Effect of locally administered ciliary neurotrophic factor on the survival of transected and repaired adult sheep facial nerve.

OBJECTIVE: to determine whether the administration of Ciliary Neurotrophic Factor (CNTF) at the site of repaired facial nerve enhances regeneration in the adult sheep model. METHODS: Ten adult sheep were divided into 2 groups: control and study group (CNTF group). In the CNTF group, the buccal branch of the facial nerve was transected and then repaired by epineural sutures. CNTF was injected over the left depressor labii maxillaris muscle in the vicinity of the transected and repaired nerve for 28 days under local anesthesia. In the CNTF group, the sheep were again anesthetized after nine months and the site of facial nerve repair was exposed. Detailed electrophysiological, tension experiments and morphometric studies were carried out and then analyzed statistically. RESULTS: The skin CV min, refractory period, Jitter and tension parameters were marginally raised in the CNTF group than the control but the difference was statistically insignificant between the two groups. Morphometric indices also did not show any significant changes in the CNTF group. CONCLUSION: CNTF has no profound effect on neuronal regeneration of adult sheep animal model. KEYWORDS: CNTF; Neurtrophic factors; Sheep; Facial nerve; Regeneration.

Success and failure of minimally invasive decompression for focal lumbar spinal stenosis in patients with and without deformity.

STUDY DESIGN: Observational cohort study. Retrospective review of prospectively collected outcomes data. OBJECTIVE: The purpose of this study was to evaluate the clinical efficacy of minimally invasive (MIS) decompression for focal lumbar spinal stenosis (FLSS) in patients with and without deformity. SUMMARY OF BACKGROUND DATA: MIS, facet-preserving decompression has the potential of offering a significantly less morbid alternative to decompression and fusion in patients with leg dominant symptoms from degenerative spondylolisthesis and/or scoliosis. METHODS: Single surgeon, consecutive series (n=75), evaluated over 5 years. All patients had MIS lumbar laminoplasty (bilateral decompression from a unilateral approach) for FLSS (1-2 level). Patients had leg dominant, claudicant/radicular pain. Patients were divided into 4 groups: (A) stenosis with no deformity, n=22; (B) stenosis with spondylolisthesis only, n=25; (C) stenosis with scoliosis, n=16; and (D) stenosis combined with spondylolisthesis and scoliosis, n=12. The primary clinical outcome measures were the Oswestry Disability Index (ODI) and surgical revision rate. Preoperative and postoperative standing radiographs were assessed. RESULTS: The average age was 68 years (40-89) with a mean time from surgery of 36.5 months (18-68). Average clinical improvement in ODI was 49.5% to 23.9% [mean postoperative follow-up of 31.8 months (24-72): group A=mean of 34.6; B=28.9; C=32.7; D=30 months]. Incidence of preoperative grade I spondylolisthesis was 46%. Spondylolisthesis progression (mean=8.4%) occurred in 9 patients and 2 patients developed spondylolisthesis. Overall revision rate was 10% [repeat decompression alone (n=2) and decompression and fusion (n=6)]. Subgroup analysis of preoperative and postoperative ODI and revision rate revealed (A) 48% to 18.7%, 0%; (B) 48% to 24.6%, 4%; (C) 50.7% to 31.5%; 25%; and (D) 53% to 22%, 25%, respectively. The revision rate for patient with scoliosis (C+D) was significant (P=0.0035) compared with those without. Six of the 8 revised patients had a preoperative lateral (rotatory) listhesis (3 in C and 3 in D). CONCLUSION: MIS decompression alone for leg dominant symptoms is a clinically effective procedure in the majority of patients including those with degenerative spondylolisthesis or scoliosis. However, patients with scoliosis, particularly those with lateral listhesis, have a significantly higher revision rate that needs to be considered in operative decision-making.

Expression and localization of rat aldo-keto reductases and induction of the 1B13 and 1D2 isoforms by phenolic antioxidants.

