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PubMed2001

Contribution of disc degeneration to osteophyte formation in the cervical spine: a biomechanical investigation.

Cervical spine disorders such as spondylotic radiculopathy and myelopathy are often related to osteophyte formation. Bone remodeling experimental-analytical studies have correlated biomechanical responses such as stress and strain energy density to the formation of bony outgrowth. Using these responses of the spinal components, the present study was conducted to investigate the basis for the occurrence of disc-related pathological conditions. An anatomically accurate and validated intact finite element model of the C4-C5-C6 cervical spine was used to simulate progressive disc degeneration at the C5-C6 level. Slight degeneration included an alteration of material properties of the nucleus pulposus representing the dehydration process. Moderate degeneration included an alteration of fiber content and material properties of the anulus fibrosus representing the disintegrated nature of the anulus in addition to dehydrated nucleus. Severe degeneration included decrease in the intervertebral disc height with dehydrated nucleus and disintegrated anulus. The intact and three degenerated models were exercised under compression, and the overall force-displacement response, local segmental stiffness, anulus fiber strain, disc bulge, anulus stress, load shared by the disc and facet joints, pressure in the disc, facet and uncovertebral joints, and strain energy density and stress in the vertebral cortex were determined. The overall stiffness (C4-C6) increased with the severity of degeneration. The segmental stiffness at the degenerated level (C5-C6) increased with the severity of degeneration. Intervertebral disc bulge and anulus stress and strain decreased at the degenerated level. The strain energy density and stress in vertebral cortex increased adjacent to the degenerated disc. Specifically, the anterior region of the cortex responded with a higher increase in these responses. The increased strain energy density and stress in the vertebral cortex over time may induce the remodeling process according to Wolff's law, leading to the formation of osteophytes.

Biomechanical Phenomena↗

PubMedDate not supplied

Human disc degeneration is associated with increased MMP 7 expression.

During intervertebral disc (IVD) degeneration, normal matrix synthesis decreases and degradation of disc matrix increases. A number of proteases that are increased during disc degeneration are thought to be involved in its pathogenesis. Matrix metalloproteinase 7 (MMP 7) (Matrilysin, PUMP-1) is known to cleave the major matrix molecules found within the IVD, i.e., the proteoglycan aggrecan and collagen type II. To date, however, it is not known how its expression changes with degeneration or its exact location. We investigated the localization of MMP 7 in human, histologically graded, nondegenerate, degenerated and prolapsed discs to ascertain whether MMP 7 is up-regulated during disc degeneration. Samples of human IVD tissue were fixed in neutral buffered formalin, embedded in paraffin, and sections stained with hematoxylin and eosin to score the degree of morphological degeneration. Immunohistochemistry was performed to localize MMP 7 in 41 human IVDs with varying degrees of degeneration. We found that the chondrocyte-like cells of the nucleus pulposus and inner annulus fibrosus were MMP 7 immunopositive; little immunopositivity was observed in the outer annulus. Nondegenerate discs showed few immunopositive cells. A significant increase in the proportion of MMP 7 immunopositive cells was seen in the nucleus pulposus of discs classified as showing intermediate levels of degeneration and a further increase was seen in discs with severe degeneration. Prolapsed discs showed more MMP 7 immunopositive cells compared to nondegenerated discs, but fewer than those seen in cases of severe degeneration.

Adult↗

PubMed1996

The relative importance of vertebral bone density and disc degeneration in spinal flexibility and interbody implant performance. An in vitro study.

