Lumbar Discectomy With Bone-Anchored Annular Closure Device in Patients With Large Annular Defects: One-Year Results.

BACKGROUND: Reherniation rates following lumbar discectomy are low for most patients; however, patients with a large defect in the annulus fibrosis have a significantly higher risk of recurrence. Previous results from a randomized controlled trial (RCT) demonstrated that the implantation of a bone-anchored annular closure device (ACD) during discectomy surgery lowered the risk of symptomatic reherniation and reoperation over one year with fewer serious adverse events (SAEs) compared to discectomy alone. OBJECTIVE: The objective of this prospective, post-market, historically controlled study was to evaluate the use of an ACD during discectomy, and to confirm the results of the RCT that was used to establish regulatory approval in the United States. METHODS: In this post-market study, all patients (N = 55) received discectomy surgery with a bone-anchored ACD. The comparison population was patients enrolled in the RCT study who had discectomy with an ACD (N = 262) or discectomy alone (N = 272). All other eligibility criteria, surgical technique, device characteristics, and follow-up methodology were comparable between studies. Endpoints included rate of symptomatic reherniation or reoperation, SAEs, and patient-reported measures of disability, pain, and quality of life. RESULTS: Fifty-five patients received ACD implants at 12 sites between May 2020 and February 2021. In the previous RCT, 272 control patients had discectomy surgery alone (RCT-Control), and 262 patients had discectomy surgery with an ACD implant (RCT-ACD). Baseline characteristics across groups were typical of the overall population undergoing lumbar discectomy. The proportion of patients who experienced reherniation and/or reoperation was significantly lower in the ACD group compared to RCT-ACD and RCT-Control groups (p < 0.05). In the ACD study, the one-year rate of symptomatic reherniation was 3.7%, compared to 8.5% in the RCT-ACD group and 17.0% in the RCT-Control group. In the ACD group, the risk of reoperation was 5.5%, compared to 6.5% in the RCT-ACD group and 12.5% in the RCT-Control group. There were no device-related SAEs or device integrity failures in the ACD, and there were clinically meaningful improvements in patient-reported measures of disability, pain, and quality of life. CONCLUSION: In this post-market study of bone-anchored ACD in patients with large annular defects, rates of symptomatic reherniation, reoperation, and SAEs were all low. Compared to the RCT, the post-market ACD study demonstrated lower rates of reherniation and/or reoperation and measures of back pain one-year post-surgery.

The mesioangular third molar--to extract or not to extract? Analysis of 776 consecutive third molars.

Introduction Distal caries in lower second molars has been associated with mesioangular third molars. Caries detection and restoration can be difficult. If caries progresses, root canal treatment or extraction of the second molar can be necessary.Aims To identify the prevalence of caries in lower third molars and the distal aspect of corresponding lower second molars in patients referred for lower third molar assessment.Methods Analysis of OPG X-rays for 420 consecutive patients (776 third molars) referred to three maxillofacial centres over a five month period.Results Thirty-four percent of third molars were mesioangular. There was radiographic evidence of distal second molar caries in 42% of these. When unerupted mesioangular third molars were excluded this increased to 54%. There was no difference in age or dental health of these patients compared to the whole group. There was no angulation of the mesioangular third molar for which distal caries in the second molar was more likely.Conclusion Distal caries in lower second molars related to a mesioangular third molar is a common finding in oral and maxillofacial patients in secondary care, especially if the third molar is fully or partially erupted. If such a third molar is left in situ, close monitoring and regular bitewing radiographs are recommended.

Characterization of pro-apoptotic and matrix-degradative gene expression following induction of osteoarthritis in mature and aged rabbits.

