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S L Woo

Publications and source records attributed to S L Woo.

At least 37 records · Page 2Linked to original sources
PubMed2000

Type V collagen is increased during rabbit medial collateral ligament healing.

To understand the reparative process of medial collateral ligament (MCL), fibrillar collagen and their relative ratios in healing MCL with anterior cruciate ligament (ACL) reconstruction were analyzed. Skeletally mature New Zealand white rabbits were subjected to a mop-end tear of MCL without repair with ACL reconstruction. Rabbits were killed 6 and 52 weeks after injury. Ligamentous tissues from the injury site and sham controls were soaked in 0.5 M acetic acid for 24 h, minced, and treated with pepsin to solubilize collagen. Pepsin solubilized about 80% of the total collagen as determined by hydroxyproline analysis of the pepsin residues. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of the solubilized collagen revealed presence of fibrillar collagen types I, III, and V. Densitometric scanning of the protein bands corresponding to types I, III, and V collagen indicated that in sham controls types III and V collagen represented about 8% and 12%, respectively, of the type I collagen whereas the healed MCL ligaments at 6 weeks showed significant increase in type III and V collagen to about 19% and 24%, respectively. By 52 weeks type III collagen in the healed MCL had returned to that of sham controls while type V collagen remained elevated at approximately 18%. These data suggest that presence of type V collagen in high concentration in healing ligaments may have an influence on collagen fibril diameters seen in healed ligament and should be included in the analysis when evaluating ligament healing.

Animals↗
PubMed2000

Effects of sectioning the posterolateral structures on knee kinematics and in situ forces in the posterior cruciate ligament.

The objective of this study was to determine the effects of sectioning the posterolateral structures (PLS) on knee kinematics and in situ forces in the posterior cruciate ligament (PCL) in response to external and simulated muscle loads. Ten human cadaveric knees were tested using a robotic/universal force-moment sensor testing system. The knees were subjected to three loading conditions: (a) 134-N posterior tibial load, (b) 5-Nm external tibial torque, and (c) isolated hamstring load (40 N biceps/40 N semimembranosus). The knee kinematics and in situ forces in the PCL for the intact and PLS-deficient knee conditions were determined at full extension, 30 degrees, 60 degrees, 90 degrees, and 120 degrees of knee flexion. Under posterior tibial loading posterior tibial translation with PLS deficiency increased significantly at all flexion angles by 5.5+/-1.5 mm to 0.8+/-1.2 mm at full extension and 90 degrees, respectively. The corresponding in situ forces in the PCL increased by 17-19 N at full extension and 30 degrees of knee flexion. Under the external tibial torque, external tibial rotation increased significantly with PLS deficiency by 15.1+/-1.6 degrees at 30 degrees of flexion to 7.7+/-3.5 degrees at 90 degrees, with the in situ forces in the PCL increasing by 15-90 N. The largest increase occurred at 60 degrees to 120 degrees of knee flexion, representing forces two to six times of those in the intact knee. Under the simulated hamstring load, posterior tibial translation and external tibial and varus rotations also increased significantly at all knee flexion angles with PLS deficiency, but this was not so for the in situ forces in the PCL. Our data suggest that injuries to the PLS put the PCL and other soft tissue structures at increased risk of injury due to increased knee motion and the elevated in situ forces in the PCL.

Aged↗
PubMed2000

Prospects for herpes-simplex-virus thymidine-kinase and cytokine gene transduction as immunomodulatory gene therapy for prostate cancer.

In completed and ongoing clinical trials, adenovirus-mediated (Ad.) expression of herpes-simplex-virus thymidine-kinase (HSV-tk) gene transduction followed by ganciclovir (GCV) therapy has produced limited toxicity and evidence of antitumor activity following injection of the prostate. Furthermore, this system has been shown to direct systemic antitumor activity in several experimental cancer models, including that of prostate cancer, which may serve as the basis for in-situ immunomodulatory gene therapy. In a mouse model of prostate cancer, natural killer (NK) cells have been identified as the mediator of antimetastatic activity following Ad.HSV-tk + GCV, resulting in the combination of Ad.HSV-tk and adenovirus-mediated expression of interleukin 12 (Ad.IL-12) to exploit this cytokine's ability to enhance NK proliferation and cytotoxicity. Combination therapy demonstrated superior local and systemic growth suppression over that obtained with either therapy alone. Importantly, when the metastatic tumor burden was increased to an extent that negated the growth-suppressive activity directed by Ad.HSV-tk + GCV or Ad.IL-12 alone, combination therapy continued to demonstrate significant growth suppression. Examination of tumor-infiltrating lymphocytes documented enhanced NK lytic activity following combination therapy. Therefore, it appears that the combination of Ad.HSV-tk and Ad.IL-12 should be validated in a clinical trial for the treatment of prostate cancer.

