4 groups at all time points, the CR ratio differed significantly between the control and treatment eyes (P < 0.05). AD grades were 0 in all control eyes and the dorzolamide/timolol-without BAK and 0.005% BAK treatment eyes. Conclusions: Nonpreservative ophthalmic solutions (and those with low BAK concentrations) do not significantly affect corneal electrical resistance. Eye drop ingredients other than BAK may be involved in altering corneal electrical resistance. CRDs may detect corneal epithelium changes not revealed by fluorescein staining.

Ocular surface inflammation induces de novo expression of substance P in the trigeminal primary afferents with large cell bodies

We evaluated the changes in substance P (SP)-expressing trigeminal neurons (TNs) innervating the cornea following ocular surface inflammation. Ocular surface inflammation was induced in Sprague–Dawley rats using 0.1% benzalkonium chloride (BAK). The corneal staining score, corneal epithelial apoptosis, conjunctival goblet cells, and density of corneal subbasal nerve plexus (SNP) were assessed, and the mRNA levels of SP, interleukin (IL)-1β, IL-6, and tumour necrosis factor-α were measured in corneas and ipsilateral trigeminal ganglia (TG). SP-immunoreactivity (IR) was measured in corneal intraepithelial nerves and TNs. The cell size of corneal TNs in the TG was calculated. All parameters were observed immediately (BAK group), at 1 week (1 w group), and 2 months (2 m group) after 2 weeks of BAK application. BAK caused an increase in the corneal staining score and the number of apoptotic cells, loss of conjunctival goblet cells, reduced density of corneal SNP, and upregulated expression of SP and inflammatory cytokines in both the cornea and TG in the BAK group but those changes were not observed in the 2 m group. On the other hand, SP-IR% and mean cell size of corneal TNs increased significantly in the BAK, 1 w, and 2 m groups, compared to the control. Our data suggest that following ocular surface inflammation, large-sized corneal TNs which normally do not express SP, expressed it and this phenotype switching lasted even after the inflammation disappeared. Long-lasting phenotypic switch, as well as changes in the expression level of certain molecules should be addressed in future studies on the mechanism of corneal neuropathic pain.

Profiling ocular surface responses to preserved and non-preserved topical glaucoma medications: A 2-year randomized evaluation study.

Use of topical glaucoma medications has been reported to cause ocular surface (OS) discomfort and inflammation. This study explores the profile of inflammatory cytokines and OS symptoms induced in response to preserved and non-preserved drops. Prospective, randomized evaluation on 36 treatment-naïve patients over 24 months of three differently preserved glaucoma drop preparations: Preservative-free (PF), polyquad (PQ) and benzalkonium chloride (BAK). Study participants were evaluated at baseline and then at 1, 3, 6, 12 and 24 months while on medication. At each visit, participants completed the OS disease index (OSDI) questionnaire, had basal tear sampling and impression cytology (IC) of the conjunctival epithelium. Quantitative polymerase chain reaction was performed to measure the gene expression of inflammatory cytokines [interleukin (IL)-6, IL-8, IL-10, IL-12A, IL-12B, IL-17A, IL-1β and tumour necrosis factor-α] in the IC samples. Corresponding protein expression of cytokines in tear samples was assessed by the Becton-Dickinson cytometric bead arrays. Compared to PF and PQ groups, mRNA and protein expression of IL-6, IL-8 and IL-1β increased in samples from the BAK group in a time-dependent fashion, whereas all other cytokines showed a non-significant increase. In the BAK group, there was a strong correlation between OSDI and the levels of IC/IL-1β (r = .832, R2 = .692 and P = .040); IC/IL-10 (r = .925, R2 = .856 and P = .008) and tear/IL-1β (r = .899, R2 = .808 and P = .014). BAK-preserved topical drops stimulate a sterile inflammatory response on the OS within 3 months which is maintained thereafter, whereas PF-drops and PQ-preserved drops showed no significant OS inflammation.

Effects of Benzalkonium Chloride and Preservative-Free Composition on the Corneal Epithelium Cells.