STUDY DESIGN: An in vitro biomechanical investigation in the human lumbar spine focuses on the functional significance of vertebral bone density and intervertebral disc degenerations. OBJECTIVE: To determine that interrelationship between vertebral bone density and intervertebral disc degeneration, their effect on normal spine motion, and their significance in the biotechnical performance of interbody fixation techniques. SUMMARY OF BACKGROUND DATA: A relationship between vertebral bone density and intervertebral disc degeneration has been suggested, but a definitive relationship has not been established. The effect of vertebral bone density and intervertebral disc degeneration on interbody stabilization remains unknown despite the rapidly increasing use of this surgical method for patients with chronic low back pain. METHODS: The vertebral bone density and intervertebral disc degeneration of 72 functional spinal units were determined using dual energy x-ray absorptiometry scans and macroscopic grading, respectively. A three-dimensional flexibility test was performed on 24 functional spinal units in the intact and stabilised conditions. The compressive behavior of the bone-implant interface was evaluated in 48 functional spinal units. RESULTS: The vertebral bone density in moderately degenerated disc was significantly lower than at all other levels of intervertebral disc degeneration. Increasing intervertebral disc degeneration resulted in more axial rotation and less lateral bending. In flexion-extension and lateral bending, better vertebral bone resulted in significantly better stabilization. This trend was observed also in axial compression in which higher failure loads were observed with greater bone densities. CONCLUSION: The authors conclude a significant relationship exists between bone density and disc degeneration, bone density is a highly important factor in the performance of interbody stabilization, and disc degeneration, is of moderate importance in signal motion.

Biomechanical Phenomena↗

PubMed1998

Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration.

STUDY DESIGN: A study in genetic epidemiology of disc degeneration, based on lifetime exposure data, findings on magnetic resonance imaging, and genotyping of intragenic markers. OBJECTIVES: To pursue the potential correlation between common allelic variations in the vitamin D receptor locus and degeneration of the intervertebral disc. SUMMARY OF BACKGROUND DATA: Familial aggregation has been observed in intervertebral disc degeneration, but the relative significance of the genetic component and shared environmental influences is unknown. The identification of relevant candidate genes associated with disc degeneration would specify a genetic component and increase our understanding of the etiopathogenesis of disc degeneration. METHODS: From the population-based Finnish Twin cohort, 85 pairs of male monozygotic twins were selected based on exposure to suspected risk factors for disc degeneration. Interview data were gathered on relevant lifetime exposures, and thoracic and lumbar disc degeneration was determined through quantitative and qualitative assessments of signal intensity on magnetic resonance imaging, and qualitative assessments of disc bulging and disc height narrowing. Possible associations were examined between disc degeneration measures and two polymorphisms of the coding region of the vitamin D receptor locus. RESULTS: Two intragenic polymorphisms of the vitamin D receptor gene revealed an association with disc degeneration. Quantitatively assessed signal intensities of thoracic and lumbar (T6-S1) discs were 12.9% worse in men with the Taql tt genotype and 4.5% worse in men with the Tt genotype, compared with signal intensity in men with the TT genotype (age adjusted P = 0.003). A similar pattern was found between disc signal intensity and Fokl genotypes; men with the ff and Ff genotypes had mean signal intensities that were 9.3% and 4.3% lower, respectively, than those in men with FF genotypes (age-adjusted P = 0.006). The summary scores of qualitatively assessed signal intensity, bulging, and disc height were 4.0% and 6.9% worse in men with Ff and ff genotypes, respectively, when compared with those in men with the FF genotype (age-adjusted P = 0.029). CONCLUSION: Specific vitamin D receptor alleles were associated with intervertebral disc degeneration as measured by T2-weighted signal intensity, demonstrating for the first time, the existence of genetic susceptibility to this progressive, age-related degenerative process.

Adult↗

PubMed2002

Risk factors for lumbar disc degeneration: a 5-year prospective MRI study in asymptomatic individuals.