The aldo-keto reductase (AKR) phase I drug metabolism enzyme superfamily is implicated in detoxification or bioactivation of a wide variety of carbonyl-bearing compounds. In this study, we have used antibodies raised against purified recombinant rat AKR isoforms 1A3, 1B4, 1C9, 1D2, and 7A1 to characterize the expression profile of these superfamily members in the rat and define their localization by immunohistochemistry. Western blotting showed that AKR1A3, AKR1B4, and AKR1C9 are ubiquitously expressed, whereas AKR1D2 and AKR7A1 are present in liver, adrenal gland, and kidney, with the latter also present in testis, spleen, and stomach. Immunohistochemical analysis of the kidney demonstrated the localization of AKR1A3 in proximal convoluted tubules, AKR1B4 in the loop of Henle, and AKR1C9 in the pars recta S3 segment of proximal tubules. We also report localization of AKR1B4 in the adrenal gland (parenchymal cells of the zona reticularis) and testis (Sertoli cells and late spermatids), of AKR1D2 in the liver (hepatocyte nuclei), and of AKR7A1 in the pancreatic duct and bronchiolar epithelium. Previous studies have shown that expression of AKR7A1 is induced in response to dietary administration of the phenolic antioxidants butylated hydroxyanisole and ethoxyquin. Here we identify AKR1B13 and AKR1D2 as further inducible members of the rat AKR superfamily.

1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic alpha,beta-unsaturated aldehyde acrolein.

Epithionitriles represent a previously unrecognized class of cancer chemopreventive phytochemical generated from alkenyl glucosinolates in cruciferous vegetables. In rat liver RL-34 epithelial cells, 1-cyano-2,3-epithiopropane (CETP), 1-cyano-3,4-epithiobutane (CETB) and 1-cyano-4,5-epithiopentane (CETPent) were shown to induce cytoprotective enzymes including NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione (GSH) S-transferase A3 and the glutamate-cysteine ligase modifier subunit; CETP was more potent in this regard than were either CETB or CETPent, with 50 microM CETP eliciting a remarkable approximately 10-fold induction of NQO1. Furthermore, 50 microM CETP stimulated a 2.0-fold overproduction of GSH in RL-34 cells. Transfection experiments demonstrated that epithionitriles induced gene expression through an antioxidant response element (ARE) and that transactivation of an Nqo1-luciferase reporter plasmid was dependent on NF-E2 p45-related factor 2 (Nrf2), a cap'n'collar basic region leucine zipper transcription factor. Evidence is presented that CETP affected Nrf2-mediated induction of ARE-driven transcription by inhibiting Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase substrate adaptor that negatively regulates Nrf2. We found that Nqo1 was expressed constitutively at high levels in Keap1(-/-) mouse embryonic fibroblasts (MEFs) and it was not further induced by CETP. However, knock-in of mouse Keap1 or zebrafish Keap1a into Keap1(-/-) MEFs repressed Nqo1-luciferase reporter gene activity, but repression by the murine or zebrafish proteins was antagonized by CETP. Pre-treatment of Nrf2(+/+) MEFs, but not Nrf2(-/-) MEFs, with 15 microM CETP for 24 h conferred 2.4-fold resistance against subsequent exposure to the alpha,beta-unsaturated aldehyde acrolein, indicating that the phytochemical exerts chemopreventive properties against genotoxic xenobiotics.

Intraoperative multimodality monitoring in adult spinal deformity: analysis of a prospective series of one hundred two cases with independent evaluation.