Purpose: Benzalkonium Chloride (BAK) is reported to have the potential to damage the cornea. We developed a composition with broad-spectrum antimicrobial activity without preservatives by combining trometamol, boric acid, and ethylenediaminetetraacetic acid (TBE). This study aimed at evaluating the corneal damage caused by TBE and comparing it with that caused by BAK. Methods: SV40-immortalized human corneal epithelial cell line (HCE-T) was treated with BAK or TBE, and the cell viability was measured. The exposure time that caused 50% cell death (CDT50) was calculated. Transepithelial electrical resistance (TEER) was measured before and after treatment with BAK or TBE. Occludin was detected with immunostaining and Western blotting after treatment with BAK or TBE. The effect of BAK or TBE on membrane-associated mucins was evaluated with rose bengal (RB) staining. Results: In the BAK group, cell viability decreased in a dose-dependent manner. The viability of the TBE group was significantly greater than that of the BAK group. The CDT50 of the TBE group is greater than that of the BAK groups. In the BAK groups, the recovery of TEER was delayed in a dose-dependent manner, whereas in the TBE group, the recovery occurred earlier. Localization of occludin was disrupted, and the amount of occludin was significantly reduced among the cells exposed to BAK. The area stained with RB in the BAK groups increased, whereas that in the TBE group did not increase. Conclusion: These results suggest that the application of TBE would be useful for developing preservative-free ophthalmic preparations that offer both sufficient safety and antimicrobial activity.

Ocular Surface Disease with BAK preserved Travoprost and Polyquaternium 1(Polyquad) preserved Travoprost

Introduction. The topical medications containing benzalkonium chloride (BAK) as preservative is known to induce corneal toxicity and ocular surface disease (OSD) in glaucoma patients. Newer preservatives like SofZia or polyquaternium-1 (Polyquad) have been developed to replace BAK in many medications. The present study aimed at comparing the OSD in glaucoma patients receiving BAK preserved travoprost versus travoprost with polyquad as preservative and controls not receiving any medications. Methods. This prospective, controlled, observational study was conducted on patients of primary open angle glaucoma (POAG) on medications for more than 6 months. The first group comprised of 40 patients receiving BAK preserved travoprost, the second group included 40 patients receiving polyquad preserved travoprost and 30 of control group not receiving any medical treatment. Ocular Surface Disease Index (OSDI) scores using Ocular Surface Disease Index (OSDI) Questionnaire were assessed and compared in all subjects. Results. The mean OSDI score was 29.09 ± 13.45 in BAK group, 12.4 ± 5.085 in polyquad group and 10.93 ± 7.36 in controls. The mean difference in OSDI scores between BAK and polyquad group 16.63 (p < 0.05) and between the BAK and control group was 18.96 (p < 0.05). The mean difference in OSDI scores between the polyquad and control group was 1.53 (p > 0.05). The mean IOP in the BAK group was 19.2 ± 3.5 and in polyquad group was 20.1 ± 4.2. The IOP measured at 12 months of treatment was 13.2 ± 2.1 in BAK group and 12.8 ± 3.3 in polyquad group. The IOP measured at baseline and 12 months showed statistically significant difference in both the groups (p <o.oo1, p=o.ooo, respectively). Conclusions. OSDI scores revealed significantly lesser symptoms in polyquad preserved travoprost when compared to BAK preserved travoprost. The OSDI scores in polyquad group were also comparable to the control group. Hence, for long term glaucoma management polyquad containing travoprost should be preferred over the BAK preserved travoprost.

Tear neuromediators in eyes on chronic topical antiglaucoma therapy with and without BAK preservatives

PurposeTo evaluate tear neuropeptides (NPs) (vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP), nerve growth factor (NGF)) in chronic ocular topical hypotensive therapy with...

Effects of Polyquaternium- and Benzalkonium-Chloride-Preserved Travoprost on Ocular Surfaces: An Impression Cytology Study