STUDY DESIGN: A longitudinal magnetic resonance imaging investigation of lumbar disc degeneration in asymptomatic individuals was conducted. OBJECTIVE: To investigate risk factors for the development or deterioration of lumbar disc degeneration. SUMMARY OF BACKGROUND DATA: Numerous studies have explored the significance of certain risk factors for the development or progression of disc degeneration, but no comprehensive longitudinal magnetic resonance imaging-based study has been reported that simultaneously considers clinical, morphologic, physical, psychosocial, and occupational risk factors. METHODS: In the 5-year follow-up evaluation of 41 asymptomatic individuals, the risk factors for the development of lumbar disc degeneration and its progression were investigated. All 41 individuals had a magnetic resonance imaging scan at baseline and at the minimum 5-year follow-up assessment using the same scanner and protocol. The magnetic resonance images were analyzed independently by two radiologists with regard to disc degeneration. Various predictor variables were assessed both at baseline and follow-up, with special emphasis on physical job characteristics, sports activities, and magnetic resonance image-based morphologic findings. RESULTS: Of the 41 individuals, 17 (41%) exhibited a deterioration of the disc status. In 10 individuals, the progression of disc degeneration was one grade or more. Only a weak correlation existed between progressive disc degeneration and low back pain development during a 5-year follow-up period. Multiple logistic regression analysis demonstrated that the extent of disc herniation (odds ratio [OR], 12.63; confidence interval [CI], 1.24-128.49), the lack of sports activities (OR, 2.71; CI, 1.04-7.07), and night shift work (OR, 23.01; CI, 1.26-421.31) were significant predictors for disc degeneration during follow-up evaluation when control was used for the number of degenerated discs at baseline, gender, age, and body mass index. CONCLUSIONS: The results indicate that the extent of disc herniation, the lack of sports activities, and night shift work are significant risk factors for the development of lumbar disc degeneration and its progression.

Adult↗

PubMed2004

Recent advances in analytical modeling of lumbar disc degeneration.

STUDY DESIGN: Review of the most recent advances in the development of poro-elastic analytical models that include physiologic parameters used for understanding lumbar disc degeneration due to repetitive loading. OBJECTIVES: To discuss how poro-elastic finite element models that include physiologic parameters such as strain-dependent permeability and porosity and regional variation of poro-elastic material properties of a motion segment can be used to understand the effect of disc degeneration due to cyclic loading on the disc biomechanical properties. SUMMARY OF BACKGROUND DATA: Mechanical response of the spine to various dynamic loading conditions can be analyzed using in vitro and in vivo studies. Ethical concerns, interpretation of conclusions reached using animal studies, and lack of detailed stress distributions in the disc components are the major disadvantages in using in vivo studies for understanding disc degeneration process. Intraspecimen variability, noninclusion of muscle activity, and difficulty of influx of fluid into the disc during unloading are some of the disadvantages while using in vitro models to understand disc degeneration. The poro-elastic finite element models can provide a method that can circumvent the disadvantages mentioned above and allow a way to understand the relationship between biomechanical performance of the disc due to cyclic loading and disc degeneration. METHODS: Several types of finite element model were developed in understanding relationship between disc degeneration and associated changes in biomechanical properties. Simplest among them include material and geometric nonlinearity of the disc and was used to predict failure in the disc anulus and endplates under static loading conditions. Response of the lumbar disc under creep loading was studied using poro-elastic models. These models were further refined by including swelling pressure and variable permeability due to change in porosity under load to understand time-dependent deformation of a lumbar disc in a multiple creep compression expansion loading. Regional variation of strain dependent permeability and osmotic pressure was included to further refine the poro-elastic finite element model. This refined model was used to study the effect of disc degeneration on biomechanical properties when cyclic loading was applied to the lumbar disc. RESULTS: The refined model that included regional variation of strain-dependent permeability and osmotic pressure was validated by comparing diurnal change in total stature measured in vivo. The study showed that disc height loss was larger after considerable number of cyclic loadings both in normal and degenerated discs. Cyclic loading also showed that Grade I discs were much more flexible than Grade IV discs. The disc stiffness also decreased as the load cycle increased. CONCLUSIONS: A number of different approaches have been used to address the issue of disc degeneration. Poro-elastic finite element model including strain-dependent permeability and osmotic pressure is the most popular analytical tool currently available that can be used to understand how cyclic loading affects the biomechanical characteristics of a degenerated lumbar disc. However, it is important to note that a complete understanding of the behavior of the intervertebral disc will ultimately be arrived using a combination of analytical models, such as the models presented here, in addition to in vitro and in vivo experimental methods.

