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Biomedical subjects

S D Cook

Publications and source records attributed to S D Cook.

At least 19 recordsLinked to original sources
PubMed2006

Keratoconus: matrix metalloproteinase-2 activation and TIMP modulation.

Keratoconus is an ocular condition that causes corneal thinning, cone formation and scarring. In view of a hypothesis that activated MMP-2 may initiate or facilitate disease progression, the MMP-2/TIMP systems of stromal cells derived from normal and keratoconic corneas have been compared. To achieve this, stromal cell cultures were established from normal, clear keratoconic (KCS-1) and scarred keratoconic (KCS-2) corneas. The secreted MMP-2 was assayed using [(3)H]Type IV collagen and analysed by zymography. Optimally maintained and nutrient deprived cells were subsequently incubated with [(3)H]lysine. The secreted radiolabelled macromolecules were separated and quantified. The results obtained indicated that optimally maintained KCS-1 stromal cells produced more MMP-2 than normal stromal cells but not TIMP. Nutrient deprivation induced MMP-2 activation and cell death. Surviving cells upregulated TIMP-1 synthesis and in this respect became similar to the KCS-2 stromal cells that did not excessively generate activated MMP-2 or die as a consequence of nutrient deprivation. From these results, it was concluded that KCS-1 stromal cells over-expressed MMP-2 without increasing TIMP production. This may facilitate MMP-2 activation in vivo and hence advance the keratoconic condition. KCS-2 cultures over-expressed both MMP-2 and TIMP-1. Because TIMP-1 inhibits MMP-2 activity and protects against cell death it may be of significance in initiating repair processes and curtailing keratoconus.

Cells, Cultured↗
PubMed2004

Doxycycline-a role in ocular surface repair.

BACKGROUND/AIMS: Doxycycline is a broad spectrum antibiotic that chelates metal ions and is frequently used as part of the treatment of ocular surface diseases. Its therapeutic value has been ascribed to an ability to inhibit matrix metalloproteinase (MMP) activity and both MMP and IL-1 synthesis. The aim of this study was to evaluate the role of doxycycline as an inhibitor of corneal MMPs and assess its contribution to ocular surface repair mechanisms. METHODS: Corneal epithelial cell and keratocyte cultures were grown to confluence and incubated with IL-1alpha, LPS, doxycycline, or doxycycline and LPS in serum free medium for 4 days. The cells were either harvested and assayed for caspase-3 activity or stained with either AE5 or antivimentin antibodies. Media samples were concentrated and assayed for MMP activity by zymography or using a fluorigenic substrate. ELISA was used to quantify IL-1alpha, MMPs -1,-2,-3,-9, and TIMPs -1 and -2. RESULTS: IL-1alpha and LPS had no effect on MMP/TIMP production by cultured corneal epithelial cells and keratocytes. Corneal MMP-2 inhibition by doxycycline was partially [Ca(2+)] dependent but irreversible. At the minimum inhibitory concentration, 100 micro m, doxycycline had no apparent effect on MMP and TIMP production, but ultimately caused the death of keratocytes and some of the epithelial cells that detached from their basement membrane. Caspase-3 activity was not detected in dead or dying keratocytes. The mechanism of cell death in cultured corneal epithelial cells was not caspase-3 related apoptosis as the activity of this enzyme, normally detectable, was lost. The epithelial cells that survived doxycycline treatment did not bind antivimentin antibody and compared with controls, reacted less with the AE5 antibody. They were probably transient amplifying cells. CONCLUSIONS: Doxycycline irreversibly inhibits corneal MMP-2 activity by chelating the metal ions that are catalytically and structurally essential. Corneal MMP/TIMP production in vitro is not modulated by IL-1alpha, LPS, or doxycycline. The therapeutic value of doxycycline may depend upon its effective concentration at the ocular surface and probably relates to its chelating properties.

Anti-Bacterial Agents↗
PubMed2002

Quantitative functional measures in MS: what is a reliable change?

As a first step toward understanding which changes should be considered as meaningful, the authors assessed the reliability of quantitative functional tests on 5 consecutive days in 63 patients with MS, determining the range of measurement variability present when patients are clinically stable. Time to walk 25 feet (T25FW) and the 9-hole peg test (9HPT) varied by <20% of individual mean scores on repeated testing. Therefore, a 20% change on these tests can be considered to be the threshold that reliably indicates a true change in function for an individual.

Adult↗
PubMed2002

Remodelling the filtration bleb.