To compare the toxicity effect of polyquaternium (PQ) and benzalkonium chloride (BAK) preservation of travoprost on the ocular surface. This prospective study included 44 eyes of 44 patients with newly diagnosed glaucoma. Twenty-two patients used PQ-preserved travoprost (PQ group) and 22 patients used BAK-preserved travoprost (BAK group). To investigate the effect on the ocular surface, conjunctival impression cytology (IC) was performed at baseline and the 1- and 6-month follow-up visits. Additionally, the ocular surface disease index (OSDI) questionnaire, Schirmer I test, and tear break-up time (TBUT) measurement were administered at baseline, and at 1-, 3-, and 6-month follow-up visits. While both groups showed statistically significant IC grade increases at 1 and 6 months when compared with baseline measurements, IC grades were significantly higher for patients using PQ-preserved travoprost compared with patients using BAK-preserved travoprost. The Schirmer I test and TBUT scores were not statistically significant between group 1 and BAK group at baseline and at 1-, 3-, and 6-month visits (P>0.05). OSDI scores did not statistically differ at baseline and the 1-month measurements between the 2 groups (P>0.05), but the 3- and 6-month OSDI scores were significantly higher for BAK group (P=0.001). Differences in OSDI and Schirmer I test scores were statistically significant at 1, 3, and 6 months in both groups as compared with baseline values (P<0.05). Statistically significant differences in the TBUT scores were seen for both groups at 3 and 6 months, while BAK group, but not PQ group, had insignificant score differences at 1 month as compared with baseline values of PQ group (P=0.083). PQ-preserved travoprost was found to be safer and better-tolerated than BAK-preserved travoprost. PQ-preserved travoprost provided better ocular surface comfort, and therefore a better patient experience, which would likely result in higher treatment compliance.

Physical properties and culture-specific factors as principles of semantic categorisation of the Gújjolaay Eegimaa noun class system

Abstract This paper investigates the semantic bases of class membership in the noun class system of Gújjolaay Eegimaa (Eegimaa henceforth), a Niger-Congo and Atlantic language of the BAK group spoken in Southern Senegal. The question of whether semantic principles underlie the overt classification of nouns in Niger-Congo languages is a controversial one. There is a common perception of Niger-Congo noun class systems as being mainly semantically arbitrary. The goal of the present paper is to show that physical properties and culture-specific factors are central principles of semantic categorisation in the Eegimaa noun class system. I argue that the Eegimaa overt grammatical classification of nouns into classes is a semantic categorisation system whereby categories are structured according to prototypicality, family resemblance, metaphorical and metonymic extensions and chaining processes, as argued within the framework of Cognitive Linguistics. I show that the categorisation of entities in the Eegimaa nominal classification system productively makes use of physical properties such as shape as well as using culture-specific, less productive parameters for the semantic categorisation of entities denoted by nouns. The analysis proposed here also shows that the cases of multiple morphosyntactic classifications of nouns reflect multiple conceptual categorisation strategies. A detailed examination of the formal and semantic instances of multiple classification reveals the existence of conceptual correlations between the physical properties and the culture-specific semantic parameters of categorisation used in the Eegimaa noun class system.

Comparison of a Travoprost BAK-Free Formulation Preserved with Polyquaternium-1 with BAK-Preserved Travoprost in Ocular Hypertension or Open-Angle Glaucoma

To demonstrate that the intraocular pressure (IOP)-lowering effect of travoprost 0.004% preserved with polyquaternium-1 (travoprost benzalkonium chloride [BAK]-free) is non-inferior to that of travoprost 0.004% preserved with benzalkonium chloride (travoprost BAK) in patients with ocular hypertension or open-angle glaucoma. A total of 371 patients randomly received travoprost BAK-free (n=185) or travoprost BAK (n=186) dosed once daily in the evening for 3 months. Patients were evaluated at 9 am, 11 AM, and 4 PM at baseline, weeks 2 and 6, and month 3. Intraocular pressure was also evaluated 36 and 60 hours after the month 3 visit. Travoprost BAK-free is non-inferior to travoprost BAK. The 95% upper confidence limits for the difference in mean IOP at month 3 (primary efficacy) were 0.5 mmHg, 0.6 mmHg, and 0.5 mmHg, at 9 AM, 11 AM, and 4 PM, respectively. Mean IOP reductions from baseline ranged from 7.6 to 8.7 mmHg in the travoprost BAK-free group and from 7.7 to 9.2 mmHg in the travoprost BAK group. At 36 and 60 hours after the last dose, mean IOP remained 6.8 mmHg and 5.7 mmHg below baseline in the travoprost BAK-free group, vs 7.3 mmHg and 6.0 mmHg in the travoprost BAK group, respectively. The safety profile of travoprost BAK-free was similar to that of travoprost BAK. Travoprost BAK-free safely and effectively lowers IOP in eyes with open-angle glaucoma or ocular hypertension. This BAK-free formulation has comparable safety, efficacy, and duration of IOP-lowering effect to travoprost preserved with BAK. Travoprost BAK-free is an effective option for IOP reduction while avoiding BAK exposure.

