Multiple sclerosis and viruses.
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Environment↗
Biomedical subjects
S D Cook
Publications and source records attributed to S D Cook.
Nerve growth factor antibody stimulates reactivation of ocular herpes simplex virus type 1 in latently infected rabbits.
Anti-nerve growth factor (anti-NGF) antibody has been shown to induce reactivation of latent herpes simplex virus type 1 (HSV-1) in vitro. We found that systemically administered anti-NGF induces ocular shedding of HSV-1 in vivo in rabbits harboring latent virus. Rabbits in which HSV-1 latency had been established were given intravenous injections of goat anti-NGF serum daily for 10 days beginning 42 days after primary viral infection. Tears were assayed for virus for 12 days beginning on the day of the first injection. All eight rabbits given high titer anti-NGF had infectious virus in their tears at least once during the 12-day period. Fifteen of 16 eyes were positive and the average duration of viral shedding for these eyes was 4.0 days. Latently infected rabbits receiving daily injections of nonimmune goat serum or saline for 10 consecutive days were controls. Only six of the 16 (38%) eyes from rabbits receiving nonimmune goat serum shed virus. Only one of 12 eyes from untreated rabbits shed virus. Sera from control rabbits had no detectable anti-NGF activity; titers in anti-NGF-treated rabbits ranged between 1:1000 and 1:10,000. NGF deprivation may act as a neuronal stressor and may share a common second messenger pathway with heat- or cold-stress induced reactivation of latent HSV-1.
Animals↗
Blood flow to the immature hip. Ultrasonic measurements in pigs.
We quantitatively analyzed blood flow through the major arteries supplying the pig's femoral head during various hip positions and following ligation of various vessels in order to identify the vascular abnormalities which may be responsible for the development of avascular necrosis during the treatment of developmental dysplasia of the hip. Our findings reveal that a decrease in total blood flow to the femoral head occurs when the hip is held in the frog leg position with ligation of the deep femoral artery and proximal ligation of the lateral femoral circumflex artery, and ligation of the deep femoral artery, together with the lateral femoral circumflex artery proximally. In contrast, neither distal ligation of the medial femoral circumflex artery nor lateral femoral circumflex artery alone nor holding the hip in the Lange position caused a statistically significant decrease in total flow. We also observed a unique steal effect on total proximal femoral blood flow, with the hip held in the frog leg position. In 4 of 7 pigs, we found a reversal of flow in the medial femoral circumflex artery.
Animals↗
A new in vivo method for the direct measurement of nutrient artery blood flow.
A new method of directly measuring nutrient artery blood flow using ultrasonic probes is described. These probes have provided reproducible results in our experiments. Advantages of ultrasonic probes include the direct measurement of blood flow through small arteries, ease of use, accuracy of measurement, applicability to a wide range of vessel diameters, the capability of chronically monitoring blood flow over time using permanently implanted probes, and the ability to use the method in conjunction with previous methods of bone blood flow measurement. The method is limited to the extent that only the contribution of the nutrient artery can be measured and total bone blood flow cannot be assessed. Tibial nutrient arterial flow and cardiac output were measured in adult mongrel dogs. Two experiments were performed: 1) bilateral baseline tibial nutrient artery blood flow measurements over time and 2) tibial nutrient blood flow comparing inhaled anesthesia (halothane/nitrous oxide/oxygen) and intravenous anesthesia (pentobarbital [Nembutal]). In 15 mongrel dogs, tibial nutrient artery blood flow averaged 1.46 +/- 0.72 mL/min (0.09 +/- 0.05 percent of cardiac output and 2.75 +/- 1.95 mL/min/100 g of bone). No significant difference in tibial nutrient artery blood flow was observed between animals given intravenous and inhaled anesthesia (P > .05). As a basic research tool, transit-time ultrasonic blood flow technology may be useful. The method is relatively easy to use and may be applied to experimental models designed to investigate various physiologic and pathologic states frequently encountered in orthopedics (eg, shock, sepsis, fractures).
Adjuvants, Anesthesia↗
Expiratory training in multiple sclerosis.