AIMS: To report remodelling of enlarged dysmorphic filtration blebs with conjunctival compression sutures and autologous blood injection. METHODS: A retrospective analysis of consecutively recruited patients with enlarged and dysmorphic filtration blebs who were managed with conjunctival compression sutures and subconjunctival autologous blood injections. Under topical anaesthesia, conjunctival (8.0-9.0 Nylon or 8.0 Vicryl) compression sutures were placed either side of blebs that were not showing signs of spontaneous resolution. In each case up to 0.75 ml of autologous blood was then injected into the areas of the bleb to be flattened. Supplemental injections of autologous blood were given in clinic as required. RESULTS: In 11 eyes of 11 patients, conjunctival compression sutures were placed and autologous blood was injected, on average, 568 days following filtration surgery (range 41-2023). Supplemental autologous blood injections were required in eight patients, with three injections being given in one patient. In each case, the sutures were well tolerated and satisfactory compression of the conjunctiva was achieved. The highest intraocular pressure following injection was 25 mm Hg (mean 17.3, SD 4.2) and in none of the cases did blood enter the anterior chamber or parts of the filtration bleb bounded by the sutures. CONCLUSION: Conjunctival compression sutures with autologous blood provide a simple and effective means for remodelling the filtration bleb. The procedure can be performed under topical anaesthesia and does not hinder further bleb surgery, should this be required.

Aged↗
PubMed2001

Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients.

OBJECTIVE: To determine levels of serum interferon beta (IFNbeta) neutralizing antibody (NAb) and neopterin-an IFN biologic response marker-in patients with MS treated with Betaseron or Avonex. BACKGROUND: Controversy exists over the relative immunogenicity of IFNbeta-1a and IFNbeta-1b and the reasons for any such difference. To determine the role of patient profile and test methodology in IFNbeta, NAb levels need to be measured blindly and simultaneously in a predefined closely matched MS patient cohort. METHODS: Serum NAb and neopterin levels were measured in closely matched patients on Avonex (n = 98) or Betaseron (n = 64). NAb were determined by Athena Diagnostics and serum neopterin levels by Covance Laboratories using a competitive binding radioimmunoassay. RESULTS: More patients taking Betaseron (22%) than Avonex (7%) had elevated titers of NAb (p = 0.008). Mean serum neopterin levels were lower in patients with high as compared to low NAb titers (p = 0.0002). No difference in mean neopterin levels was found comparing the total Betaseron group to the Avonex group; however, in the subset of patients with low NAb titers, mean neopterin levels were higher in the Betaseron than in the Avonex group (p = 0.027). A random cross-sectional sampling of patients on Avonex showed a decrease in neopterin levels over time between weekly doses. CONCLUSION: NAb are more commonly found with Betaseron than Avonex. More studies are needed to determine the correlation among serum neopterin levels, other biologic response markers, NAb, and disease activity in patients with MS being treated with IFNbeta.

Adult↗
PubMed2001

The use of osteogenic protein-1 in reconstructive surgery of the hip.

Osteogenic proteins (OPs), also referred to as bone morphogenetic proteins (BMPs), are a family of bone matrix polypeptides that induce a sequence of cellular events that lead to the formation of new bone. This article reports the use of recombinant human OP-1 (rhOP-1, rhBMP-7) in preclinical animal models and initial human clinical experience in hip reconstructive surgery. The use of rhOP-1 in conjunction with morcellized cancellous bone and cortical strut allograft in preclinical models dramatically improved the biologic activity of the graft, resulting in greater and earlier new bone formation and graft incorporation. The clinical use of rhOP-1 in hip reconstructive procedures also resulted in greater and earlier new bone formation in the more challenging biologic environment compared with allograft bone alone.

Animals↗
PubMed2001

Improved cartilage repair after treatment with low-intensity pulsed ultrasound.

Low-intensity pulsed ultrasound accelerates bone healing via upregulation of cartilage formation and maturation phases of endchondral bone formation. The current authors evaluated the effect of ultrasound therapy on the repair of full-thickness osteochondral defects. Bilateral, 3.2 mm diameter by 5.0 mm deep osteochondral defects were created in the patellar groove of 106 adult male New Zealand rabbits. The defects were treated with daily low-intensity pulsed ultrasound therapy on the right knee. The left knee was not treated. In Part I, the effect of ultrasound therapy was evaluated at 4, 8, 12, 24, and 52 weeks after surgery. In Part II, the effect of the length of treatment (5, 10, or 40 minutes of daily ultrasound therapy) compared with standard 20 minute therapy was evaluated. The repair cartilage was evaluated and graded on a standard scale for the gross and histologic appearance. Ultrasound treatment significantly improved the morphologic features and histologic characteristics of the repair cartilage compared with nontreated controls. Earlier, better repair with less degenerative changes at later times was observed in defects treated with ultrasound. Doubling the treatment time to 40 minutes daily significantly increased the histologic quality of the repair cartilage. In the current animal model, daily low-intensity pulsed ultrasound had a significant positive effect on the healing of osteochondral defects.

Animals↗
PubMed2001

The effect of osteogenic protein-1 on the healing of segmental bone defects treated with autograft or allograft bone.