Prospective, randomized, multicenter Food and Drug Administration investigational device exemption study of lumbar total disc replacement with the CHARITÉ artificial disc versus lumbar fusion: Five-year follow-up

Background context The CHARITÉ artificial disc, a lumbar spinal arthroplasty device, was approved by the United States Food and Drug Administration in 2004 based on two-year safety and effectiveness data from a multicenter, prospective, randomized investigational device exemption (IDE) study. No long-term, randomized, prospective study on the CHARITÉ disc or any other artificial disc has been published to date. Purpose The purpose of this study was to compare the safety and effectiveness at the five-year follow-up time point of lumbar total disc replacement using the CHARITÉ artificial disc (DePuy Spine, Raynham, MA) with that of anterior lumbar interbody fusion (ALIF) with BAK cages and iliac crest autograft, for the treatment of single-level degenerative disc disease from L4 to S1, unresponsive to nonoperative treatment. Study design/setting Randomized controlled trial—five-year follow-up. Patient sample Ninety CHARITÉ patients and 43 BAK patients. Outcome measures Self-reported measures: visual analog scale (VAS); validated Oswestry disability index (ODI version 1.0); Short-Form 36 Questionnaire, and patient satisfaction. Physiologic measures: radiographic range of motion, disc height, and segmental translation. Functional measures: work status. Methods Of the 375 subjects enrolled in the CHARITÉ IDE trial, 277 were eligible for the five-year study and 160 patients thereof completed the five-year follow-up. The completers included 133 randomized patients. Overall success was defined as improvement≥15 pts in ODI vs. baseline, no device failure, absence of major complications, and maintenance or improvement of neurological status. Additional clinical outcomes included an ODI questionnaire as well as VAS, SF-36, and patient satisfaction surveys. Work status was tracked for all patients. Safety assessments included occurrence and severity of adverse events and device failures. Radiographic analyses such as index- and adjacent-level range of motion, segmental translation, disc height, and longitudinal ossification were also carried out. Results Overall success was 57.8% in the CHARITÉ group vs. 51.2% in the BAK group (Blackwelder's test: p=0.0359, Δ=0.10). In addition, mean changes from baseline for ODI (CHARITÉ: −24.0 pts vs. BAK: −27.5 pts), VAS pain scores (CHARITÉ: −38.7 vs. BAK: −40.0), and SF-36 questionnaires (SF-36 Physical Component Scores [PCS]: CHARITÉ: 12.6 pts vs. BAK: 12.3 pts) were similar across groups. In patient satisfaction surveys, 78% of CHARITÉ patients were satisfied vs. 72% of BAK patients. A total of 65.6% patients in the CHARITÉ group vs. 46.5% patients in the BAK group were employed full-time. This difference was statistically significant (p=0.0403). Long-term disability was recorded for 8.0% of CHARITÉ patients and 20.9% of BAK patients, a difference that was also statistically significant (p=0.0441). Additional index-level surgery was performed in 7.7% of CHARITÉ patients and 16.3% of BAK patients. Radiographic findings included operative and adjacent-level range of motion (ROM), intervertebral disc height and segmental translation. At the five-year follow-up, the mean ROM at the index level was 6.0° for CHARITÉ patients and 1.0° for BAK patients. Changes in disc height were also similar for both CHARITÉ and BAK patients (0.7 mm for both groups, p=0.9827). Segmental translation was 0.4 and 0.8 mm in patients implanted with CHARITÉ at L4–L5 vs. L5–S1, respectively, and 0.1 mm in BAK patients. Conclusions The results of this five-year, prospective, randomized multicenter study are consistent with the two-year reports of noninferiority of CHARITÉ artificial disc vs. ALIF with BAK and iliac crest autograft. No statistical differences were found in clinical outcomes between groups. In addition, CHARITÉ patients reached a statistically greater rate of part- and full-time employment and a statistically lower rate of long-term disability, compared with BAK patients. Radiographically, the ROMs at index- and adjacent levels were not statistically different from those observed at two-years postsurgery.