Adenoviridae↗
PubMed2000

In-situ force in the medial and lateral structures of intact and ACL-deficient knees.

The anterior cruciate ligament (ACL) is the major contributor to limit excessive anterior tibial translation (ATT) when the knee is subjected to an anterior tibial load. However, the importance of the medial and lateral structures of the knee can also play a significant role in resisting anterior tibial loads, especially in the event of an ACL injury. Therefore, the objective of this study was to determine quantitatively the increase in the in-situ forces in the medial collateral ligament (MCL) and posterolateral structures (PLS) of the knee associated with ACL deficiency. Eight fresh-frozen cadaveric human knees were subjected to a 134-N anterior tibial load at full extension and at 15 degrees, 30 degrees, 60 degrees, and 90 degrees of knee flexion. The resulting 5 degrees of freedom kinematics were measured for the intact and the ACL-deficient knees. A robotic/universal force-moment sensor testing system was used for this purpose, as well as to determine the in-situ force in the MCL and PLS in the intact and ACL-deficient knees. For the intact knee, the in-situ forces in both the MCL and PLS were less than 20 N for all five flexion angles tested. But in the ACL-deficient knee, the in-situ forces in the MCL and PLS, respectively, were approximately two and five times as large as those in the intact knee (P < 0.05). The results of this study demonstrate that, although both the MCL and PLS play only a minor role in resisting anterior tibial loads in the intact knee, they become significant after ACL injury.

Adult↗
PubMed2000

The effect of the point of application of anterior tibial loads on human knee kinematics.

Coupled axial tibial rotation in response to an anterior tibial load has been used as a common diagnostic measurement and as a means to load the ligamentous structures during laboratory tests. However, the exact location of the point of application of these loads as well as the corresponding sensitivity of the coupled tibial rotation to this point can have an effect on the function of the soft tissues at the joint. Therefore, the purpose of this study was to determine the effects of four different points of application of the anterior tibial load on the anterior tibial translation and coupled axial tibial rotation. The four points include: (1) geometric point - midway between the collateral ligament insertion sites on the tibia, (2) clinical point - a position that attempts to simulate clinical diagnostic tests, (3) medial point - a position medial to the geometric point and (4) lateral point - a position lateral to the clinical point. A robotic/universal force-moment sensor testing system was used to apply the anterior tibial load at the four points of application and to record the resulting joint motion. Anterior tibial translation in response to an anterior tibial load of 100N was found not to vary between the four points of application of the anterior tibial load at all flexion angles examined. However, internal tibial rotation was found for the lateral point (13+/-10 degrees at 30 degrees of knee flexion) in all specimens and clinical point (8+/-10 degrees at 30 degrees of knee flexion) while external rotation resulted when the load was applied at the medial point (-8+/-7 degrees at 30 degrees of knee flexion). Both internal and external tibial rotations occurred throughout the range of flexion when the tibial load was applied at the geometric point. The results suggest that the clinical point should be used as the point of application of the anterior tibial load whenever clinical examinations are simulated and multi-degree-of-freedom joint and soft tissue function are examined.

Aged↗
PubMed2000

Anti-tumor immunity induced by interleukin-12 gene therapy in a metastatic model of breast cancer is mediated by natural killer cells.

An intrahepatic tumor model for metastatic breast cancer was generated in syngeneic mice by direct inoculation of JC cells, a murine mammary adenocarcinoma cell line. Intratumoral administration of a recombinant adenoviral vector expressing the murine Interleukin-12 (ADV-mIL-12) resulted in significant reduction in the tumor volume compared to control vector. Tumor regression was also evident on histopathologic analysis of the liver, where inflammatory changes as opposed to nuclear atypia predominated after IL-12 vector treatment. There was a significant prolongation in the long term survival of IL-12 treated animals, with complete tumor rejection in 40% of the animals. In vivo depletion studies using specific monoclonal antibodies against the various lymphocyte subsets showed a significant reduction in long term survival after natural killer (NK) cell depletion. This suggests that the NK cell is a critical effector in the antitumor effect mediated by IL-12. These results strongly support the potential role of gene mediated cytokine therapy for the treatment of metastatic breast cancer.