STUDY DESIGN: A retrospective analysis of prospectively collected data of 102 consecutive adult patients who underwent intraoperative neurophysiological monitoring (IOM) during spinal deformity corrective surgery. OBJECTIVE: To report the sensitivity and specificity of combined IOM in this study population using the postoperative neurologic examination as the "gold standard." SUMMARY OF BACKGROUND DATA: IOM is recommended during corrective spinal surgery and has been widely used in the pediatric deformity population. However, there are limited data describing the application of IOM in adults undergoing spinal deformity corrective surgery. METHODS: The study group consisted of 102 patients undergoing spinal deformity corrective surgery between 2001 and 2004. Patients were monitored using at least 2 or more electrophysiological methods including somatosensory-evoked potentials (SSEP), motor-evoked potentials (MEP), and electromyography (EMG). RESULTS: The mean age of patients was 41.5 years (+/-17). The majority of the operative procedures involved instrumented fusion from thoracic to lumbar/sacral spine (n = 55), thoracic-pelvis fusion (n = 26), and a combined total of 32 osteotomies (including 25 pedicle subtraction osteotomies and 7 Smith-Peterson osteotomies). SSEPs were recorded successfully in 101 (99%), EMGs in 89 of 102 (87%), and MEPs in 12 of 16 (75%). Five cases were true positives (4.95%), and these were all detected by combined monitoring (2-SSEP, 2-EMG, 1-MEP). There were no false positives with SSEPs, but EMG resulted in 30 of 89 (34%) false positives. There were 4 false negatives with SSEPs, which reduced its sensitivity to 33%. There was 1 false negative with EMG, and 0 with MEPs. When these results were collated, the overall sensitivity of combined multimodality IOM in this adult deformity series was 100%, specificity 84.3%, PPV 13.9%, and NPV 97%. The combined sensitivity in the osteotomy group (n = 32) was 67%, specificity 98%, PPV 80%, and NPV 96%. In comparison, there were no IOM abnormalities in those patients who had in situ/minor corrective procedures (n = 18; largely adult degenerative scoliosis). CONCLUSION: Multimodality IOM of spinal cord sensory and motor function during surgical correction of adult spinal deformity is feasible and provides useful neurophysiological data with an overall sensitivity of 100% and a specificity of 84.3% (67% and 98%, respectively in patients undergoing major deformity correction).

Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents.

Sulforaphane can stimulate cellular adaptation to redox stressors through transcription factor Nrf2. Using mouse embryonic fibroblasts (MEFs) as a model, we show herein that the normal homeostatic level of glutathione in Nrf2(-/-) MEFs was only 20% of that in their wild-type counterparts. Furthermore, the rate of glutathione synthesis following its acute depletion upon treatment with 3 micromol/l sulforaphane was very substantially lower in Nrf2(-/-) MEFs than in wild-type cells, and the rebound leading to a approximately 1.9-fold increase in glutathione that occurred 12-24 h after Nrf2(+/+) MEFs were treated with sulforaphane was not observed in Nrf2(-/-) fibroblasts. Wild-type MEFs that had been pre-treated for 24 h with 3 micromol/l sulforaphane exhibited between 1.4- and 3.2-fold resistance against thiol-reactive electrophiles, including isothiocyanates, alpha,beta-unsaturated carbonyl compounds (e.g. acrolein), aryl halides and alkene epoxides. Pre-treatment of Nrf2(+/+) MEFs with sulforaphane also protected against hydroperoxides (e.g. cumene hydroperoxide, CuOOH), free radical-generating compounds (e.g. menadione), and genotoxic electrophiles (e.g. chlorambucil). By contrast, Nrf2(-/-) MEFs were typically approximately 50% less tolerant of these agents than wild-type fibroblasts, and sulforaphane pre-treatment did not protect the mutant cells against xenobiotics. To test whether Nrf2-mediated up-regulation of glutathione represents the major cytoprotective mechanism stimulated by sulforaphane, 5 micromol/l buthionine sulfoximine (BSO) was used to inhibit glutathione synthesis. In Nrf2(+/+) MEFs pre-treated with sulforaphane, BSO diminished intrinsic resistance and abolished inducible resistance to acrolein, CuOOH and chlorambucil, but not menadione. Thus Nrf2-dependent up-regulation of GSH is the principal mechanism by which sulforaphane pre-treatment induced resistance to acrolein, CuOOH and chlorambucil, but not menadione.