Quantitative analysis of conjunctival goblet cells after chronic application of topical drops

Chronic topical glaucoma therapy has been reported to cause deleterious changes to the ocular surface epithelial layers. We compare changes in the number of goblet cells after chronic exposure to latanoprost preserved with 0.02% benzalkonium chloride (BAK) eye drops (Xalatan; Pfizer, NY, USA), travoprost preserved with sofZia eye drops (Travatan Z; Alcon, Fort Worth, TX, USA), or preservative-free artificial tears (Refresh Plus; Allergan, Irvine, CA, USA). Fifteen New Zealand white rabbits were randomised into groups of five (one eye was randomised for treatment) and received once-daily topical application of one of the three treatments for 30 days. Enucleation was performed at the end of the study followed by histologic analysis using mucin stains to identify goblet cells. Goblet cells were quantified and analysed using Student t tests to compare means between groups. Goblet cells per high-power field were 2.21 (+/-0.40) in the latanoprost with BAK group, 6.02 (+/-1.20) in the travoprost with sofZia group, and 7.03 (+/-1.33) in the preservative-free artificial tear group. The number of goblet cells in the latanoprost with BAK group was significantly lower than the other two groups (P=0.0001). There was no statistically significant difference in goblet cell numbers between the travoprost with sofZia and preservative-free artificial tear group (P=0.24). Our study illustrates that, in this animal model, once-daily dosing of latanoprost with 0.02% BAK resulted in goblet cell loss compared with dosing with either travoprost with sofZia or preservative-free artificial tears.

Duration of IOP Reduction With Travoprost BAK-free Solution

To compare the duration of action of travoprost ophthalmic solution 0.004% (Travatan Z) formulated without benzalkonium chloride (BAK) to travoprost ophthalmic solution 0.004% formulated with BAK (Travatan). This was a prospective, randomized, double-masked study. Patients with open-angle glaucoma or ocular hypertension were randomized to receive 2 weeks of once-daily therapy with travoprost BAK-free or travoprost with BAK. Patients received the last dose of medication on day 13 and then intraocular pressure (IOP) was assessed every 12 hours for 60 hours. Statistical analysis included change in IOP from baseline for each group and comparison of mean IOP between groups. Of the 109 patients enrolled, 106 patients completed the study. Untreated mean baseline IOP at 8 AM was 26.9 mm Hg in the travoprost BAK-free group and 27.1 mm Hg in the travoprost with BAK group. At 12, 24, 36, 48, and 60 hours after the last dose, mean IOP in the travoprost BAK-free group was 18.7, 17.2, 19.5, 18.7, and 20.8 mm Hg, respectively; whereas mean IOP in the travoprost with BAK group was 18.5, 16.8, 19.7, 18.0, and 20.8 mm Hg, respectively. Mean IOP at all time points after the last dose of medication was >6 mm Hg lower than the 8 AM baseline in both groups. Between-group differences were within +/-0.6 mm Hg at all postdose time points. There were no statistically significant differences between the 2 treatment groups at baseline or at any postdose time point. Drug-related side effects were uncommon, mild in intensity, and comparable between groups. Travoprost without BAK has similar IOP-lowering efficacy and safety compared with travoprost preserved with BAK. Both formulations of travoprost have a prolonged duration of action, with statistically and clinically significant reductions from baseline persisting up to 60 hours after the last dose.