Adenocarcinoma↗
PubMed2000

Gene therapy of metastatic colon carcinoma: regression of multiple hepatic metastases by adenoviral expression of bacterial cytosine deaminase.

Colon carcinoma accounts for 20% of deaths due to malignancies in the Western world. Once metastases occur, therapeutic options are limited, with an approximate 5-year survival of only 5%. To investigate the potential of new gene therapeutic approaches, a hepatic micrometastasis model of colon carcinoma in BALB/c mice was established. Inoculation of syngeneic MCA26 colon carcinoma cells into the spleens of 18- to 20-week-old mice resulted in the formation of multiple hepatic metastases. Selective transduction of developing hepatic metastases was demonstrated using a beta-galactosidase-expressing recombinant adenovirus. Cytosine deaminase (CD) can metabolize 5-fluorocytosine into the chemotherapeutic reagent 5-fluorouracil (5FU). The antitumoral potential of this suicide gene therapy approach was explored by systemic application of a recombinant replication-deficient adenovirus encoding for the bacterial CD gene under the control of the cytomegalovirus promoter (Ad.CMV-CD). Injection into the tail vein of tumor-bearing mice resulted in delayed tumor growth with significant reduction in hepatic metastases. The potential of this experimental approach for possible future clinical applications was evaluated by investigating adenoviral transduction efficiency, 5FU sensitivity, and 5-fluorocytosine-dependent Ad.CMV-CD toxicity in a variety of human colon cancer cell lines. Although the murine cell lines MCA26 and CC36 were highly sensitive to 5FU, the human colon cancer cell lines showed a 1-100 times higher resistance to 5FU. Specific Ad.CMV-CD toxicity correlates with 5FU toxicity. Transduction efficiency in human colon carcinoma cell lines was shown to be 10-1700 times higher compared with murine cell lines, thus compensating for 5FU resistance. In conclusion, suicide gene therapy using CD may be promising as an adjuvant treatment regimen for hepatic micrometastases of human colon carcinoma.

Adenoviridae↗
PubMed2000

Glucose-stimulated and self-limiting insulin production by glucose 6-phosphatase promoter driven insulin expression in hepatoma cells.

The liver is an attractive target organ for insulin gene expression in type 1 diabetes as it contains appropriate cellular mechanisms of regulated gene expression in response to blood glucose and insulin. We hypothesize that insulin production regulated by both glucose and insulin may be achieved using the promoter of the glucose 6-phosphatase gene (G6Pase), the expression of which in the liver is induced by glucose and suppressed by insulin. Recombinant adenoviral vectors expressing the reporter gene CAT or insulin under transcriptional direction of the G6Pase promoter were constructed. Glucose-stimulated as well as self-limiting insulin production was achieved in vector-transduced hepatoma cells in which expression of the insulin gene was controlled by the G6Pase promoter. While insulin strongly inhibited the G6Pase promoter activity under low glucose conditions, its inhibitory capacity was attenuated when glucose levels were elevated. At the physiologic glucose level of 5.5 mM glucose, vector-transduced hepatoma cells produced a self-limited level of insulin at approximately 0.2-0.3 ng/ml, which is within the range of fasting levels of insulin in normal animals. These results indicate that the G6Pase promoter possesses desirable features and may be developed for regulated hepatic insulin gene expression in type 1 diabetes.

Adenoviridae↗
PubMed2000

The forces in the anterior cruciate ligament and knee kinematics during a simulated pivot shift test: A human cadaveric study using robotic technology.