The cancer chemopreventive actions of phytochemicals derived from glucosinolates.

This article reviews the mechanisms by which glucosinolate breakdown products are thought to inhibit carcinogenesis. It describes how isothiocyanates, thiocyanates, nitriles, cyano-epithioalkanes and indoles are produced from glucosinolates through the actions of myrosinase, epithiospecifier protein and epithiospecifier modifier protein released from cruciferous vegetables during injury to the plant. The various biological activities displayed by these phytochemicals are described. In particular, their abilities to induce cytoprotective genes, mediated by the Nrf2 (NF-E2 related factor 2) and AhR (arylhydrocarbon receptor) transcription factors, and their abilities to repress NF-kappaB (nuclear factor-kappaB) activity, inhibit histone deacetylase, and inhibit cytochrome P450 are outlined. Isothiocyanates appear to alter gene expression through modification of critical thiols in regulatory proteins such as Keap1 (Kelch-like ECH-associated protein 1) or IKK (IkappaB kinase), causing activation of Nrf2 and inactivation of NF-kappaB, respectively. Certain indoles act as ligands for AhR. Isothiocyanates and indoles are also capable of affecting cell cycle arrest and stimulating apoptosis. The mechanisms responsible for these anti-proliferative responses are discussed.

Predictive value of intraoperative neurophysiological monitoring during cervical spine surgery: a prospective analysis of 1055 consecutive patients.

OBJECT: Despite the growing use of multimodal intraoperative monitoring (IOM) in cervical spinal surgery, limited data exist regarding the sensitivity, specificity, and predictive values of such a technique in detecting new neurological deficits in this setting. The authors sought to define the incidence of significant intraoperative electrophysiological changes and new postoperative neurological deficits in a cohort of patients undergoing cervical surgery. METHODS: The authors conducted a prospective analysis of a consecutive series of patients who had undergone cervical surgery during a 5-year period at a university-based neurosurgical unit, in which multimodal IOM was recorded. Sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) were determined using standard Bayesian techniques. The study population included 1055 patients (614 male and 441 female) with a mean age of 55 years. RESULTS: The IOM modalities performed included somatosensory evoked potential (SSEP) recording in 1055 patients, motor evoked potential (MEP) recording in 26, and electromyography (EMG) in 427. Twenty-six patients (2.5%) had significant SSEP changes. Electromyographic activity was transient in 212 patients (49.6%), and 115 patients (26.9%) had sustained burst or train activity. New postoperative neurological deficits occurred in 34 patients (3.2%): 6 had combined sensory and motor deficits, 7 had new sensory deficits, 9 had increased motor weakness, and 12 had new root deficits. Of these 34 patients, 12 had spinal tumors, of which 7 were intramedullary. Overall, of the 34 new postoperative deficits, 21 completely resolved, 9 partially resolved, and 4 had no improvement. The deficits that completely resolved did so on average 3.3 months after surgery. Patients with deficits that did not fully resolve (partial or no improvement) were followed up for an average of 1.8 years after surgery. Somatosensory evoked potentials had a sensitivity of 52%, a specificity of 100%, a PPV of 100%, and an NPV of 97%. Motor evoked potential sensitivity was 100%, specificity 96%, PPV 96%, and NPV 100%. Electromyography had a sensitivity of 46%, specificity of 73%, PPV of 3%, and an NPV of 97%. CONCLUSIONS: Combined neurophysiological IOM with EMG and SSEP recording and the selective use of MEPs is helpful for predicting and possibly preventing neurological injury during cervical spine surgery.

Intermittent atlantoaxial subluxation caused by a prolapsing neurofibroma. Case report.