44 POSTER Regulating hypoxia-driven VEGF by inhibiting IGF-1 signaling in childhood cancer cells

The CHARITÉ artificial disc, a lumbar spinal arthroplasty device, was approved by the United States Food and Drug Administration in 2004 based on two-year safety and effectiveness data from a multicenter, prospective, randomized investigational device exemption (IDE) study. No long-term, randomized, prospective study on the CHARITÉ disc or any other artificial disc has been published to date.The purpose of this study was to compare the safety and effectiveness at the five-year follow-up time point of lumbar total disc replacement using the CHARITÉ artificial disc (DePuy Spine, Raynham, MA) with that of anterior lumbar interbody fusion (ALIF) with BAK cages and iliac crest autograft, for the treatment of single-level degenerative disc disease from L4 to S1, unresponsive to nonoperative treatment.Randomized controlled trial—five-year follow-up.Ninety CHARITÉ patients and 43 BAK patients.Self-reported measures: visual analog scale (VAS); validated Oswestry disability index (ODI version 1.0); Short-Form 36 Questionnaire, and patient satisfaction. Physiologic measures: radiographic range of motion, disc height, and segmental translation. Functional measures: work status.Of the 375 subjects enrolled in the CHARITÉ IDE trial, 277 were eligible for the five-year study and 160 patients thereof completed the five-year follow-up. The completers included 133 randomized patients. Overall success was defined as improvement≥15 pts in ODI vs. baseline, no device failure, absence of major complications, and maintenance or improvement of neurological status. Additional clinical outcomes included an ODI questionnaire as well as VAS, SF-36, and patient satisfaction surveys. Work status was tracked for all patients. Safety assessments included occurrence and severity of adverse events and device failures. Radiographic analyses such as index- and adjacent-level range of motion, segmental translation, disc height, and longitudinal ossification were also carried out.Overall success was 57.8% in the CHARITÉ group vs. 51.2% in the BAK group (Blackwelder's test: p=0.0359, Δ=0.10). In addition, mean changes from baseline for ODI (CHARITÉ: −24.0 pts vs. BAK: −27.5 pts), VAS pain scores (CHARITÉ: −38.7 vs. BAK: −40.0), and SF-36 questionnaires (SF-36 Physical Component Scores [PCS]: CHARITÉ: 12.6 pts vs. BAK: 12.3 pts) were similar across groups. In patient satisfaction surveys, 78% of CHARITÉ patients were satisfied vs. 72% of BAK patients. A total of 65.6% patients in the CHARITÉ group vs. 46.5% patients in the BAK group were employed full-time. This difference was statistically significant (p=0.0403). Long-term disability was recorded for 8.0% of CHARITÉ patients and 20.9% of BAK patients, a difference that was also statistically significant (p=0.0441). Additional index-level surgery was performed in 7.7% of CHARITÉ patients and 16.3% of BAK patients.Radiographic findings included operative and adjacent-level range of motion (ROM), intervertebral disc height and segmental translation. At the five-year follow-up, the mean ROM at the index level was 6.0° for CHARITÉ patients and 1.0° for BAK patients. Changes in disc height were also similar for both CHARITÉ and BAK patients (0.7 mm for both groups, p=0.9827). Segmental translation was 0.4 and 0.8 mm in patients implanted with CHARITÉ at L4–L5 vs. L5–S1, respectively, and 0.1 mm in BAK patients.The results of this five-year, prospective, randomized multicenter study are consistent with the two-year reports of noninferiority of CHARITÉ artificial disc vs. ALIF with BAK and iliac crest autograft. No statistical differences were found in clinical outcomes between groups. In addition, CHARITÉ patients reached a statistically greater rate of part- and full-time employment and a statistically lower rate of long-term disability, compared with BAK patients. Radiographically, the ROMs at index- and adjacent levels were not statistically different from those observed at two-years postsurgery.

Prospective randomized study of the Charité artificial disc: data from two investigational centers

Background context For decades there has been a desire to restore motion of a painful degenerated spinal segment. Artificial discs have been used in Europe for almost 20 years. In the few reports available in the literature, the results have been promising. However, there have been no prospective randomized studies comparing artificial discs with spinal fusion. Purpose The purpose of this study was to determine if patients with symptomatic degenerative disc disease treated with Charité artificial disc (DePuy Spine, Raynham, MA) arthroplasty would show significant improvement in functional outcome measures and to compare these results to fusion. Study design/setting This was a prospective randomized clinical trial comparing total disc replacement with anterior lumbar interbody fusion using cages. The data reported were collected from two spine specialty centers participating in a Food and Drug Administration regulated trial. Methods A consecutive series of 144 patients were randomized using a 2:1 ratio of Charité versus BAK (Zimmer Spine, Minneapolis, MN). All patients were being treated for single-level discogenic pain confirmed by plain radiography, magnetic resonance imaging and provocative discography. Data were collected at designated follow-up periods for up to 24 months. Results The mean age was 40.1 years (range, 21 to 56 years). Forty-four cases had BAK anterior interbody fusion, and 100 cases were randomized to Charité disc replacement. The mean operating time was 76.2 minutes (range, 54 to 137 minutes) for the Charité cases. The mean estimated blood loss was 196.2 cc (range, 50 to 1,800 cc). Most patients were discharged in 1 to 2 days with a soft corset and returned to normal activities within 3 weeks if they underwent the disc replacement. The mean Oswestry Disability Index score for the BAK group was 69.6±12.8 preoperatively and 27.5±26.4 at 24-month follow-up (p<.001) The corresponding mean Oswestry score for the Charité disc patients was 70.9 preoperatively and 30.0 at 24-month follow-up (p<.001). Conclusions In this prospective randomized study, both surgical groups improved significantly. Complications of total disc replacement were similar to those encountered with anterior lumbar interbody fusion. Total disc replacement appears to be a viable alternative to fusion for the treatment of single-level symptomatic disc degeneration unresponsive to nonoperative management.