OBJECTIVE: The genetic and molecular changes leading to the distinctive alterations of aged cartilage and its propensity for developing osteoarthritis (OA) are unknown. We hypothesized that pro-apoptotic and matrix-degradative gene expression in a rabbit model of induced OA using mature and aged animals might elucidate this relationship. METHODS: Groups of six mature and aged rabbits underwent anterior cruciate ligament transection (ACLT) and were sacrificed 4 weeks after surgery to create an Outerbridge grade II OA. RNA was extracted from the articular cartilage and menisci of the affected knee and was examined with regard to expression of the following genes: Caspase 8, Fas, Fas ligand (Fas-L), p53, aggrecanase, matrix metalloproteinase (MMP)-1, and MMP-3-MMP-13. A second cohort of mature and aged animals was sacrificed with no intervention to the joint and gene expression was assessed in a similar manner. RESULTS: Fas and Caspase 8 showed significantly increased expression in the cartilage of mature animals with induced OA when compared to unoperated controls while induction of OA in aged rabbits did not significantly increase expression of any of the apoptosis genes. Among unoperated animals, the aged cohort showed significantly increased expression of MMP-1 and aggrecanase in cartilage when compared to mature animals. MMP-13 expression was upregulated in aged cartilage following induction of OA. Although ACLT animals showed gross thinning and irregularities within the meniscus, only the expression of Caspase 8 in the aged rabbits was significantly increased after induction of OA. CONCLUSIONS: Aging of articular cartilage shares some qualities with the development of OA, as seen in the parallel increases in gene expression of Caspase 8 and Fas. Although this may imply a common mechanism of cartilage degeneration in aging and OA or even a spectrum of disease, both are complex processes requiring further study.

Sustained Akt/PKB activation and transient attenuation of c-jun N-terminal kinase in the inhibition of apoptosis by IGF-1 in vascular smooth muscle cells.

Characteristics of hVSMC apoptosis and its inhibition by insulin-like growth factor-1 (IGF-1) remain unclear. Also unclear is whether a balance in hVSMCs exists whereby c-Jun N-terminal stress kinases (JNK) promote apoptosis while extracellular signal-regulated (ERK1/2) MAP kinases inhibit cell death. In this study, we examined the involvement of Akt/PKB and its upstream kinase, PDK1 and whether JNK activation correlated with human and rat VSMC apoptosis induced by staurosporine and by c-myc, respectively. We observed a strong, sustained JNK activation (and c-Jun phosphorylation), which correlated with VSMC apoptosis. IGF-1 (13.3 nM), during apoptosis inhibition, transiently inhibited JNK activity at 1 h in a phosphatidylinositol 3-kinase (PI3-K)- and MEK-ERK-dependent manner, as wortmannin (100 nM) or PD98059 (30 muM) partially attenuated the IGF-1 effect. PKC down-regulation had no effect on JNK inhibition by IGF-1. While IGF-1 alone produced a strong phosphorylation of Akt/PKB in hVSMCs up to 6 h, it was notably stronger and more sustained during ratmyc and hVSMCs apoptosis inhibition. Further, whereas transient expression of phosphorylated Akt protected VSMCs from apoptosis by nearly 50%, expression of dominant interfering alleles of Akt or PDK1 strongly inhibited IGF-1-mediated VSMC survival. These results demonstrate for the first time that transient inhibition of a pro-apoptotic stimulus in VSMCs may be sufficient to inhibit a programmed cell death and that sustained anti-apoptotic signals (Akt) elicited by IGF-1 are augmented during a death stimulus. Furthermore, PI3-K and ERK-MAPK pathways may cooperate to protect VSMCs from cell death.

Mechanisms controlling cellular suicide: role of Bcl-2 and caspases.

Apoptosis is an essential and highly conserved mode of cell death that is important for normal development, host defense and suppression of oncogenesis. Faulty regulation of apoptosis has been implicated in degenerative conditions, vascular diseases, AIDS and cancer. Among the numerous proteins and genes involved, members of the Bcl-2 family play a central role to inhibit or promote apoptosis. In this article, we present up-to-date information and recent discoveries regarding biochemical functions of Bcl-2 family proteins, positive and negative interactions between these proteins, and their modification and regulation by either proteolytic cleavage or by cytosolic kinases, such as Raf-1 and stress-activated protein kinases. We have critically reviewed the functional role of caspases and the consequences of cleaving key substrates, including lamins, poly(ADP ribose) polymerase and the Rb protein. In addition, we have presented the latest Fas-induced signalling mechanism as a model for receptor-linked caspase regulation. Finally, the structural and functional interactions of Ced-4 and its partial mammalian homologue, apoptosis protease activating factor-1 (Apaf-1), are presented in a model which includes other Apafs. This model culminates in a caspase/Apaf regulatory cascade to activate the executioners of programmed cell death following cytochrome c release from the mitochondria of mammalian cells. The importance of these pathways in the treatment of disease is highly dependent on further characterization of genes and other regulatory molecules in mammals.