PURPOSE: Although it is well known that the anterior cruciate ligament (ACL) is a primary restraint of the knee under anterior tibial load, the role of the ACL in resisting internal tibial torque and the pivot shift test is controversial. The objective of this study was to determine the effect of these 2 external loading conditions on the kinematics of the intact and ACL-deficient knee and the in situ force in the ACL. TYPE OF STUDY: This study was a biomechanical study that used cadaveric knees with the intact knee of the specimen serving as a control. MATERIALS AND METHODS: Twelve human cadaveric knees were tested using a robotic/universal force-moment sensor testing system. This system applied (1) a 10-Newton meter (Nm) internal tibial torque and (2) a combined 10-Nm valgus and 10-Nm internal tibial torque (simulated pivot shift test) to the intact and the ACL-deficient knee. RESULTS: In the ACL-deficient knee, the isolated internal tibial torque significantly increased coupled anterior tibial translation over that of the intact knee by 94%, 48%, and 19% at full extension, 15 degrees, and 30 degrees of flexion, respectively (P <.05). In the case of the simulated pivot shift test, there were similar increases in anterior tibial translation, i.e., 103%, 61%, and 32%, respectively (P <.05). Furthermore, the anterior tibial translation under the simulated pivot shift test was significantly greater than under an isolated internal tibial torque (P <.05). Under the simulated pivot shift test, the in situ forces in the ACL were 83 +/- 16 N at full extension and 93 +/- 23 N at 15 degrees of knee flexion. These forces were also significantly higher when compared with those for an isolated internal tibial torque (P <.05). CONCLUSION: Our data indicate that the ACL plays an important role in restraining coupled anterior tibial translation in response to the simulated pivot shift test as well as under an isolated internal tibial torque, especially when the knee is near extension. These findings are also consistent with the clinical observation of anterior tibial subluxation during the pivot shift test with the knee near extension.

Adult↗
PubMed2000

Role of the forearm interosseous ligament: is it more than just longitudinal load transfer?

The objective of our study was to measure 3-dimensional force vectors (magnitude and direction) acting in the forearm when load is applied to the hand and to measure the actual force in the interosseous ligament (IOL). Fourteen cadaveric forearms were loaded to 136 N of compression while special load cells measured force vectors in the forearm. Computer forearm models were used to display the 3-dimensional force vector directions. The study results showed that the radius bears most of the load at the wrist but load on the radius at the elbow is reduced because the IOL transfers load to the ulna between the wrist and the elbow. In addition to this role in longitudinal load transfer, our measurement of 3-dimensional forces allowed identification of transverse vectors which suggest that the IOL also functions to keep the radius and ulna from splaying apart. Our results imply that the IOL participates not only in longitudinal load transfer but also in the maintenance of transverse stability of the forearm during compressive load transfer from the hand to the elbow.

Aged↗
PubMed2000

Interaction between the ACL graft and MCL in a combined ACL+MCL knee injury using a goat model.

The optimal treatment for the MCL in the combined ACL and MCL-injured knee is still controversial. Therefore, we designed this study to examine the mechanical interaction between the ACL graft and the MCL in a goat model using a robotic/universal force-moment sensor testing system. The kinematics of intact, ACL-deficient, ACL-reconstructed, and ACL-reconstructed/ MCL-deficient knees, as well as the in situ forces in the ACL, ACL graft, and MCL were determined in response to two external loading conditions: 1) anterior tibial load of 67 N and 2) valgus moment of 5 N-m. With an anterior tibial load, anterior tibial translation in the ACL-deficient knee significantly increased from 2.0 and 2.2 mm to 15.7 and 18.1 mm at 30 degrees and 60 degrees of knee flexion, respectively. The in situ forces in the MCL also increased from 8 to 27 N at 60 degrees of knee flexion. ACL reconstruction reduced the anterior tibial translation to within 2 mm of the intact knee and significantly reduced the in situ force in the MCL to 17 N. However, in response to a valgus moment, the in situ forces in the ACL graft increased significantly by 34 N after transecting the MCL. These findings show that ACL deficiency can increase the in situ forces in the MCL while ACL reconstruction can reduce the in situ forces in the MCL in response to an anterior tibial load. On the other hand, the ACL graft is subjected to significantly higher in situ forces with MCL deficiency during an applied valgus moment. Therefore, the ACL-reconstructed knee with a combined ACL and MCL injury should be protected from high valgus moments during early healing to avoid excessive loading on the graft.

Animals↗
PubMed2000

Injury and repair of ligaments and tendons.

