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Biomedical subjects

Jason Wong

Publications and source records attributed to Jason Wong.

16 recordsLinked to original sources
PubMed2006

Melanocortin 1 receptor variants and skin cancer risk.

Melanocortin 1 receptor (MC1R) gene variants are associated with red hair and fair skin color. We assessed the associations of common MC1R genotypes with the risks of 3 types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 873 controls). We found that the 151Cys, 160Trp and 294His variants were significantly associated with red hair, fair skin color and childhood tanning tendency. The MC1R variants, especially the 151Cys variant, were associated with increased risks of the 3 types of skin cancer, after controlling for hair color, skin color and other skin cancer risk factors. Carriers of the 151Cys variant had an OR of 1.65 (95% CI, 1.04-2.59) for melanoma, 1.67 (1.12-2.49) for SCC and 1.56 (1.03-2.34) for BCC. Women with medium or olive skin color carrying 1 nonred hair color allele and 1 red hair color allele had the highest risk of melanoma. A similar interaction pattern was observed for red hair and carrying at least 1 red hair color allele on melanoma risk. We also observed that the 151Cys variant contributed additional melanoma risk among red-haired women. The information on MC1R status modestly improved the risk prediction; the increase was significant for melanoma and BCC (p, 0.004 and 0.05, respectively). These findings indicated that the effects of the MC1R variants on skin cancer risk were independent from self-reported phenotypic pigmentation.

Adult↗
PubMed2006

Microscopic and histological examination of the mouse hindpaw digit and flexor tendon arrangement with 3D reconstruction.

Mice are currently the species of choice for the in vivo study of injury, but few detailed anatomical descriptions have been made of rodent digits, limiting their use for the investigation of intrasynovial tendon healing. In this study a detailed microscopic and histological investigation was performed using C57/BL6 and Tie2 LacZ reporter gene transgenic mice. Serial-sectioned mouse hindpaw digits were characterized using haematoxylin and eosin, Masson's trichrome (collagen), Alcian blue (fibrocartilage), Miller's stain (elastin) and TRITC-phalloidin (cellular cytoskeleton) staining. Digital vasculature was demonstrated using FITC-labelled dextran perfusion studies supplemented with LacZ expression in Tie2 LacZ transgenic mice digits. Imaging of the digit used a combination of brightfield and confocal microscopy with three-dimensional reconstruction. Our findings demonstrated that the mouse hindpaw possesses deep and superficial flexor tendons within a synovial sheath comparable with that found in other mammalian species. The intrasynovial tendons were avascular and had regions of fibrocartilaginous specialization relating to areas of compression. Corresponding vascular networks were demonstrated around the sheath using Tie2 LacZ mice and FITC-perfused hindpaws. Furthermore, there is an area of digit where both deep and superficial tendons reside between two pulleys, similar to zone 2 in the human hand where it would be possible to study intrasynovial tendon injury and adhesion formation. In conclusion, although the dimensions of the mouse digit pose technical challenges for surgical intervention, we have identified a model for the study of flexor tendon injury that will permit future genetic manipulation studies.

Animals↗
PubMed2006

Rethinking glycaemic control in critical illness--from concept to clinical practice change.

OBJECTIVE: To examine the practical difficulties in managing hyperglycaemia in critical illness and to present recently developed model-based glycaemic management protocols to provide tight control. BACKGROUND: Hyperglycaemia is prevalent in critical care. Current published protocols require significant added clinical effort and have highly variable results. No currently published methods successfully address the practical clinical difficulties and patient variation, while also providing safe, tight control. METHODS: We developed a unique model-based approach that manages both nutritional inputs and exogenous insulin infusions. Computerised glycaemic control methods and proof-of-concept clinical trial results are presented. The protocol has been simplified to a set of tables and adopted as a clinical practice change. Eight pilot test cases are presented to demonstrate the overall approach. RESULTS: Computerised control methods lowered blood glucose (BG) levels to the range 4.0-6.1 mmol/L within 10 hours. Over 90% of pre-set hourly blood glucose targets were achieved within measurement error. Eight pilot tests of the simplified, table-based SPRINT protocol, covering 1651 patient-hours produced an average BG level of 5.7 mmol/L (SD, 0.9 mmol/L). BG levels were in the 4.0-6.1 mmol/L band for 60% of the controlled time. Just under 90% of measurements were in the range 4.0-7.0 mmol/L, with 96% in the range 4.0-7.75 mmol/L. There were no hypoglycaemic episodes, with a minimum glucose level of 3.2 mmol/L, and no additional clinical intervention was required. SUMMARY: The overall approach of modulating nutrition as well as insulin challenges the current practice of relying on insulin alone to reduce glycaemic levels, which often results in large variability and poor control. The protocol was developed from model-based analysis and proof-of-concept clinical trials, and then generalised to a simple, clinical practice improvement. The results show extremely tight control within safe glycaemic bands.