9:40 Comparative study of titanium interbody spacer and BAK fusion devices: a prospective randomized clinical study with minimum 2-year follow-up

Purpose of study: Lumbar interbody fusion devices have been developed. These devices are packed with the patient's own cancellous bone and provide immediate segmental fixation. The purpose of the TIS Equivalence Study was to evaluate the safety and effectiveness of the titanium interbody spacer (TIS) compared to the commercially available BAK.Methods used: This was a randomized, multicenter, prospective study approved by the Food and Drug Administration with a minimum follow-up of 2 years. Patients were randomized in a 1:1 ratio. Both the TIS and the BAK were filled with autogenous bone and implanted using an open, anterior approach to the lumbar spine. The protocol did not allow for additional anterior or posterior instrumentation to be used during the initial surgery. Subjects up to 70 years of age with degenerative disc disease at one to two consecutive levels between L2 and S1, and with at least 6 months of nonoperative treatment, were enrolled in the study. Patients were evaluated preoperatively and at 6, 12, 18 and 24 months by means of Short Form (SF)-36 McGill Pain Questionnaire, Oswestry Questionnaire and independent clinical examination. All radiographs were sent out for digitization and blinded evaluation by board-certified radiologists. Study success was based on deomonstrating that the proportion of subjects in the TIS group achieving success at 24 months was equivalent to or better than that for subjects in the BAK group. Patient success was defined as the occurrence of fusion, improvement in pain, maintenance or improvement of functional ability, maintenance or improvement of neuromuscular status, maintenance of device integrity and placement and absence of a device-related surgical intervention. Patient success requires success for each of the six criteria. Failure in any criteria equaled overall failure.of findings: Eighty-seven percent of patients were available for 24-month evaluation. A total of 116 were treated with the TIS cage and 111 were treated with the BAK fusion cages. Minimum follow-up was 2 years. There was no significant difference in demographic data between the two groups. Average age was 42 years; 39% were receiving workers compensation benefits. Sixty-one percent of the TIS group and 63% of the BAK group had no prior back surgery. Forty percent of the TIS group and 37% of the BAK group were smokers. Ninety-five percent of patients had surgery performed at L4–L5 or L5–S1. The average operative time was 171 minutes for the 73% TIS and 70% of the BAK patients had a single-level fusion. At 2-year follow-up, overall fusion rate was 77% TIS and 71% BAK; pain improvement 64% both TIS and BAK groups; functional improvement 87% TIS and BAK; neurologic improvement 94% TIS and 78% BAK patients. There were no reports of device breakage for either the TIS or the BAK device. Twenty-two patients (12 TIS, 10 BAK) required additional surgery for pseudarthrosis or continued pain. There were no infections or catastrophic vascular injuries. At 24 months, the patient success rate was 42% for TIS patients and 25% for BAK patients.Relationship between findings and existing knowledge: This is the first study evaluating the Synthes TIS device.Overall significance of findings: The TIS cage is as effective and safe as the BAK fusion cage. The low success rates for both treatment groups in this study suggests that requiring a subject to succeed on six individual criteria may be too rigorous an analysis. The success rates for the six criteria are all substantially higher than the overall success rate. Unless there is a strong relationship between the six outcomes, the success rates for each outcome must be high if the overall success rate is to be even moderate.Disclosures: Device or drug: TIS interbody fusion cage. Status: investigational.Conflict of interest: Patrick Connolly, Institutional research support from Synthes USA.

$G$-surgery on 3-dimensional Manifolds for Homology Equivalences

For a finite group G and a G -map f :X → Y of degree one, where X and Y are compact, connected, oriented, 3-dimensional, smooth G -manifolds, we give an obstruction element σ(f) in a K -theoretic group called the Bak group, with the property: σ(f) = 0 guarantees that one can perform G -surgery on X so as to convert f to a homology equivalence f': X' → Y . Using this obstruction theory, we determine the G -homeomorphism type of the singular set of a smooth action of A_5 on a 3-dimensional homology sphere having exactly one fixed point, where A_5 is the alternating group on five letters.