OBJECTIVE: To compare the effects of expiratory muscle training and sham training on respiratory muscle strength in patients with multiple sclerosis (MS). DESIGN: A randomized control trial; subjects were randomly assigned to either expiratory muscle training or sham training. SETTING: Training and measurement of respiratory muscle pressures were conducted in patients' homes. Weekly home visits were conducted to assure compliance with the training protocols and to obtain measurements. PATIENTS: Twenty subjects with clinically definite MS and decreased expiratory muscle strength entered the study; 10 subjects completed 3 months of expiratory training using a threshold training device and 5 subjects completed 3 months of sham training using the same device but without an expiratory training threshold load. MEASUREMENT: Respiratory muscle strength was assessed at baseline and after 1, 2, and 3 months of training; maximal inspiratory and expiratory pressures were used as measures of respiratory muscle strength. RESULTS: There was a significant increase in expiratory muscle strength after 3 months of training when the expiratory training group was compared to the sham group (p = .003); no significant change in inspiratory muscle strength was observed. CONCLUSIONS: The results of this pilot study suggest that the strength of the expiratory muscles of persons with MS can be increased through respiratory muscle training targeted to the expiratory muscles. Further research is indicated to determine if increasing the strength of the expiratory muscles in MS has an effect on clinical outcomes in this patient population.
Adolescent↗
Topographic analysis in pellucid marginal corneal degeneration and keratoglobus.
Pellucid marginal corneal degeneration (PMCD) is an uncommon cause of inferior peripheral corneal ectasia, affecting patients between the ages of 20 and 40 years. Although histopathologically it is considered a variant of keratoconus, it differs in that the marked corneal steepening occurs more inferiorly, above a narrow band of corneal stromal thinning concentric to the inferior limbus. Here we present two cases. The first case is a clinically typical bilateral PMCD with a characteristic pattern of irregular against-the-rule astigmatism on corneal topography. The second case had an uncommon presentation of hydrops in a clinically keratoglobic eye which showed a marked steepening of the inferior corneal periphery on corneal topography. The other eye showed both clinically and topographically the features of PMCD. Corneal topography suggested that in the second patient, PMCD may have preceded the development of keratoglobus. Keratoconus, PMCD and keratoglobus are considered to be associated as part of the spectrum of non-inflammatory corneal thinning disorders. However, although the finding of PMCD and keratoconus in fellow eyes has been reported, to the best of our knowledge progression from PMCD to keratoglobus has not previously been shown.
Corneal Diseases↗
Comparison between multiple sclerosis in India and the United States: a case-control study.
The prevalence of MS in India is low, and it is unclear whether the manifestations of the disease in India are similar to the United States. We carried out a case-control study to compare the disease in the two populations and used clinical, evoked potential, and MRI criteria to assess similarities and differences. Our results indicate that the rate of disease progression and frequency of involvement of the cerebral hemispheres, cerebellum, spinal cord, and brainstem were similar in the two populations. The visual system was more frequently involved in Indian patients. No Indian patient had a family history of MS; this suggests an environmental disease-triggering agent.
Adult↗
Osteogenic protein-1: biology and applications.
Osteogenic proteins, also referred to as BMPs, are a family of bone matrix polypeptides isolated from a variety of mammalian species. These proteins are members of the transforming growth factor-beta superfamily of molecules that contain a highly conserved 7 cysteine transforming growth factor-beta domain in their C-termini. Use of recombinantly produced human osteogenic protein-1, also referred to as BMP-7, implanted in conjunction with bovine bone derived Type 1 collagen or various non-proteinaceous biodegradable carriers into surgically created large diaphyseal segmental defects in animals leads to the regeneration of new bone that is fully functional biologically and biomechanically. Further study has shown that osteogenic protein-1 can be used as a bone graft substitute to promote spinal fusion and to aid in the incorporation of metal implants. Finally, osteogenic protein-1 shows promise as an agent for repair of osteochondral defects.
Amino Acid Sequence↗
Spinocerebellar degeneration and cerebral hypomyelination in a family.