In this chapter, biomechanical methods used to analyze healing and repair of ligaments and tendons are initially described such that the tensile properties of these soft tissues as well as their contribution to joint motion can be determined. The focus then turns to the important mechanical and biological factors that improve the healing process of ligaments. The biomechanics of surgical reconstruction of the anterior cruciate ligament and the key surgical parameters that affect the performance of the replacement grafts are subsequently reviewed. Finally, injury mechanisms and the biomechanical analysis of various treatment techniques for various types of tendon injuries are described.

Achilles Tendon↗
PubMed1999

Imaging adenoviral-mediated herpes virus thymidine kinase gene transfer and expression in vivo.

The feasibility of noninvasive imaging of adenoviral-mediated herpes virus type one thymidine kinase (HSV1-tk) gene transfer and expression was assessed in a well-studied animal model of metastatic colon carcinoma of the liver. Tumors were produced in syngeneic BALB/c mice by intrahepatic injection of colon carcinoma cells (MCA-26). Seven days later, three different doses (3 x 10(8), 1 x 10(8), and 3 x 10(7) plaque-forming units (pfu) of the recombinant adenoviral vector ADV. Rous sarcoma virus (RSV)-tk bearing the HSV1-tk gene were administered by intratumoral injection in separate groups of mice. Two control groups of tumor-bearing mice received intratumoral injections of the control adenoviral vector dl-312 or buffer alone, respectively. T2-weighted magnetic resonance (MR) images of mice were obtained before administering the virus and provided an anatomical reference of hepatic tumor localization. Eighteen h after the virus injection, one group of animals was given i.v. injections of 300 microCi of no-carrier-added 5-[131I]-2'-fluoro-1-beta-D-arabinofuranosyluracil (FIAU) and imaged 24 h later with a gamma camera. In some animals, the tumors were sampled and processed for histology and quantitative autoradiography (QAR). The gamma camera images demonstrated highly specific localization of [131I]FIAU-derived radioactivity to the area of ADV.RSV-tk-injected tumors in the liver, which was confirmed by coregistering the gamma camera and T2-weighted MR images. There was no accumulation of [131I]FIAU-derived radioactivity in tumors that were injected with the control vector or injection solution alone. A more precise distribution of radioactivity in the area of transfected tumor was obtained by histological and QAR comparisons. A heterogeneous pattern of radioactivity distribution in transfected tumors was observed. A punctate pattern of radioactivity distribution was observed in peritumoral liver tissue in animals given injections of 3 x 10(8) and 1 x 10(8) pfu of ADV.RSV-tk but not in animals given injections of 3 x 10(7) pfu nor in control animals. A QAR-microscopic comparison showed that the punctate areas of radioactivity colocalized with cholangial ducts. The level of [131I]FIAU-derived radioactivity accumulation (HSV1-tk expression) in the transfected tumors was viral dose-dependent. The viral dose-dependency of radioactivity accumulation was more pronounced in peritumoral liver, which was confirmed by reverse transcription-PCR analysis. A separate group of tumor-bearing animals received different doses of ADV.RSV-tk vector followed by treatment with ganciclovir (GCV), 10 mg/kg i.p. b.i.d. for 6 days. The ADV.RSV-tk transfected tumors significantly regressed with GCV treatment; the control tumors continued to grow. During the GCV treatment, the levels of liver transaminases (ALT and AST) were significantly increased in animals that received injections of 3 x 10(8) and 1 x 10(8) pfu of ADV.RSV-tk but not in animals that received injections of 3 x 10(7) pfu and in control animals. The observed liver toxicity confirms the results of gamma camera and QAR imaging, which demonstrated an unwanted spread of ADV.RSV-tk vector and HSV1-tk expression in peritumoral and remote liver tissue at higher doses. These and our previous results indicate that noninvasive imaging of adenoviral-mediated HSV1-tk gene expression is feasible for monitoring cancer gene therapy in patients.

Adenoviridae↗
PubMed1999

Role of NK and T cells in IL-12-induced anti-tumor response against hepatic colon carcinoma.