Animals↗

PubMedDate not supplied

Degeneration patterns in human ears exposed to noise.

Various forms of sensorineural degeneration patterns related to noise exposure are illustrated in six pairs of temporal bones selected from a group of 33 male patients with histories of noise exposure. For the entire group the commonest form of lesion, associated with a 4-kHz dip in the audiogram, was a relatively diffuse degeneration in the second quadrant of the basal turn, in the 9-13 mm area. An advanced form of this lesion had a wide gap of more or less complete sensorineural degeneration affecting the entire second quadrant and displaying various degrees of extension toward the apex and base. The pattern associated with an "abrupt high-tone loss," with more or less complete hair cell and nerve degeneration in both the second and first quadrants and extending to the basal end of the cochlea, was rare. In one case this pattern appeared to have evolved from the first type of lesion as the remaining nerve fibers in the first quadrant had degenerated. The protective effect of the acoustic shadow of the head for the right ear, in shooting from the right shoulder, is demonstrated for the higher frequencies. Two almost identical cases of sharply-circumscribed single areas of degeneration in the first quadrant and one case with two such areas represent the third type of lesion. In one of these cases there was a history of firearm usage. It is postulated that this type of lesion is caused by impulse noise. In most of the material the degeneration pattern differed markedly from the diffuse degeneration seen with presbycusis. Degeneration patterns with knife-sharp transitions between completely degenerated and apparently undamaged areas appear to be characteristic of noise-induced injuries.

Adult↗

PubMed1978

A scanning electron-microscopic study of the local degeneration of cilia during sexual reproduction in Paramecium.

The location and extent of local degeneration of cilia during sexual reproduction of Paramecium was studied using scanning electron microscopy to examine cells undergoing conjugation and autogamy. At some time during the mating reaction, but prior to conjugant pair formation, ciliary degeneration begins at the antero-ventral tip of cells and proceeds posteriorly along the suture. In the anterior part of the cell, degeneration occurs on both sides of the suture, but in the posterior part it is restricted to the right side of the suture. In 5 species of Paramecium examined, degeneration occurred in nearly the same region. No degeneration of cilia is observed in natural autogamy of P. tetraurelia, whereas in chemically induced autogamy of P. caudatum degeneration occurs as in ordinary conjugation. Conjugant pairs never expose any deciliated cell surface except at the postero-ventral tip. The maximum extent of ciliary degeneration is best seen in the chemically induced autogamous cells: 7 kinetics (rows of unit teritories) at the anterior-left, 4 kinetics at the anterior-right, 10 or more kinetics at the posterior-right and the right wall of the vestibule of the mouth. Before complete disappearance of the cilia, many short cilia are observed. This suggests that ciliary degeneration is due to resorption. Degeneration extends more rapidly in cells with stronger mating reactivity. The relations between mating reactivity, ciliary degeneration and nuclear activation are discussed.

Animals↗

PubMed1977

The early stages of Wallerian degeneration in the severed optic nerve of the newt (Triturus viridescens).

The initiation of Wallerian degeneration in the severed optic nerve of the newt (Triturus viridescens) was very rapid and intense. Significant degeneration of nonmyelinated axons was observed as early as six hours after lesion (h.a.l.) and was almost complete by 48 h.a.l. Initial degeneration of non-myelinated axons began in "extracellular digestion chambers" formed between burgeoning ependymoglial processes. The remaining fragments and debris were later phagocytized by surrounding ependymoglial processes. Many axons of myelinated fibers have degenerated as early as 6 h.a.l. However, the overall population of myelinated axons degenerates at a much slower rate than nonmyelinated ones, for many of them appear intact as late as 48 h.a.l. Some myelin sheaths show significant signs of degeneration by 6 h.a.l. Indeed, by this time a number of myelinated fibers have completely degenerated leaving only large vacuolated spaces in the nerve parenchyma. Swelling and vacuolization of the sheath are among the earliest signs of myelin degeneration. The ependymoglial cell response to optic nerve lesion is manyfold and dramatic. By 6 h.a.l. there are signs of burgeoning ependymoglial processes which begin to resemble scar formation (gliosis) by 48 h.a.l. The morphological evidence is consistent with the concept of an important phagocytic role of ependymoglial cells during the early stages of optic nerve degeneration.