Aged↗
PubMed2005

Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma.

We have shown that the proteasome inhibitor bortezomib (formerly known as PS-341) triggers significant antitumor activity in multiple myeloma (MM) in both preclinical models and patients with relapsed refractory disease. Recent studies have shown that unfolded and misfolded ubiquitinated proteins are degraded not only by proteasomes, but also by aggresomes, dependent on histone deacetylase 6 (HDAC6) activity. We therefore hypothesized that inhibition of both mechanisms of protein catabolism could induce accumulation of ubiquitinated proteins followed by significant cell stress and cytotoxicity in MM cells. To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively. Tubacin specifically triggers acetylation of alpha-tubulin as a result of HDAC6 inhibition in a dose- and time-dependent fashion. It induces cytotoxicity in MM cells at 72 h with an IC50 of 5-20 microM, which is mediated by caspase-dependent apoptosis; no toxicity is observed in normal peripheral blood mononuclear cells. Tubacin inhibits the interaction of HDAC6 with dynein and induces marked accumulation of ubiquitinated proteins. It synergistically augments bortezomib-induced cytotoxicity by c-Jun NH2-terminal kinase/caspase activation. Importantly, this combination also induces significant cytotoxicity in plasma cells isolated from MM patient bone marrow. Finally, adherence of MM cells to bone marrow stromal cells confers growth and resistance to conventional treatments; in contrast, the combination of tubacin and bortezomib triggers toxicity even in adherent MM cells. Our studies therefore demonstrate that tubacin combined with bortezomib mediates significant anti-MM activity, providing the framework for clinical evaluation of combined therapy to improve patient outcome in MM.

Anilides↗
PubMed2005

Evaluation of a monovalent companion animal periodontal disease vaccine in an experimental mouse periodontitis model.

Periodontal disease in companion animals is clinically similar to that of human periodontal disease. Despite the usage of veterinary procedures and antibiotic therapy, the disease still remains as one of the most highly prevalent disorders seen by veterinarians. The goal of this study was to evaluate the immunogenic properties and vaccine performance of a monovalent canine periodontal disease vaccine in the mouse oral challenge model of periodontitis. Mice vaccinated subcutaneously with inactivated, whole-cell bacterin preparations of Porphyromonas gulae displayed both high titers of anti-P. gulae specific antibodies and significantly reduced alveolar bone loss in response to homologous, heterologous, and cross-species challenge. Based on the results of these studies, a periodontal disease vaccine may be a useful tool in preventing the progression of periodontitis in animals.

Alveolar Bone Loss↗
PubMed2005

The synergistic combination of the farnesyl transferase inhibitor lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase.

Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arrest and cell death. Mechanistically, we show that the combination of lonafarnib and paclitaxel inhibits the in vitro deacetylating activity of the only known tubulin deacetylase, histone deacetylase 6 (HDAC6). In addition, the lonafarnib/taxane combination is synergistic only in cells lines expressing the wild-type HDAC6, but not a catalytic-mutant HDAC6, revealing that functional HDAC6 is required for the synergy of lonafarnib with taxanes. Furthermore, tubacin, a specific HDAC6 inhibitor, synergistically enhanced tubulin acetylation in combination with paclitaxel, similar to the combination of lonafarnib and paclitaxel. Taken together, these data suggest a relationship between FT inhibition, HDAC6 function, and cell death, providing insight into the putative molecular basis of the lonafarnib/taxane synergistic antiproliferative combination.

Acetylation↗
PubMed2005

Pigmented-anaerobic bacteria associated with canine periodontitis.

