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David Williams

Publications and source records attributed to David Williams.

At least 19 recordsLinked to original sources
PubMed2025

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

Setdb2↗
PubMed2006

Effect of the UK incentive-based contract on the management of patients with stroke in primary care.

BACKGROUND AND PURPOSE: We wished to ascertain whether a new contract based on financial incentives for general practitioners has been associated with improved recording of quality indicators for patients with stroke and whether there was evidence of any difference in change between sex, age, and deprivation groups. METHODS: In a serial cross-sectional study, patients from 310 general practices with a computer record of transient ischemic attack or stroke in Scotland were analyzed for their recording of quality indicators before and after the introduction of a new quality-based contract on March 31, 2004. Multivariate analyses were used to explore any differences in recording between age, sex, and deprivation groups. RESULTS: Documentation of quality indicators increased over time, with absolute increases for individual indicators ranging from 32.3% to 52.1%. There was a large increase in the documentation of quality indicators among the oldest patients (>75 years) and the most affluent patients. This tended to attenuate age groups differences and to exacerbate differences between deprivation groups. Women tended to have larger increases in documentation than men; however, sex differences persisted, with women less likely than men to have smoking habits recorded (adjusted odds ratio, 0.87; 95% confidence interval, 0.81 to 0.95) or to receive antiplatelet or anticoagulant therapy (adjusted odds ratio, 0.93; 95% confidence interval, 0.86 to 0.99). CONCLUSIONS: The recording and management of quality indicators among patients with stroke increased substantially. However, inequitable care exists, which may have important implications for female, older, and more deprived subgroups in terms of stroke recurrence and mortality.

Age Distribution↗
PubMed2006

The good, the bad and the ugly: Australian snake taxonomists and a history of the taxonomy of Australia's venomous snakes.

The Australian snake fauna is unique in harbouring more venomous species than non-venomous ones. Although taxonomic research on the elapid snakes of Australia goes back to the late 18th century, in stark contrast to other developed regions of the world (e.g. the continental USA), Australian snake taxonomy is very much in its infancy. Despite this, or perhaps because of this, the taxonomy of Australian snakes has been extraordinarily controversial, and many of the taxonomists involved correspondingly colourful. In this review, we explore the sometimes-tortured history of the taxonomic exploration of the venomous snake fauna of Australia, looking at some of the more colourful and notable contributors and highlighting systematic pitfalls that persist even today.

Animals↗
PubMed2006

Physical and functional interaction between protocadherin 15 and myosin VIIa in mechanosensory hair cells.

Hair cells of the mammalian inner ear are the mechanoreceptors that convert sound-induced vibrations into electrical signals. The molecular mechanisms that regulate the development and function of the mechanically sensitive organelle of hair cells, the hair bundle, are poorly defined. We link here two gene products that have been associated with deafness and hair bundle defects, protocadherin 15 (PCDH15) and myosin VIIa (MYO7A), into a common pathway. We show that PCDH15 binds to MYO7A and that both proteins are expressed in an overlapping pattern in hair bundles. PCDH15 localization is perturbed in MYO7A-deficient mice, whereas MYO7A localization is perturbed in PCDH15-deficient mice. Like MYO7A, PCDH15 is critical for the development of hair bundles in cochlear and vestibular hair cells, controlling hair bundle morphogenesis and polarity. Cochlear and vestibular hair cells from PCDH15-deficient mice also show defects in mechanotransduction. Together, our findings suggest that PCDH15 and MYO7A cooperate to regulate the development and function of the mechanically sensitive hair bundle.

Animals↗
PubMed2006

Significant clinical impact and prognostic stratification provided by FDG-PET in the staging of oesophageal cancer.

PURPOSE: To evaluate the clinical impact of FDG-PET in staging oesophageal cancer and whether this information improves prognostic stratification. METHODS: Impact was based on comparison of a prospectively recorded pre-PET plan with post-PET treatment in 68 consecutive patients undergoing primary staging. Survival was analysed using the Kaplan-Meier product limit method and the Cox proportional hazards regression model. RESULTS: FDG-PET findings impacted on the management of 27/68 patients (40%): in 12 therapy was changed from curative to palliative and in three from palliative to curative, while in 12 other patients there was a change in the treatment modality or delivery but not in the treatment intent. The median survival was 21 months, with post-PET stage and treatment intent both strongly associated with survival (p<0.001). Conventional stage was not able to clearly stratify this population. CONCLUSION: The use of FDG-PET for primary staging of oesophageal cancer changed the clinical management of more than one-third of patients and provided superior prognostic stratification compared with conventional investigations.

Adult↗
PubMed2006

Genetic engineering of taxol biosynthetic genes in Saccharomyces cerevisiae.