Animals↗

PubMed1989

Corticofugal axonal degeneration in rats after middle cerebral artery occlusion.

We used the Fink-Heimer method to study degenerating corticofugal axons after unilateral middle cerebral artery occlusion in 14 adult male Long-Evans hooded rats. Axonal degeneration in the pyramidal tracts was prominent at 1-3 weeks, manifesting in well-defined silver-impregnated axonal bundles coursing from the internal capsule to the pyramids and crossing completely to the contralateral spinal cord. In half of eight rats examined at 1-3 weeks, the cortical infarct included the forelimb region of the sensorimotor cortex, and degenerating corticospinal axons could be traced to the lower cervical segments; in rats with involvement of the hindlimb cortical area as well, axonal degeneration extended to the lumbosacral segments. Terminal degeneration products were present in the forebrain, midbrain, and brainstem within 2 days after arterial occlusion; the number of degenerating terminals peaked at 7 days and decreased gradually thereafter up to 6 weeks. Dense terminal degeneration was observed in the trigeminal nuclear complex of all seven rats studied at 2 and 7 days. In these seven rats, five had small cortical infarcts, and silver-impregnated terminals were observed in the lateral reticular formation; in two rats with large cortical lesions, terminal degeneration was prominent in the medial reticular formation as well. We conclude that infarcts produced by middle cerebral artery occlusion cause axonal degeneration in the brainstem and spinal cord. The Fink-Heimer method may be useful for evaluating the rat middle cerebral artery occlusion model.

Animals↗

PubMed2001

The gene for slow Wallerian degeneration (Wld(s)) is also protective against vincristine neuropathy.

Neurological diseases are frequently associated with axonal degeneration, which leads to dysfunction though separation of neurons from their targets. The mechanisms of axonal degeneration are largely unknown and in many cases are independent of those occurring within cell bodies in neurodegenerative disorders. The Wld(s) mouse mutant demonstrates the unique phenotype of resistance to axonal degeneration after axotomy (slow Wallerian degeneration), making it a powerful tool for studying mechanisms of axonal degeneration. We asked whether the Wld(s) mutation also provides resistance to axonal degeneration in a slowly progressing neuropathy. Using cultured dorsal root ganglion neurons we compared the course of axonal degeneration in response to exposure to the neurotoxin vincristine and found that Wld(s) neurites were relatively resistant to vincristine neuropathy. These findings suggest common pathophysiologic mechanisms between axotomy-induced Wallerian degeneration and toxic neuropathy. The implications are wide-ranging and are relevant to the pathophysiology of axonal degeneration seen in a wide spectrum of neurological diseases ranging from stroke and head trauma to spinal cord injury and peripheral neuropathy.

Animals↗

PubMed1993

Unilateral retrogasserian rhizotomy causes contralateral degeneration in spinal trigeminal nuclei of cats: an ultrastructural study.