The etiology of human periodontal disease has been the focus of considerable research, yet relatively little is known about the causative agents of companion animal periodontitis. In humans, Porphyromonas gingivalis, a black-pigmented anaerobic bacteria (BPAB), has been implicated as the primary periopathogen. It has been demonstrated that BPAB are also found in companion animal periodontal pockets. While some animal BPAB have been individually identified, a study to identify the most frequently isolated subgingival BPAB has not been completed using genetic tools. The objective of this work was to identify the types and relative frequencies of pigmented anaerobic bacteria found in the periodontal pockets of dogs. Porphyromonas salivosa, Porphyromonas denticanis (a novel species) and Porphyromonas gulae were found to be the most frequently isolated BPAB associated with canine periodontitis.

Animals↗
PubMed2005

Serial tumour blood-flow measurements in androgen-dependent and -independent Shionogi tumour models.

OBJECTIVE: To investigate the relationship between blood supply and hormonal status of hormone-dependent and -independent tumours in mice. MATERIALS AND METHODS: Contrast-enhanced dynamic magnetic resonance imaging (MRI) was used to measure tumour blood flow (TBF) in Shionogi tumours implanted subcutaneously in mice. Serial measurements were taken throughout the initial tumour growth period, and during regression and subsequent androgen-independent (AI) relapse of the tumours in male mice, and throughout the growth of AI tumours in female mice. Average TBF values and coefficients of variation were calculated from tumour tissue perfusion maps reconstructed from MRI data. The Tukey-Kramer test was used to identify differences between androgen-dependent (AD), male AI and female AI tumours. RESULTS: The mean TBF strongly depended on tumour size in all three stages of the tumour growth cycle. AI tumours had a significantly higher TBF than AD tumours, with mean (sd) values of 0.8 (0.3) (male AI) and 0.27 (0.1) mL/g/min (AD), (P < 0.001), and 0.61 (0.31) (female AI) and 0.27 (0.1) mL/g/min (AD) (P < 0.01), respectively. Tumour tissue perfusion was more homogenous in AI than in AD tumours, with a coefficient of variation of 0.91 (0.31) in male AI and 1.89 (0.48) in AD tumours (P < 0.001), and 1.47 (0.38) in female AI and 1.89 (0.48) in AD tumours (P < 0.05). CONCLUSIONS: AI Shionogi tumours have a higher TBF than AD tumours; this could have implications in the diagnosis, prognosis, therapy and monitoring of hormone-sensitive tumours.

Animals↗
PubMed2004

Helical chirality in donor-acceptor catenanes.

A [2]catenane in which the macrocyclic polyether, bisparaphenylene[34]crown-10, is interlocked with the tetracationic cyclophane, cyclobis(paraquat-p-phenylene), is shown by dynamic (1)H NMR spectroscopy, using (i). neutral and (ii). anionic chiral shift reagents (CSRs), to exist at low temperatures (197 K) in acetone-d(6) solutions as 1:1 and 2:1 mixtures of diastereoisomeric complexes and salts, respectively, as a consequence of the helical chirality associated with the [2]catenane interacting with the CSRs.

Journal Article↗
PubMed2004

Grouping of visual objects by honeybees.

Recent work has revealed that monkeys as well as pigeons are able to categorise complex visual objects. We show here that the ability to group similar, natural, visual images together extends to an invertebrate - the honeybee. Bees can be trained to distinguish between different types of naturally occurring scenes in a rather general way, and to group them into four distinct categories: landscapes, plant stems and two different kinds of flowers. They exhibit the same response to novel visual objects that differ greatly in their individual, low-level features, but belong to one of the four categories. We exclude the possibility that they might be using single, low-level features as a cue to categorise these natural visual images and suggest that the categorisation is based on a combination of low-level features and configurational cues.

Animals↗
PubMed2003

Types and epidemiology of tendinopathy.

During the last few decades, the role of sports and physical activity has become more and more important in all modern communities. The risk of tendon injury has thus increased, and prevention has become important. Epidemiologic studies are important when planning prevention programs for tendon injuries. Because of individual sport cultures and different sport habits in different countries, national epidemiologic studies are of importance in each individual country.

Achilles Tendon↗
PubMed2003

Rupture of the Achilles and patellar tendons.