Baccatin III, an intermediate of Taxol biosynthesis and a useful precursor for semisynthesis of the anti-cancer drug, is produced in yew (Taxus) species by a sequence of 15 enzymatic steps from primary metabolism. Ten genes encoding enzymes of this extended pathway have been described, thereby permitting a preliminary attempt to reconstruct early steps of taxane diterpenoid (taxoid) metabolism in Saccharomyces cerevisiae as a microbial production host. Eight of these taxoid biosynthetic genes were functionally expressed in yeast from episomal vectors containing one or more gene cassettes incorporating various epitope tags to permit protein surveillance and differentiation of those pathway enzymes of similar size. All eight recombinant proteins were readily detected by immunoblotting using specific monoclonal antibodies and each expressed protein was determined to be functional by in vitro enzyme assay, although activity levels differed considerably between enzyme types. Using three plasmids carrying different promoters and selection markers, genes encoding five sequential pathway steps leading from primary isoprenoid metabolism to the intermediate taxadien-5alpha- acetoxy-10beta-ol were installed in a single yeast host. Metabolite analysis showed that yeast isoprenoid precursors could be utilized in the reconstituted pathway because products accumulated from the first two engineered pathway steps (leading to the committed intermediate taxadiene); however, a pathway restriction was encountered at the first cytochrome P450 hydroxylation step. The means of overcoming this limitation are described in the context of further development of this novel approach for production of Taxol precursors and related taxoids in yeast.

Alkaloids↗
PubMed2006

Calcineurin nephrotoxicity.

Calcineurin inhibitors, cyclosporine and tacrolimus, have improved allograft survival in solid organ transplantation. Indeed, they have reduced the incidence of acute rejection episodes of cadaveric allograft recipients. Although marked progression has been made in initial survival rates, long-term kidney graft survival has yet to show such encouraging results. Chronic allograft dysfunction is the major hindrance to long-term graft survival and many components contribute to this entity, both immunologic and nonimmunologic. Chronic calcineurin nephrotoxicity is a major factor in chronic allograft dysfunction. This review will highlight the current understanding and management of calcineurin nephrotoxicity in kidney transplantation.

Animals↗
PubMed2006

Results of a multicenter trial for the treatment of traumatic vascular injury with a covered stent.

BACKGROUND: The safety and efficacy of endovascular treatment of arterial trauma using the Wallgraft Endoprosthesis was evaluated in a subgroup analysis of a prospective, multicenter, nonrandomized registry trial with a historical control to surgical management. Endpoints were exclusion success at procedure and at 12-months, primary patency and freedom-from-bypass at 12-months, and major adverse events. METHODS: Sixty-two patients were treated for arterial trauma from October 1997 to June 2003. The anatomic locations of the injuries were: iliac (33), subclavian (18), and femoral (11) arteries. Indication for treatment was perforation/rupture (33), acute pseudoaneurysm (10), AV fistula (16), and dissection (3). Exclusion and patency were assessed using arteriography, duplex ultrasound, CT, or MRA at postprocedure and 12-months. Major adverse event and mortality rates were compared with surgical intervention of arterial trauma using literature based objective performance criteria. RESULTS: The Wallgraft Endoprosthesis achieved postprocedure exclusion in 58 of 62 cases (93.5%). One-year exclusion rates were 91.3% iliac, 90.0% subclavian, and 62.3% femoral. One-year primary patency rates were 76.4% iliac, 85.7% subclavian, and 85.7% femoral. Freedom-from-bypass was achieved in 74.3% iliac and 100% femoral and subclavian injuries. The most common adverse events were stenosis (4.8%) and occlusion (6.5% early, 1.6% late). There were no device- or procedure-related deaths. Analysis of the literature revealed the rates and severity of complications are less than those associated with surgical repair. CONCLUSION: The Wallgraft Endoprosthesis for the treatment of traumatic arterial injuries offers a promising alternative to conventional operative repair with comparable patency and less major morbidity and mortality.

Angioplasty↗
PubMed2006

3.0-T MRI of meniscal tears.

OBJECTIVE: The sensitivity and specificity of 3.0-T MRI of the knee for meniscal tears have not been specifically assessed. We undertook a retrospective review of 100 consecutive MR examinations of the knee followed by arthroscopy to evaluate the sensitivity and specificity of 3.0-T MRI compared with arthroscopy in the detection of meniscal tears. MATERIALS AND METHODS: Two experienced musculoskeletal radiologists retrospectively reviewed MR scans of the knees of 100 patients who underwent consecutive knee arthroscopic procedures after MRI examinations. Interpretations were performed by consensus review with the reviewers blinded to arthroscopic results at the time of consensus review. All patients underwent complete MRI of the knee on a 3.0-T unit. All patients underwent fast spin-echo proton density sagittal imaging at 2-mm slice thickness. Fat-saturated fast spin-echo T2 axial, coronal, and sagittal imaging and T1 coronal imaging also were performed. All 100 patients underwent arthroscopy, and the results were compared with MR interpretations. RESULTS: Consensus retrospective review of the 100 knee MR examinations revealed 111 meniscal tears. Four meniscal tears seen on arthroscopy were not seen on MR examination. There were three false-positive MR interpretations of meniscal tear compared with arthroscopy. In this study, the sensitivity of MRI in the detection of meniscal tears was 96%, and the specificity was 97%. CONCLUSION: MRI of the knee at 3.0 T is sensitive and specific compared with arthroscopy in the detection of meniscal tears. Findings at 3.0 T compare favorably with results at 1.5-T or lower field strength.