We are studying the response to injury within the brainstem trigeminal nucleus following trigeminal nerve lesions. We have previously shown with light microscopy and reduced silver stains that unilateral retrogasserian rhizotomy results not only in massive degeneration throughout the ipsilateral spinal trigeminal nucleus; in addition, degeneration is seen in a ventral position at the periobex region (involving caudal pars interpolaris and rostral pars caudalis) in the contralateral spinal trigeminal nucleus. In the present study, we have used electron microscopy to identify the source of the degenerating elements seen bilaterally after unilateral retrogasserian rhizotomy in eight adult felines with survival times ranging from 3 to 20 days. At short survival times (3-7 days) degenerating terminals with round synaptic vesicles (R terminals) and type 1, asymmetric contacts predominate bilaterally, while fewer degenerating terminals with flattened synaptic vesicles (F terminals) and type 2, symmetric contacts are seen. At longer survival times more F terminal degeneration is seen, especially on the contralateral side. Postsynaptic sites and dendrites show minimal alterations. These findings suggest that the degenerating R terminals seen on the contralateral side originate from primary afferents while the degenerating F terminals seen on the contralateral side originate from intrinsic sources involving a crossed internuclear pathway. In addition, the finding of degenerating F terminals may represent a novel form of selective transynaptic change of intrinsic neurons, associated with minimal dendritic or somatic alterations.

Animals↗

PubMed1979

The projection of the visual cortex on the Clare-Bishop area in the cat. A degeneration study with the electron microscope.

Following large lesions of the cat visual cortex, the distribution of degenerating terminal boutons in the Clare-Bishop area was studied electron microscopically. Degenerating boutons were found throughout the cortical layers but mostly in layer III (51% of the total number of degenerating boutons) and layer V (24%). A smaller number of boutons were found in layers II (12%) and IV (9%), and very few in layers VI (3%) and I (1%). No degenerating terminals were observed in the upper two-thirds of layer I. Seventy-six per cent of the total degenerating boutons terminated on dendritic spines, 22% on dendritic shafts, and 2% on somata. Some degenerating boutons made synaptic contacts with somata and dendrites of nonpyramidal neurons. For example, one degenerating bouton was observed in contact with an apical dendrite of a fusiform cell. Three examples of dendritic spines, with which degenerating boutons made synaptic contracts, were found to belong to spinous stallate cells. No degenerating boutons were observed making synaptic contacts with profiles that could conclusively be traced to pyramidal cell somata.

Animals↗

PubMed1989

Changes in features of degenerating primary sensory neurons with time after capsaicin treatment.

Capsaicin (50 mg/kg) was injected into new born mice and 5 and 12 h, and 1, 2, 3, and 5 days later, their lumbar dorsal root ganglia (DRG) with the nerve roots were fixed by immersion. The morphological changes which ensued with time after treatment were examined by light and electron microscopy. The findings were as follows: (a) rapid degeneration of certain smaller B-type neurons, indicating their prompt death, was seen 5 h after treatment. Later, accumulated neurofilaments appeared in larger B-type neurons. Fissures of the cytoplasm and cell fragmentation were also observed as particular features of degeneration. Finally, these degenerating neurons, destined to die, appeared as small round figures with a disorganized nucleus. Severely degenerated neurons were seen throughout the survival time after treatment, but seemed to be most numerous after 2-3 days. (b) Three days after treatment the Nissl substances of large A-type neurons appeared dispersed, forming ring-like bundles in the periphery of cells. Cytoplasmic rupture and large membrane-bound spaces with fine granular or fibrillar materials, indicating peripheral cytolysis, were also conspicuous. Some of these cells showed severe degeneration clearly leading to cell death. The A-type neurons began to degenerate later than the B-type neurons. (c) Satellite cells showed an increased amount of electron-opaque cytoplasm that contained large vacuoles and neuronal cell debris. Mitotic figures were increased in satellite cells 3 days after treatment. (d) Unmyelinated axons in the dorsal root of mice treated with capsaicin became enlarged with accumulation of neurofilaments, synaptic vesicles or various kinds of vesicles, multivesicular bodies and mitochondria. Numerous dense lamellar bodies appeared in the unmyelinted axons within DRG 3 days after treatment, but were scarcely seen in the dorsal roots. Degeneration of the myelinated fibers increased with time. Interestingly, capsaicin seemed to have both a direct and indirect action on DRG neurons: its direct action induced rapid degeneration of the smaller neurons, whereas its indirect action induced relatively slow degeneration of the larger neurons, causing chromatolytic changes similar to those induced by periphal nerve axotomy. The injury to DRG neurons due to the indirect action seemed to be induced retrogradely.