Certain similarities can clearly be appreciated between Achilles and patellar tendon ruptures. Both are strong tendons that transmit force bridging at least one joint of the lower limb. When healthy, both require massive forces to be disrupted, and both can be weakened through certain systemic disease processes, steroids, and fluoroquinones. Both allow for a variety of innovative management possibilities that ultimately lend themselves to individual surgical preference. We feel that, although surgical management plays an important role in restoring continuity in knee extension and in plantar flexion, functional outcome inevitably relies on patient motivation and a well-established physiotherapy regime. Sports physicians should be able to identify both conditions early in their presentation, but still hold a high index of suspicion for these problems in athletes who have an acute exacerbation of ongoing tendinopathy.

Achilles Tendon↗
PubMedDate not supplied

Endodermal heterotopia of the atrioventricular node associated with transposition of the great arteries.

A 13-year-old girl with surgically corrected complete transposition of the great arteries died suddenly while walking to school. Postmortem examination revealed endodermal heterotopia of the atrioventricular node, a condition not previously associated with transposition of the great arteries. New immunohistochemical observations are described, and the embryogenesis of the condition and its association with complete transposition are discussed.

Adolescent↗
PubMedDate not supplied

Quantitative review of operative and nonoperative management of achilles tendon ruptures.

BACKGROUND: There is no consensus on the best method for management of acute Achilles tendon ruptures. Individual preferences, drawn from experience and study, determine whether treatment is operative or nonoperative. PURPOSE: Our goal was to review the literature to try to determine what management method was the most popular and effective. We wanted to ascertain the best results in terms of complication rates and patient outcomes. STUDY DESIGN: Retrospective review of retrospectively and prospectively collected data. METHODS: We analyzed 125 articles in peer-reviewed journals for year of publication, patient numbers, sex, management method, follow-up complications, and patient satisfaction. Each article was graded using a validated methods score. Methods, patient satisfaction, and complication rates were correlated with the year each article was published. RESULTS: Skin-healing complications were lowest in conservatively managed patients (3 of 578, 0.5%) and highest in open repair and immobilized patients (543 of 3718, 14.6%). General complication rates were lowest in open repair and early-mobilization groups (16 of 238, 6.7%) and highest in percutaneous and early-mobilization groups (19 of 122, 15.6%). Rerupture rates were highest in immobilized conservative management groups (62 of 578, 10.7%) and lowest in groups with external fixation (0%). CONCLUSIONS: In general, the number of publications reporting Achilles tendon ruptures is increasing, the quality of articles is increasing, and the trend for the number of reported complications is decreasing. The published articles had a low methods score (mean, 50.9; range, 25 to 77) and showed a trend toward earlier mobilization. Open repair and early mobilization give the best functional recovery and an acceptable complication rate.

Achilles Tendon↗
PubMedDate not supplied

Early weightbearing and ankle mobilization after open repair of acute midsubstance tears of the achilles tendon.

PURPOSE: To study the effects of early weightbearing and ankle mobilization after acute repair of ruptured Achilles tendon. STUDY DESIGN: Comparative longitudinal study. METHODS: Patients in group 1 were postoperatively immobilized with their ankle in gravity equinus, they were encouraged to bear weight on the operated limb as soon as possible to full weightbearing, and they received a single cast change at 2 weeks, with the ankle accommodated in an anterior splint in a plantigrade position, allowing the ankle to be plantar flexed fully but not dorsiflexed above neutral. Patients in group 2 were immobilized with their ankle in full equinus with a cast change at 2 weeks, when the ankle was immobilized in mid equinus, and at 4 weeks, when the ankle was immobilized in a plantigrade position, and they were advised to bear weight. RESULTS: Patients in group 1 attended fewer outpatient visits, completely discarded their crutches at an average of 2.5 weeks, and more were satisfied with the results of surgery. At ultrasonography, the average thickness of the repaired tendon was 12.1 mm, with no difference in the thickness of the ruptured tendon regardless of postoperative management. There was no significant difference in isometric strength between the two groups. CONCLUSIONS: Early weightbearing with the ankle plantigrade is not detrimental to the outcome of repair after acute rupture of the Achilles tendon and shortens the time needed for rehabilitation. However, strength deficit and muscle atrophy are not prevented.

Achilles Tendon↗