The proband is a 24-year-old woman who developed symptoms of a spinocerebellar degeneration in early childhood. Neurological examination revealed normal cognitive function, optic atrophy, dysarthria, titubation, action tremors, increased deep tendon reflexes, Babinski's signs, and a spastic scissoring gait. The magnetic resonance imaging (MRI) showed an abnormal increased signal on long TR images involving white matter throughout the cerebral hemispheres, most striking in the subcortical white matter, and to a lesser degree in the brainstem, compatible with diffuse hypomyelinating or dysmyelinating diseases. Metabolic and chromosomal studies were normal. Her 49-year-old mother developed similar symptoms in her 20s and is now wheelchair-bound. Findings on neurological examination and MRI were similar to her daughter but more severe. The proband's maternal grandfather had a female cousin who had a neurological illness beginning in her 20s with similar symptoms and signs and died at the age of 44 years. Spinocerebellar degenerations are a group of syndromes with similar clinical manifestations but heterogeneous etiology. We report a family with spinocerebellar degeneration with distinct MRI findings compatible with hypomyelination or dysmyelination which has not heretofore been described. This family may represent a new spinocerebellar syndrome due to an abnormality of as yet an undetermined gene.
Adult↗
Simian immunodeficiency virus (human HIV-II) transmission in allograft bone procedures.
STUDY DESIGN: Infection of rhesus monkeys (Macaca mulatta) with simian immunodeficiency virus (SIV, HIV-II) was used to study disease transmission in allograft bone. Four allograft bone processing techniques--fresh, fresh frozen, double freeze-thaw, and double freeze-thaw with chemical decontamination--were evaluated. OBJECTIVES: To determine if SIV could be transmitted in allograft bone and if processing techniques could be used to eliminate the potential for disease transmission. SUMMARY OF BACKGROUND DATA: Although the risk of HIV transmission in bone allograft was reported to be low, HIV transmission had occurred. In all cases, frozen allograft was used. Donor screening and serologic testing significantly reduced the risk of transmission, although a window of time existed in which an individual was infected but had not seroconverted. Experimental infection of rhesus monkeys with SIV induced a disease syndrome similar to AIDS and provided an ideal model to study disease transmission. METHODS: Corticocancellous cylinders were obtained aseptically from SIV-infected rhesus monkeys. The grafts were randomly placed into one of four processing groups and implanted into noninfected animals. The presence of SIV antibody was monitored by serologic testing. After the monkeys were killed, the graft sites were studied by histology. RESULTS: All animals receiving fresh allograft or allograft bone that had been subjected to either single or double -70 C freeze-thaw cycles became infected with SIV. Animals receiving allograft that had been subjected to a double freeze-thaw cycle and chemical decontamination were disease-free after 26 weeks when the animals were killed. CONCLUSIONS: The results show that SIV (HIV-II) can be transmitted in bone allograft procedures. Although freeze-thaw cycles and lavaging to remove blood elements can reduce the infectivity of a graft, it appears chemical decontamination is necessary to provide a high level of confidence in its safety.
Animals↗
In vivo evaluation of demineralized bone matrix as a bone graft substitute for posterior spinal fusion.
STUDY DESIGN: Posterior lumbar spinal fusion segments were evaluated in 9 adult mongrel dogs 6, 12, and 26 weeks after implantation. Four sites on each animal received implants consisting of demineralized bone matrix alone, demineralized bone matrix with allograft bone, allograft bone alone, and autograft bone. Each unilateral fusion spanned one motion segment with one intervening vertebral level left undisturbed using T13-L7. The fusions were evaluated radiographically, mechanically, and histologically. OBJECTIVE: The purpose of this study was to determine the efficacy of demineralized bone matrix as a bone graft substitute for stable posterior spinal fusion. SUMMARY OF BACKGROUND DATA: Posterior spinal fusion is a procedure commonly performed for spinal stabilization. Increasing the incidence and speed of stable spinal fusion is a primary goal in spinal surgery. Concerns have developed regarding the graft material used to induce bone healing at the fusion site. The advent of osteoinductive materials, such as demineralized bone matrix, may eliminate the need to harvest autograft bone and may circumvent the immunologic response and lower osteogenic potential associated with allograft bone. METHODS: The quality of fusion and new bone formation was evaluated radiographically using plain films, computed tomography, and magnetic resonance imaging. After the dogs were killed, each fusion segment was evaluated mechanically in torsion to determine stiffness and histologically to determine qualitative parameters of new bone formation and remodeling. RESULTS: Radiographic studies showed that autograft bone sites achieved stable fusion by 26 weeks after surgery. Conversely, the demineralized bone matrix alone and with allograft bone demonstrated some new bone formation at 6 and 12 weeks, but did not achieve fusion by 26 weeks. The fusion sites of allograft bone alone showed minimal new bone formation at all time periods. Mechanically, the autograft fusion sites demonstrated torsional stability that was significantly greater than that of all other fusion sites at all time periods. The remaining fusion sites showed equivalent torsional stiffness at all time periods. Histologic analysis confirmed the radiographic and mechanical findings. CONCLUSIONS: The results indicate that demineralized bone matrix alone or with allograft bone is ineffective in achieving stable posterior spinal fusions.