In this report, the authors describe a unique case of intermittent high cervical cord compression caused by a prolapsing neurofibroma at the C1-2 level. This 21-year-old man with known neurofibromatosis Type 1 presented with a mass between the anterior arch of the atlas and the odontoid peg, causing atlantoaxial dissociation and cord compression. The cervicomedullary compression appeared to be caused in part by the neurofibroma but also by the abnormal alignment and thickening of the ligaments between the clivus and C-2. Preoperative imaging repeated on the morning of surgery revealed that the atlantoaxial dissociation had reduced with relief of cord compression and the lesion prolapsed inferiorly. The authors discuss this unusual lesion and describe the associated operative findings and surgical management.

Electrical conductivity measurement: a new technique to detect iatrogenic initial pedicle perforation.

Pedicle screw fixation has achieved significant popularity amongst spinal surgeons for both single and multi-level spinal fusion. Misplacement and pedicle cortical violation occurs in over 20% of screw placement and can result in potential complications such as dysthesia, paraparesis or paraplegia. There have been many advances in techniques available for navigating through the pedicle; however, these techniques are not without drawbacks. A new electrical conductivity-measuring device, previously evaluated on the porcine model to detect the pedicle violation, was evaluated amongst nine European Hospitals to be used in conjunction with the methods currently used in that centre. This new device is based on two original principles; the device is integrated in the drilling or screwing tool. The technology allows real-time detection of perforation through two independent parameters, impedance variation and evoked muscle contractions. Data was collected twofold. Initially, the surgeon was given the device and a comparison was made between the devices ability to detect a breech and the surgeon's ability to detect one using his traditional methods of pedicle preparation. In the second module of the study, the surgeon was limited to using the electrical conductivity detection device as their sole guide to detect pedicle breaches. A comparison was made between the detection ability of the device and the other detection possibilities. Post-operative fine cut CT scanning was used to detect the pedicle breaches. Overall, the 11 trial surgeons performed a total of 521 pedicle drillings on 97 patients. Initially there were 147 drillings with 23 breaches detected. The detection rate of these breaches were 22/23 for the device compared to 10/23 by the surgeon. Over both parts of the study 64 breaches (12.3%) were confirmed on post-operative CT imaging. The electrical conductivity detection device detected 63 of the 64 breaches (98.4%). There was one false negative and four false positives. This gives the device an overall sensitivity of 98% and specificity of 99% for detecting a pedicle breach. The negative predictive value was 99.8%, with a positive predictive value of 94%. No adverse event was noted with the use of the electrical conductivity device. Electrical conductivity monitoring may provide a simple, safe and sensitive method of detecting pedicle breech during routine perforation of the pedicle, in the course of pedicle screw placement.

Non-syndromic trigonocephaly: surgical decision making and long-term cosmetic results.

BACKGROUND: Surgical correction is often required for cosmetic correction of trigonocephaly. The purpose of this paper was to report the long-term aesthetic outcome as appreciated by the parents/patients themselves. The self-evaluation of cosmetic outcome after trigonocephaly correction has not previously been reported. The management and different surgical techniques utilized over a 16-year period are discussed. MATERIALS AND METHODS: An observational study was undertaken of the clinical outcome, operative data, complications and cosmetic satisfaction of these trigonocephaly patients. The parents/child were asked to rate their satisfaction with the cosmetic outcome both in terms of head shape and scar appearance, on a five-point scale (excellent-5, very good-4, good-3, fair-2 and poor-1). RESULTS: Sixty-three patients presented with non-syndromic trigonocephaly over the 16 years. Nineteen of 63 had a mild form of trigonocephaly and were managed conservatively. The remainder underwent surgical correction. Forty-two of 44 (95%) underwent fronto-orbital advancement with either barrel staving (26/44) or frontal bone rotation/re-modelling (16/44), with 2 of 44 having burring of the metopic ridge. Head shape rating was regarded as excellent in 25 of 63 (40%), very good in 18 of 63 (28%), good in 18 of 63 (28%) and fair in 2 of 63 (4%). Of those that underwent surgery, the scar was zigzag in 32 of 44 and straight in 12 of 44. Scar was rated as being excellent in 21 of 44 (48%), very good in 12 of 44 (28%) good in 11 of 44 (24%). CONCLUSIONS: Metopic synostosis can result in varying degrees of severity. Milder forms can be treated conservatively, with more severe forms requiring both frontal bone re-modelling and fronto-orbital advancement. Surgical correction results in a high level of patient/parent satisfaction.