BACKGROUND: Large amounts of bone graft are frequently used to elicit the healing of bone defects resulting from reconstructive procedures. Autograft and allograft bone are often used, but each has its limitations. Bone morphogenetic proteins (BMPs) improve the healing of segmental bone defects treated with autograft or allograft. The objective of the present study was to determine the effect of implantation of a recombinant osteogenic protein-1 (OP-1) in combination with bone graft on the healing of a critical-sized (2.5-cm) segmental defect in canine ulnae. METHODS: Either autograft bone, allograft bone, osteogenic protein-1 (OP-1) mixed with type-1 bovine collagen, or various combinations of OP-1 and collagen (OP-1 device) mixed with allograft or autograft were implanted in the segmental bone defects. The combinations included 67% bone graft with 33% OP-1 device and 33% bone graft with 67% OP-1 device. The healing of the defects was assessed with radiographic, biomechanical, and histological studies. The animals were killed at twelve weeks postoperatively. RESULTS: The use of the OP-1 device alone or any combination of autograft or allograft bone and the OP-1 device demonstrated improved healing on radiographic, mechanical, and histological studies compared with that demonstrated after use of autograft or allograft bone alone. The highest radiographic and histological grades and the greatest mechanical strength were achieved with the use of 33% allograft and 67% OP-1 device, although no significant differences were observed among the different groups containing the OP-1 device. At twelve weeks postoperatively, the defects treated with any amount of the OP-1 device obtained greater mechanical strength than that obtained by autograft bone alone. CONCLUSIONS: Major bone defects may be treated with allograft bone combined with the OP-1 device, instead of autograft alone, to avoid complications associated with the use of autograft. The combination of allograft bone and the OP-1 device resulted in optimum healing of the defect, according to the radiographic, mechanical, and histological parameters measured in this study. CLINICAL RELEVANCE: The combination of freeze-dried allograft bone with the OP-1 device is an attractive graft material for the treatment of large bone defects. Although similar results were observed when autogenous bone graft was used in combination with the OP-1 device, the results of the present study suggest that allograft, because of its relatively unlimited supply, can be substituted without reduced efficacy. In addition, avoiding the need to harvest autogenous bone eliminates the additional operative time and risk associated with a second surgical procedure.

Animals↗
PubMed2001

Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions.

BACKGROUND: The role of bone morphogenetic proteins (BMPs) in osseous repair has been demonstrated in numerous animal models. Recombinant human osteogenic protein-1 (rhOP-1 or BMP-7) has now been produced and was evaluated in a clinical trial conducted under a Food and Drug Administration approved Investigational Device Exemption to establish both the safety and efficacy of this BMP in the treatment of tibial nonunions. The study also compared the clinical and radiographic results with this osteogenic molecule and those achieved with fresh autogenous bone. MATERIALS AND METHODS: One hundred and twenty-two patients (with 124 tibial nonunions) were enrolled in a controlled, prospective, randomized, partially blinded, multi-center clinical trial between February, 1992, and August, 1996, and were followed at frequent intervals over 24 months. Each patient was treated by insertion of an intramedullary rod, accompanied by rhOP-1 in a type I collagen carrier or by fresh bone autograft. Assessment criteria included the severity of pain at the fracture site, the ability to walk with full weight-bearing, the need for surgical re-treatment of the nonunion during the course of this study, plain radiographic evaluation of healing, and physician satisfaction with the clinical course. In addition, adverse events were recorded, and sera were screened for antibodies to OP-1 and type-I collagen at each outpatient visit. RESULTS: At 9 months following the operative procedures (the primary end-point of this study), 81% of the OP-1-treated nonunions (n = 63) and 85% of those receiving autogenous bone (n = 61) were judged by clinical criteria to have been treated successfully (p = 0.524). By radiographic criteria, at this same time point, 75% of those in the OP-1-treated group and 84% of the autograft-treated patients had healed fractures (p = 0.218). These clinical results continued at similar levels of success throughout 2 years of observation, and there was no statistically significant difference in outcome between the two groups of patients at this point (p = 0.939). All patients experienced adverse events. Forty-four percent of patients in each treatment group had serious events, none of which were related to their bone grafts. More than 20% of patients treated with autografts had chronic donor site pain following the procedure. CONCLUSIONS: rhOP-1 (BMP-7), implanted with a type I collagen carrier, was a safe and effective treatment for tibial nonunions. This molecule provided clinical and radiographic results comparable with those achieved with bone autograft, without donor site morbidity.

Adult↗
PubMed2001

Biomechanical testing and clinical experience with the OMEGA-21 spinal fixation system.