Animals↗
Multiple sclerosis: immune mechanism and update on current therapies.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) afflicting approximately 250,000 individuals in the United States. This inflammatory disease has variable clinical manifestations, ranging from a relapsing-remitting course to a chronic progressive disease. Approximately one third of MS patients have chronic progressive disease often leading to severe impairment of mobility, paralysis, poor vision, and disturbances of bladder and bowel function. Although the etiology and pathogenesis remain unknown, accumulating evidence supports the hypothesis that exposure to an as-yet-unidentified infectious agent(s) triggers an aberrant immune response against self nervous tissue in genetically susceptible individuals. The tenfold higher concordance rate for MS in monozygotic twins compared to dizygotic twins, the increased incidence of MS in women compared to men (2:1), and the familial and racial occurrence of MS provide strong evidence that genetic factors influence susceptibility to MS. The major predisposing genes in MS are the human leukocyte antigen (HLA) class II molecules, DR15 and DQw6, molecularly defined as HLA-DRB1, 1501-DQA1 0102-DQB1 0602. In certain ethnic groups, MS susceptibility is more strongly associated with other DR molecules. Environmental factors are also believed to play a role, as suggested by the unique worldwide prevalence, migration effects, and epidemiological studies. Increased serum and cerebrospinal fluid antibody titers to numerous viruses have been reported; however, there have been no confirmed studies detecting viral RNA or antigen in MS brain tissue. At the present time, no known treatment can significantly alter the progression of MS. Based on the postulate that MS is an autoimmune disease associated with abnormalities in immunoregulation, a number of different immunosuppressive and immunomodulating agents have been tested as therapeutic modalities. In this article, we review the circumstantial evidence suggesting that immune system abnormalities are associated with the disease process, and provide an update on current therapies used in MS.
Animals↗
Influence of implant location on the mechanical characteristics using the transcortical model.
Mechanical evaluation of implants harvested following surgical implantation is often performed as part of the screening process for new materials or surface textures. The question of randomization with respect to implant placement often arises when attempting to design a study to evaluate several implant types, while minimizing the number of animals required to perform the investigation. The purpose of this study was to analyze the effects of implant placement within the canine femur on mechanical characteristics of the bone-implant interface when using the transcortical model. Both smooth and porous-surfaced implants were evaluated at several time periods to determine the effects of placement in the medial versus left cortex, proximal versus distal placement, and left versus right femur. The smooth-surfaced implants demonstrated a significant effect due to proximal versus distal placement within the femur only. There were no other significant comparisons. Porous-surfaced implants demonstrated no significant effects due to placement within the femur. The results demonstrate the necessity for careful study design when evaluating smooth surfaced implants; however, paired comparisons in either the medial versus lateral cortex or left versus right femur will provide unbiased comparisons between the implants.
Alloys↗
In vivo mechanical and histological characteristics of HA-coated implants vary with coating vendor.