Morphologic and temporal analysis of vascular smooth muscle cell apoptosis induced by c-myc and E1A.

Apoptosis is a physiologic form of cell death present in many disease conditions. When the balance of mitosis versus apoptosis is altered, tumor-like growth or degeneration of tissues may ensue. This appears to occur in several diseases, including those of the cardiovascular system, where apoptosis plays a key role in atherosclerosis and restenosis following angioplasty. Since c-myc is upregulated in the pathogenesis of these diseases, we chose to study the sequential morphologic features of programmed cell death in vascular smooth muscle cells induced by c-myc and by the adenovirus early gene E1A. Morphology and timed events in apoptotic cell cultures were analyzed by scanning electron microscopy, transmission electron microscopy, and time-lapse videomicroscopy. We observed that both c-myc- and E1A-induced apoptosis (in serum-free medium) resulted in numerous, tightly packed clusters of apoptotic blebs, as well as in one or two asymmetrically larger blebs. Transmission electron miscroscopy analysis revealed the larger blebs contained mostly nuclear chromatin, whereas the many smaller fragments often had little or no chromatin. Time-lapse studies showed that apoptosis was induced at a slower rate in cells stably transfected with c-myc versus those stably transfected with E1A. The early changes of apoptosis, including cell shrinkage and intense blebbing, occurred in under 5 min in both cells. Slight alterations such as cell size and further rounding occurred up to 8 h following the initial changes of apoptosis. Rather than being a part of the apoptotic response, release from the culture floor almost entirely resulted from movement of the culture flask. These studies provide a framework of timed morphologic events for future mechanistic investigation into the key aspects of myc- and E1A-induced apoptosis in vascular smooth muscle.

Morphological and biochemical characterization and analysis of apoptosis.

Apoptosis is a form of programmed cell death serving physiologic and homeostatic functions. However, recent evidence implicating apoptosis in the etiology and pathophysiology of known human diseases, such as heart diseases, cancer, AIDS, and neurodegenerative and autoimmune diseases are continually surfacing. This has spawned the need for identifying which methods are the most effective and well accepted to decipher its presence in a variety of research settings. We have therefore detailed the morphology and biochemical features of apoptotic cell death, with an emphasis on discriminating it from necrosis. In addition, we describe specific and selective techniques which are optimal to target hallmark apoptotic features, such as microscopy, Annexin V labeling, in situ nick-end labeling (TUNEL), and DNA fragmentation analysis by gel electrophoresis and ELISA for oligonucleosome-sized DNA. The advantages and disadvantages of each technique are discussed, as well as their experimental importance relative to one another. The methods have been described in a stepwise fashion, and can readily be applied in the majority of cell systems. Whether working on the tissue or single cell level, these methods are highly effective in qualifying and quantifying apoptosis. The application of these methods in conjunction with molecular techniques can further delineate the underlying mechanisms of apoptosis.

Cell adhesion molecules and insulin-like growth factor-1 in vascular disease.