The role of spinal instrumentation is to provide mechanical stability, obtain and maintain anatomic alignment, and promote fusion. The American Society for Testing and Materials (ASTM) introduced guidelines and procedures so that biomechanical properties of different implant designs could be compared in a consistent manner. Combined with biomechanical analyses, clinical evaluation allows the safety and efficacy of a spinal implant system to be determined before construction. The objective of our study was to determine the biomechanical properties and clinical performance of the OMEGA-21 Spinal Fixation System. Static and dynamic (fatigue) biomechanical testing was performed per ASTM guidelines and recommendations on individual components and on the system assembled in a corpectomy model. Clinical and radiographic evaluation of 57 consecutive patients with indications for instrumented spinal arthrodesis of the lower dorsal lumbar and sacral segments of the spine was performed at a mean follow-up of 31.9 months. Static and fatigue testing revealed superior biomechanical properties of the individual components and of the assembled system. The mechanical-strength values of the system were comparable with maximum reported values for existing implant designs. At final clinical follow-up, 86% of patients obtained relief of their symptoms; 84% considered their clinical results to be excellent or good. Ninety-one percent of patients satisfied radiographic criteria for bony fusion. There were 5 implant-related complications: 2 misplaced screws (2 patients), local pain above the implant (2 patients), and 2 broken expansive screws (1 patient). Biomechanical and clinical results indicate that the OMEGA-21 system is feasible and performs well as a spinal instrumentation system for the lower dorsal, lumbar, and sacral spine.

Adult↗
PubMed2001

Immunoglobulin G subclass distribution of autoantibodies to gangliosides in patients with Guillain-Barre syndrome.

IgG anti-ganglioside antibodies are present in a proportion of patients with the Guillain-Barré syndrome (GBS). To determine if antibodies to gangliosides are restricted in IgG subclass distribution, we evaluated IgG subclass antibody responses to gangliosides in sera of patients with GBS. Sera from GBS patients with IgG activity against gangliosides were analyzed for IgG subclass distribution using an enzyme-linked immunosorbent assay. The anti-LM1 antibodies in sera from GBS patients were predominantly of the IgG3 subclass while anti-GM1 and anti-GT1a antibodies were predominantly of the IgG1 and IgG3 subclasses. The results indicate a Th2-dependent antibody response.

Autoantibodies↗
PubMed2000

Biomechanical evaluation and preliminary clinical experience with an expansive pedicle screw design.

The advantages of pedicle screw fixation depend on their ability to retain bony purchase until the fusion mass is stable. Osteoporotic bone and removal and replacement of pedicle screws in revision procedures substantially reduce screw mechanical fixation strength and can lead to clinical failure. The objective of this study was to determine if an expansive pedicle screw design could be used to improve biomechanical fixation in bone of compromised quality. Axial mechanical pullout testing was performed on paired expansive and conventional pedicle screws placed in fresh, unembalmed cadaveric vertebrae. Bone mineral density measurements (made using a dual-energy X-ray absorption meter) were used to characterize bone quality. A preliminary clinical and radiographic evaluation of 14 patients was also performed at a minimum 2-year follow-up. The mean axial pullout force in bone of all qualities was increased 30% when the expansive pedicle screw design was used. This included an appropriate 50% increase in pullout force in bone of poor quality (low bone mineral density). The preliminary clinical and radiographic results were supportive of the biomechanical design rationale and mechanical testing. The results were similar to those expected for spinal instrumentation using pedicle screws, even though compromised bone was present in two thirds of the cases in which the expansive screw was used.

Adult↗
PubMed2000

The Otto Aufranc Award. Strut allograft healing to the femur with recombinant human osteogenic protein-1.

Allograft struts are used to reinforce the deficient proximal femur in hip arthroplasty or for fixation of a periprosthetic fracture. Although the use of strut grafts wired or cabled to the proximal femur generally has been successful, the time for healing is slow. The purpose of the current study was to determine whether cortical strut graft healing to the femur could be enhanced by the addition of recombinant human osteogenic protein-1. Fourteen adult dogs underwent bilateral onlay allograft strut procedures to the midfemur using stainless steel cables. In each animal one femur received 500 mg of osteogenic protein-1 device (2.5 mg recombinant human osteogenic protein-1/g Type I collagen) interposed between the graft and host bone. The results showed that the healing of cortical strut grafts to the femur was enhanced dramatically by the addition of the osteogenic protein-1 device. The sites treated with osteogenic protein-1 had significantly greater radiographic, histologic, and microradiographic scores at all times. Rapid formation of new bone and graft incorporation was observed in sites treated with the osteogenic protein-1 device. Strut healing with the osteogenic protein-1 device at 4 weeks postoperative was superior to the healing in control sites at 8 weeks. Improving and accelerating the course of cortical strut graft healing should provide a substantial clinical benefit in lowering the risk of graft nonunion and fracture and shorten the time of protected weightbearing and functional disability.

Animals↗