The purpose of this study was to evaluate the interface attachment strength and histology of hydroxylapatite (HA) coated and uncoated titanium and cobalt-chromium alloy implants. The canine transcortical plug model was utilized. Four different hydroxylapatite coatings were evaluated. In vitro analysis confirmed that all coatings met FDA guidelines for HA coatings. An unspecified FDA parameter, porosity was found to range from 5-15%. Mechanical testing of the bone-implant interface demonstrated large variation in the performance of the coatings. However, further evaluation of two of the coatings did not demonstrate variations in mechanical characteristics. The histologic findings confirmed the mechanical testing results. The coatings which demonstrated the best mechanical characteristics had excellent bone apposition and uniformity and maintenance of the HA coating at all time periods upon histologic evaluation. Conversely, the coatings which demonstrated inferior mechanical characteristics demonstrated variable amounts of bone apposition and moderate to severe coating degradation and breakup. Cell-mediated osteolysis was observed in regions of severe coating degradation, and particle migration was noted in regions far from the interface. It was hoped that the four coatings would behave similarly as they all met current FDA guidelines. The only parameter which differed significantly among the coatings was coating porosity. Our results indicate that coatings with large porosities were associated with increased coating degradation and poor mechanical performance and osteolysis at the bone-coating interface.
Alloys↗
Myelin basic protein and multiple sclerosis.
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Humans↗
Effects of indomethacin on biologic fixation of porous-coated titanium implants.
The effect of perioperative administration of indomethacin on attachment strength and bone growth into porous-coated titanium implants was evaluated in the canine transcortical plug model. Various drug administration protocols simulating clinical use of indomethacin were studied. These included chronic treatment (starting 2 weeks prior to surgery), treatment immediately after surgery, and treatment 3, 6, 9, and 18 weeks following surgery. Indomethacin therapy was continued until sacrifice at 3, 6, 12, 18, or 24 postoperative weeks. Push-out testing was performed to determine the maximum bone-implant interface shear strength, and quantitative histologic analysis was used to determine percentage of bone ingrowth. When indomethacin was administered chronically or immediately after surgery, a statistically significant decrease in bone-implant interface attachment strength was seen at 3 postoperative weeks but not at later periods. No adverse effect was observed in any group after the 3-week period. Quantitative histologic analysis demonstrated no significant differences in percentage bone ingrowth among any of the treatment protocols at 3 or 6 weeks after surgery. No significant difference was observed between any of the groups at 18 or 24 weeks. The results of this study suggest that perioperative administration of indomethacin does not significantly affect attachment strength or bone ingrowth into porous-coated implants except at early periods, in which cases a transient decrease in attachment strength occurs.
Animals↗
Combination total lymphoid irradiation and low-dose corticosteroid therapy for progressive multiple sclerosis.
Total lymphoid irradiation (TLI) has been reported to delay deterioration in patients with progressive multiple sclerosis and other autoimmune disorders. METHODS--In an open trial, the effect of TLI combined with a one year course of low dose prednisone was compared to the effect of sham TLI and TLI only in a prior double-blind study of patients with progressive multiple sclerosis. RESULTS--Twenty-seven patients receiving TLI combined with corticosteroids had significantly greater lymphocytopenia in the year post-therapy than those receiving TLI only or sham TLI and Kaplan Meier product-limit survival analysis showed significantly less progression in the TLI plus steroid group over 4 years of follow-up. No difference in lymphocytopenia or progression was found with TLI plus corticosteroid therapy when the spleen was removed from the field of irradiation. CONCLUSION--These results lend further support to the hypothesis that TLI may be effective in progressive MS, and indicates that adding low-dose prednisone may enhance this effect. The study also suggests that TLI may be equally effective whether or not the spleen is irradiated.
Adult↗
Evidence for multiple sclerosis as an infectious disease.
Evidence for a viral cause of multiple sclerosis (MS) is indirect since no infectious agent has been reproducibly isolated from MS tissues nor has viral genome or antigen been consistently identified. The occurrence of spontaneous human and animal models of demyelination, serologic studies, and epidemiologic data provide persuasive circumstantial evidence for an infectious trigger in this disease. Potential mechanisms for viral induced demyelination include persistent infection of host tissues or immune mediated organ damage either in the presence or absence of the infectious agent. Any proposed viral candidate should cause demyelination in animals or man and the pattern of infection should be consistent with the unique geographic features of MS epidemiology. In addition, serologic studies should support an infection by the agent and/or viral genome should be detected in MS tissues. At this time no virus can be unequivocally linked to MS but cumulative evidence is more supportive of canine distemper virus than other viruses.
Animals↗