Sagittal synostosis: a review of 53 cases of sagittal suturectomy in one unit.

The role of sagittal suturectomy in the treatment of scaphocephaly remains controversial. The purpose of this study was to report the experience of the National Craniofacial Unit in Dublin. This unit is the referral centre for the Republic of Ireland and serves a population of approximately 3.5 million. Quantitative assessments were made using radiographs and the pre- and postoperative cephalic index (CI) was calculated. Patients were asked to score their head shapes in a questionnaire. The mean age at surgery for the 53 children was 4.9 months with a mean follow up of 8 years. Pre- and postoperative radiographs were available for analysis in 24 patients. The mean preoperative CI was 65.3. There was a statistically significant increase in the CI postoperatively to 73.7. Seventy five per cent of children achieved a 'normal' CI and 86% scored their head shapes as good to excellent. There was no correlation between the age at surgery and the CI achieved. Although only one child was not happy with the shape of the head, the impression was that the CI correlated poorly with the clinical assessment of the head shape. There were no significant complications. We therefore conclude that the sagittal suturectomy is a safe procedure that has a limited but definite potential to improve the CI. This procedure still has a place in the surgical repertoire of the craniofacial surgeon dealing with scaphocephaly.

Use of a static magnetic field to promote recovery after peripheral nerve injury.

OBJECT: While pulsed electromagnetic stimulation has been shown to enhance peripheral nerve regeneration, the effect of a static magnetic field on nerve repair is less clear. The aim of this study was to establish what effect an imposed exogenous static magnetic field has on peripheral nerve regeneration after transection and repair. METHODS: Three groups of six adult sheep were used. The first group acted as normal controls. In the second group, the median nerve was divided and immediately repaired by entubulation within a "controlled-release" biodegradable glass tube. In the third group, small magnets were applied to the sides of the biodegradable glass tubes before the median nerve was repaired using these magnetic tubes. The sheep were allowed to recover and were reexamined 10 months later. The animals underwent comprehensive morphometric (cross-sectional morphometry and measurement of internodal lengths), electrophysiological (determinations of stimulated jitter, maximum conduction velocity, refractory period, and F waves), and isometric tension (isometric twitch and tetanic tension) assessments. CONCLUSIONS: Exogenously applied static electromagnetic fields do not enhance peripheral nerve regeneration.

Behavioral, developmental, and educational problems in children with nonsyndromic trigonocephaly.

OBJECT: The neurobehavioral morbidity of nonsyndromic trigonocephaly is incompletely understood. The purpose of this study was twofold: first, to assess the degree of developmental, educational, and behavioral problems in patients with nonsyndromic trigonocephaly and second, to establish whether patients with mild degrees of trigonocephaly had a lower frequency of such problems. METHODS: The authors performed an observational study of the frequency of developmental, educational, and behavioral problems in 63 children with trigonocephaly at the National Craniofacial Centre in the Republic of Ireland between 1989 and 2004. The parents of the children completed a follow-up questionnaire. Thirty percent of patients had a mild form of trigonocephaly and were treated conservatively. The remainder underwent surgical correction. Speech and/or language delay was reported in 34% of the children. Thirty-three percent of the children needed to be assessed by a school psychologist, and 47% were receiving remedial or resource hours within the school system. Twenty percent of children required a special needs classroom assistant because of behavioral issues, and 37% of parents expressed concerns about their child's behavior. There were no statistically significant differences between children treated with surgery and those who had a mild deformity and were treated conservatively. CONCLUSIONS: Nonsyndromic trigonocephaly is associated with a high frequency of developmental, educational, and behavioral problems. The frequency of these problems is not related to the severity of the trigonocephaly.