Animals↗

PubMed1994

Quantification of the mononuclear phagocyte response to Wallerian degeneration of the optic nerve.

We investigated the numbers, origin and phenotype of mononuclear phagocytes (macrophages/microglia) responding to Wallerian degeneration of the mouse optic nerve in order to compare it with the response to Wallerian degeneration in the PNS, already described. We found macrophage/microglial numbers elevated nearly four fold in the distal segments of crushed optic nerves and their projection areas in the contralateral superior colliculus 1 week after unilateral optic nerve crush. This relative increase in mononuclear phagocyte numbers compared well with the four-to-five-fold increases reported in the distal segments of transected saphenous or sciatic nerves. Moreover, maximum numbers are reached at 3, 5 and 7 days in the saphenous, sciatic and optic nerves respectively, suggesting that the very slow clearance of axonal debris and myelin in CNS undergoing Wallerian degeneration is not simply due to a slow or small mononuclear phagocyte response. The apparent delay in the response in the CNS occurs because the mononuclear phagocytes respond to the Wallerian degeneration of axons, which is slightly slower in the CNS than the PNS, rather than to events associated with the crush itself, such as the abolition of normal electrical activity in the distal segment. This was demonstrated by the protracted time course of the mononuclear phagocyte response in the distal segment following optic nerve crush in mice carrying the Wlds mutation which dramatically slows the rate at which the axons undergo Wallerian degeneration. By [3H]-Thymidine labelling or by blocking microglial proliferation by X-irradiation of the head prior to optic nerve crush, we showed that the majority of macrophages/microglia initiating the response to Wallerian degeneration were of local, CNS origin but these cells rapidly (from 3 days post crush) upregulate endocytic and phagocytic functional markers although they do not resemble rounded myelin-phagocytosing macrophages observed in degenerating peripheral nerves. We speculate that the poor clearance of myelin in CNS fibre tracts undergoing Wallerian degeneration compared to the PNS, in the face of a mononuclear phagocyte response which is similar in relative magnitude and time course, is because Schwann cells in degenerating peripheral nerves promptly modify their myelin sheaths such that they can be recognized and phagocytosed by macrophages, whilst in the CNS oligodendrocytes do not.

Analysis of Variance↗

PubMed1986

Degeneration of myelinated sympathetic nerve fibres following treatment with guanethidine.

The specificity and characteristics of the degeneration of myelinated axons after chronic guanethidine treatment have been investigated in sympathetic and non-sympathetic nerves. Adult male Sprague-Dawley rats aged approximately 43 weeks were treated with guanethidine sulphate (50 mg per kg body weight per day) for between ten days and six weeks. Tissues were examined by qualitative and quantitative light and electron microscopy. In the superior cervical (sympathetic) ganglion (SCG), guanethidine treatment produced a 78% decrease (P = 0.009) in the mean number of myelinated fibres at a standard level of section, compared to the contralateral control ganglion which was removed surgically prior to drug treatment. This reduction in the treated SCG was apparent after 10 days, though complete degeneration of nerve cell bodies was not widespread at this stage. Degeneration of unmyelinated axons was extensive. Degenerating myelinated fibres were consistently small in diameter (up to approximately 3 microns). In individual myelinated fibres the earliest signs of degeneration involved disruption of axonal organelles, particularly the cytoskeleton, and focal widening of the periaxonal space. Myelin breakdown followed these events; degeneration of myelin still associated with a structurally intact axon was not observed. Myelin breakdown appeared to take place initially within the Schwann cell, at least to the stage of 'loosened' membranes. However, infiltrating cells were also involved in myelin phagocytosis. At all stages of treatment some small diameter myelinated fibres remained intact, and there was no evidence of degeneration of the larger diameter fibres (up to approximately 15 microns) which are consistently present in small numbers in the SCG. In the cervical sympathetic trunk, which carries preganglionic axons to the SCG and the vagus and sciatic nerves, degeneration only of unmyelinated axons was detected. These results indicate that guanethidine does not exert a primary degenerative influence on myelin or myelinating Schwann cells and that the myelin degeneration observed in the SCG is a secondary result of the previously documented selectively destructive effect of guanethidine on postganglionic sympathetic neurons. Surviving, small diameter myelinated fibres in the SCG could be either preganglionic or processes of resistant postganglionic neurons, while the larger diameter fibres are likely to be somatic. While the cervical sympathetic trunk, vagus and sciatic nerves all contain postganglionic sympathetic fibres it appears that few of these are myelinated, at least at the levels sampled in this study.