Adolescent↗
PubMed2006

3.0-T MRI of the supraspinatus tendon.

OBJECTIVE: MRI of the shoulder has been found to be highly sensitive and specific for detection of full-thickness supraspinatus tendon tears at 1.5-T or lower field strength compared with arthroscopy. MRI of the shoulder at 3.0 T has not been specifically assessed. This study assesses the sensitivity and specificity of MRI at 3.0 T for supraspinatus tendon tears compared with arthroscopy. MATERIALS AND METHODS: Two experienced musculoskeletal radiologists retrospectively reviewed MR images of the shoulder in 150 consecutive patients who had subsequent arthroscopy. All patients had oblique coronal and sagittal T1-weighted and fat-saturated T2-weighted axial, oblique coronal, and sagittal imaging performed. The radiologists interpreted the MR images by consensus without knowledge of the arthroscopy results. Scans were interpreted for full-thickness or partial-thickness supraspinatus tendon tears. If partial-thickness supraspinatus tendon tears were seen on MRI, the reviewers noted whether the partial-thickness tear was articular or bursal in location. The radiologists also separated the supraspinatus tendon tears into small (< 1 cm retraction from the humeral head) and large (> 1 cm retraction from the humeral head). All 150 patients went on to arthroscopy. After consensus review of the MR images, arthroscopy results were compared with consensus MR interpretations. RESULTS: Ninety-eight of the 150 patients had full-thickness supraspinatus tendon tears at arthroscopy. Twenty-six of the 150 patients had partial-thickness supraspinatus tendon tears. Seventeen of these 26 partial-thickness tears were along the articular surface and nine were along the bursal surface. Ninety-six of 98 full-thickness tears seen at arthroscopy were seen on consensus MRI interpretation. All 26 partial-thickness tears seen at arthroscopy were seen at consensus MR interpretation; however, two of the partial-thickness articular surface tears seen at arthroscopy were interpreted as full-thickness tears on consensus MRI interpretation. Twenty-eight of the 98 full-thickness supraspinatus tendon tears were small tears (< 1 cm retraction from the humeral head) on arthroscopy. Two of these 28 small tears seen on arthroscopy were not seen on consensus MRI interpretation. Twenty-six patients had intact supraspinatus tendons on both retrospective consensus MRI interpretation and at arthroscopy. CONCLUSION: MRI of the shoulder at 3.0 T is highly sensitive and specific compared with arthroscopy in the detection of full-thickness and partial-thickness supraspinatus tendon tears.

Adolescent↗
PubMed2006

Tisseel to reduce postparotidectomy wound drainage: randomized, prospective, controlled trial.

BACKGROUND: Tisseel (Baxter Corp. Ontario, Canada) is a fibrin-based tissue glue that has been widely used to reduce wound drainage, achieve hemostasis, and decrease surgical complications. To date, Tisseel has not been evaluated in a randomized prospective trial for use in parotid surgery. OBJECTIVES: To determine whether the use of Tisseel in parotidectomy decreases postoperative wound drainage, the duration of percutaneous drainage, the length of hospital stay, and the frequency of complications. METHODS: Sixty consecutive parotidectomy patients were randomized into two groups: a group treated with 2 cc of Tisseel prior to wound closure and a control group. Postoperative wound drainage was measured for all patients by blinded hospital staff. The duration of percutaneous drainage, duration of hospital stay, and incidence of complications at the 3-week follow-up were assessed. RESULTS: A statistically significant difference in total drainage volume (p < .02) and frequency of postoperative seroma (p < .05) was demonstrated between patients treated with Tisseel prior to wound closure and the control group. CONCLUSION: The use of Tisseel in parotidectomy patients prior to wound closure significantly decreases total drainage volume and the frequency of postoperative seroma.

Adult↗
PubMed2006

New interests in magnesium.

After decades of developing strategies to minimise the corrosion of metallic biomaterials, there is now increasing interest in using an intentionally corrodible alloy in a number of critical medical device applications. This article examines the rationale for using magnesium alloys in cardiovascular and orthopaedic devices.

Absorbable Implants↗
PubMed2006

Quantum dots in medical technology.

During the past few years, the rapidly emerging technology of quantum dots has started to have an impact on the techniques of molecular and cellular imaging in medicine. Their advantages are examined here.

Diagnostic Imaging↗
PubMed2006

A registry for tissue engineering clinical trials.

Because tissue engineering products and processes are now being transferred from laboratory research into clinical applications, questions are being raised about what is the scope of an optimal clinical trial in this sector. A registry for these clinical trials is currently being established.

Clinical Trials as Topic↗