IL-12 is an immuno-regulatory cytokine that has been shown to generate a potent NK and Th1 response in a variety of laboratory models. However, the detailed immune development in the hepatic tumor model by IL-12-mediated gene therapy has not been clarified. In our previous study, intra-tumoral transfer of Adv.mIL-12 (5 x 10(8) pfu) to the MCA26 colon carcinoma liver tumor induced an effective anti-tumor response, extending the median survival time from 29 to over 54 days, while 25% of the animals became tumor-free after a single treatment. In this work, we show that NK cells are responsible for the early, and both NK and T cells for the long-term, Adv.mIL-12-induced immune response. Immunohistopathological analysis of the tumor and in vitro cytotoxicity study of the mononuclear cells of the liver show that NK cells are the first to infiltrate and mediate tumor cell killing, as early as 48 hr after Adv.mIL-12 treatment. In vivo and in vitro depletion of these cells completely abolishes this early anti-tumor response. This activity can be observed in both populations of conventional NK and NKT cells in vitro and in athymic nude mice in vivo. However, the early NK response alone is not sufficient. In vivo T-cell depletion in both the primary tumor treatment and the long-term survival rechallenge study reveals that T cells in addition to NK cells are required in the development of the long-term survival and immunity attributed to Adv.mIL-12 gene therapy in this orthotopic tumor model of colon carcinoma.

Adenoviridae↗
PubMed1999

Gene therapy to promote thromboresistance: local overexpression of tissue plasminogen activator to prevent arterial thrombosis in an in vivo rabbit model.

Tissue-type plasminogen activator (tPA) catalyzes the rate-limiting initial step in the fibrinolytic cascade. Systemic infusion of tPA has become the standard of care for acute myocardial infarction. However, even the relatively short-duration protocols currently employed have encountered significant hemorrhagic complications, as well as complications from rebound thrombosis. Gene therapy offers a method of local high-level tPA expression over a prolonged time period to avoid both systemic hemorrhage and local rebound thrombosis. To examine the impact of local tPA overexpression, an adenoviral vector expressing tPA was created. The construct was characterized functionally in vitro, and the function of the vector was confirmed in vivo by delivery to the rabbit common femoral artery. Systemic coagulation parameters were not perturbed at any of the doses examined. The impact of local overexpression of tPA on in vivo thrombus formation was examined subsequently in a stasis/injury model of arterial thrombosis. The construct effectively prevented arterial thrombosis in treated animals, whereas viral and nonviral controls typically developed occluding thrombi. This construct thus offers a viable technique for promoting a locally thromboresistant small-caliber artery.

Adenoviridae↗
PubMed1999

Early expression of marker genes in the rabbit medial collateral and anterior cruciate ligaments: the use of different viral vectors and the effects of injury.

Gene therapy is a technique that may offer advantages over current methods of cytokine delivery to ligaments. To determine if implanted genes could be expressed in normal and injured knee ligaments, the medial collateral ligament and anterior cruciate ligament were studied in 18 rabbits. A retroviral ex vivo technique using allograft medial collateral ligament and anterior cruciate ligament fibroblasts and an adenoviral in vivo technique were compared as methods for delivering the LacZ marker gene to knee ligaments. Bilateral knee surgeries were performed, and the rabbits were equally divided into three groups. Group 1 received the retrovirus and the medial collateral ligament was ruptured, Group 2 received the adenovirus and the medial collateral ligament was ruptured, and Group 3 received the adenovirus and the medial collateral ligament was not injured. The anterior cruciate ligament was not injured in any group. The medial collateral and anterior cruciate ligaments of the right knees received 10(6) allografted, transduced ligament fibroblasts or 10(9) adenovirus particles, whereas the ligaments of the left knee received a similar volume of saline solution only. Equal numbers of rabbits were killed at 10 days, 3 weeks, and 6 weeks following the procedure. Ligament samples were stained with X-gal to detect the expression of the LacZ gene product, beta-galactosidase. LacZ gene expression was evident in ruptured and uninjured medial collateral ligaments as well as in the anterior cruciate ligament. The expression lasted between 10 days and 3 weeks in the medial collateral and anterior cruciate ligaments with use of the retrovirus and between 3 and 6 weeks in the medial collateral ligament and at least 6 weeks in the anterior cruciate ligament with the adenovirus. The length of gene expression in the ruptured and uninjured medial collateral ligaments did not differ. These preliminary studies indicate that gene transfer to normal and injured knee ligaments is possible.

Adenoviridae↗