Adrenergic Fibers↗

PubMed2001

Phototoxic retinal degeneration and toxicokinetics of sitafloxacin, a quinolone antibacterial agent, in mice.

We examined drug concentrations and the incidence of retinal degeneration in the eyes of albino BALB/c mice after a single intravenous administration of sitafloxacin plus a 4 h period of UVA irradiation. Retinal degeneration was induced at 40 mg/kg or more plus UVA irradiation, and there was little decrease in ocular sitafloxacin concentration under UVA irradiation. We then examined the incidence of retinal degeneration with various periods of UVA irradiation in BALB/c mice given a single intravenous administration of 40 mg/kg sitafloxacin. Retinal degeneration occurred in all the groups receiving UVA irradiation immediately after sitafloxacin administration, whereas no retinal degeneration occurred in the groups receiving UVA irradiation starting 30 min or later after administration. In addition, we examined both the retinal degeneration and auricular inflammation in BALB/c mice given a 7-day repeated administration of sitafloxacin at 1, 3.3 and 10 mg/kg per day, which never induce retinal or auricular change by a single administration. Retinal degeneration was not induced at any dose level, although auricular skin inflammation was augmented by repeated administration. These results suggest that the occurrence of retinal degeneration depends on maximum ocular sitafloxacin concentration during UVA irradiation, whereas the severity of auricular inflammation is directly proportional to the total decrease in area under the drug concentration curve for auricular sitafloxacin under UVA irradiation. This difference between retinal degeneration and auricular inflammation may derive from their respective mechanisms of pathogenesis.

Animals↗

PubMed1977

Involvement of complement in degeneration of sympathetic nerves after administration of antiserum to dopamine beta-hydroxylase.

The involvement of complement in the degeneration of noradrenergic nerves in the guinea-pig iris produced by administration of antibody to dopamine beta-hydroxylase (DBH) in vivo was investigated histochemically. When 500 microliter of antiserum to DBH was injected systemically, no evidence of degeneration was observed in the iris although the noradrenergic supply of the myenteric plexus of the ileum degenerated within 2 days. However, injection of 20 microliter of complement (C) into the anterior chamber of one eye within 2 days of the systemic administration of anti-DBH produced a degeneration of 50--90% of noradrenergic terminals in the iris, the nerves of the iris of the contralateral uninjected eye being unaffected. Electron microscopy confirmed the presence of degenerating nerve terminals in the iris. The extent of degeneration produced by addition of C decreased when C was injected at increasing intervals after the antiserum. Intraocular injection of 5 microliter of anti-DBH together with 20 microliter of C caused a substantial degeneration of noradrenergic nerves in the iris. In contrast, intraocular injection of the Fab'2 fragment of anti-DBH (which did not bind C, but still bound DBH in vitro and in vivo) failed to cause degeneration in the presence of 20 microliter of C. The degeneration of guinea-pig sympathetic nerves caused by antibodies to DBH thus appears to be due to a complement mediated lysis of sympathetic axon membranes. The relative susceptibilities of the noradrenergic fibres in different tissues probably depend on the local concentrations of anti-DBH and C.

Adrenergic Fibers↗