PURPOSE: Recent advances in the understanding of the biologic mechanisms of vascular diseases suggest that multifactorial stimulation of the endothelial cell and its subsequent adhesion to leukocytes is a prerequisite to the formation of atherosclerotic and restenotic lesions. As leukocyte-endothelial cell interaction is coordinated by a variety of cell adhesion molecules (CAMs), we hypothesized that the expression of certain CAMs is up-regulated in the vasculature of patients who have peripheral vascular disease. In addition, we proposed that insulin-like growth factor-1 (IGF-1) increases monocyte-endothelial adhesion by means of upregulation of these CAMs. METHODS: Using immunohistochemical techniques, the expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin was examined in human vascular disease specimens. Normal aortas obtained from the organ retrieval system were studied as control specimens. Adhesion studies between human umbilical vein endothelial cells (HUVECs) incubated with IGF-1 and purified human blood monocytes labeled with 51chromium were completed. Western blotting and flow cytometry were performed to show CAM expression on IGF-1-treated HUVECs. RESULTS: Of the CAMs, ICAM-1, P-selectin, and E-selectin were distinctly increased in diseased specimens when compared with control specimens (p < 0.05). Adhesion studies showed an increase in monocyte-endothelial cell adhesion of as much as 40% to 45% (p < 0.01) over baseline, with peak adherence occurring 4 hours after treatment with IGF-1. IGF-1 increased adherence in a dose- and time-dependent manner. The threshold concentration of IGF-1 that induced increased adhesion was 20 ng/ml, with a maximum effect occurring at 150 ng/ml. This increased adhesion was attenuated by pretreatment with IGF-I receptor antibody, as well as with genistein and herbimycin-A, which are potent and selective tyrosine kinase inhibitors. Increased adhesion correlated with an increase in the expression of CAMs on the surface of the HUVECs. An additive effect on adhesion was observed between IGF-1 and tumor necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1). Finally, immunohistochemical analysis of human vascular disease specimens revealed an increased expression of IGF-1 receptors as compared with control specimens (p < 0.05). CONCLUSIONS: These results suggest that IGF-1 may be important in the pathogenesis of peripheral vascular disease by increasing endothelial cell-monocyte adhesion by means of an increase in the expression of ICAM-1 and VCAM-1.

Recurrent nerve palsy due to parathyroid cyst.

Cysts of the parathyroid gland are uncommon neck masses and difficult to diagnose. They can cause symptoms by endocrinological function or by pressure on surrounding structures. A case of recurrent nerve palsy due to a parathyroid cyst is presented. Aspiration of parathyroid cysts can be diagnostic and therapeutic in some cases.

Follicular carcinoma of the thyroid following radioactive iodine treatment for Graves' disease.

A 67 year old man presented with a well differentiated follicular carcinoma of the thyroid 17 years after he had been given radioactive iodine for Graves' disease. As this was insufficient to cure him he had continued to take propylthiouracil regularly. The tumour, which had completely replaced the thyroid, was apparently maintaining thyrotoxicosis. The implications of this management are discussed and it is concluded that antithyroid drugs should not be given on a long term basis after therapeutic radioiodine has been administered.

A new approach to the surgical management of paralysis of the laryngeal nerve after thyroidectomy.

Recurrent nerve palsy, immediate or delayed, or unilateral or bilateral, is a recognized complication of operations upon the thyroid gland and is not considered to be remediable as a presumed consequence of division of the nerve (or nerves). Removal of sutures and neurolysis of the nerve have met with variable success in restoration of function. In a prospective study over a period of 14 years, paralysis after thyroidectomy was assessed in 31 patients. Five had undergone previous operations upon the thyroid gland, four of these patients had known unilateral paralysis and 26 underwent operations which involved exploring the nerves. Immediate removal of the sutures was followed by complete recovery in four of the patients. Fifteen nerves of 13 patients with delayed paralysis were operated upon within six months of the original procedure; ligatures were removed in four patients, the nerve of one patient was sutured and the remaining underwent neurolysis. Some recovery of function within six months was seen in 13 nerves. Nine nerves were operated upon up to one year later, three divided nerves were sutured, one suture around a nerve was removed and five nerves were freed from fibrous tissue; recovery of function was seen in only two nerves. Of all the nerves which were sutured, slight mass movement of the corresponding vocal cord was seen in two. The results indicate that immediate paralysis after thyroidectomy should be investigated immediately, not only to excluded severance but also to relieve, if possible, physical involvement of the nerve by suture or ligature; the outcome of the operation is often beneficial. The benefits of neurolysis when the onset of paralysis is delayed due to fibrosis surrounding the nerve is also discussed; earlier intervention is associated with better results. Direct suture of the divided nerve is not recommended.