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Biomedical subjects

C Anderson

Publications and source records attributed to C Anderson.

At least 19 recordsLinked to original sources
PubMed2006

AFM imaging of protein movements: histone H2A-H2B release during nucleosome remodeling.

Being able to follow assembly/disassembly reactions of biomolecular complexes directly at the single molecule level would be very useful. Here, we use an AFM technique that can simultaneously obtain topographic images and identify the locations of a specific type of protein within those images to monitor the histone H2A component of nucleosomes acted on by human Swi-Snf, an ATP-dependent nucleosome remodeling complex. Activation of remodeling results in significant H2A release from nucleosomes, based on recognition imaging and nucleosome height changes, and changes in the recognition patterns of H2A associated directly with hSwi-Snf complexes.

Enzyme-Linked Immunosorbent Assay↗
PubMed2006

Interaction of HIV Tat and matrix metalloproteinase in HIV neuropathogenesis: a new host defense mechanism.

Tat, the HIV transactivating protein, and matrix metalloproteinases (MMPs), a family of extracellular matrix (ECM) endopeptidases, have been implicated in the pathogenesis of HIV-associated dementia. However, the possibility that MMPs interact with viral proteins has remained unexplored. We therefore treated mixed human fetal neuronal cultures with recombinant Tat and select MMPs. Neurotoxicity was determined by measuring mitochondrial membrane potential and neuronal cell death. Previous studies have shown that Tat and MMP independently cause neurotoxicity. Surprisingly, we found the combination of Tat and MMP produced significant attenuation of neurotoxicity. To determine whether there was a physical interaction between Tat and MMP, we used protein electrophoresis and Western blot techniques, and found that MMP-1 can degrade Tat. This effect was blocked by MMP inhibitors. Furthermore, MMP-1 decreased Tat-mediated transactivation of the HIV long terminal repeat region, and this functionality was restored when MMP-1 activity was inhibited. These results suggest that the decrease in Tat-induced neurotoxicity and HIV transactivation is due to Tat's enzymatic cleavage by MMP-1. The direct interaction of human MMPs with viral proteins has now been demonstrated, with resultant modulation of Tat-mediated neurotoxicity and transactivation. This study elucidates a unique viral-host interaction that may serve as an innate host defense mechanism.

Cells, Cultured↗
PubMed2006

Mice with skin-specific DNA repair gene (Ercc1) inactivation are hypersensitive to ultraviolet irradiation-induced skin cancer and show more rapid actinic progression.

Ercc1 has an essential role in the nucleotide excision repair (NER) pathway that protects against ultraviolet (UV)-induced DNA damage and is also involved in additional repair pathways. The premature death of simple Ercc1 mouse knockouts meant that we were unable to study the role of Ercc1 in the skin. To do this, we have used the Cre-lox system to generate a skin-specific Ercc1 knockout. With a Cre transgene under control of the bovine keratin 5 promoter we achieved 100% recombination of the Ercc1 gene in the epidermis. Hairless mice with Ercc1-deficient skin were hypersensitive to the short-term effects of UV irradiation, showing a very low minimal erythemal dose and a dramatic hyperproliferative response. Ultraviolet-irradiated mice with Ercc1-deficient skin developed epidermal skin tumours much more rapidly than controls. These tumours appeared to arise earlier in actinic progression and grew more rapidly than tumours on control mice. These responses are more pronounced than have been reported for other NER-deficient mice, demonstrating that Ercc1 has a key role in protecting against UV-induced skin cancer.

Animals↗
PubMed2006

Intracerebral microdialysis in neurosurgical intensive care patients utilising catheters with different molecular cut-off (20 and 100 kD).

OBJECTIVE: To compare the properties of a new intracerebral micro-dialysis catheter with a high cut-off membrane (molecular cut-off 100 kDalton) with a standard catheter (CMA70, molecular cut-off 20 kDalton). METHODS: Paired intracerebral microdialysis catheters were inserted in fifteen comatose patients treated in a neurosurgical intensive care unit following subarachnoid haemorrhage or traumatic brain injury. The high-cut-off catheter (D(100)) differed from the CMA 70 catheter by the length (20 mm) and cut-off properties of the catheter membranes (100 kDalton) and the perfusion fluids used (Ringer-Dextran 60). Samples were collected every 4-6 hours, analyzed bedside (for glucose, glutamate, glycerol, lactate, pyruvate and urea) and later in the laboratory (for total protein). RESULTS: Fluid recovery was similar for the two types of catheters, but significantly more protein was recovered by the D(100) catheter. The recovery of glycerol and pyruvate did not differ, while minor differences in recovery of glutamate and glucose were observed. The recovery of lactate was considerably lower in the D(100) catheter (p < 0.01), influencing the lactate/pyruvate-ratio. The patterns of concentration changes over time were consistent for all metabolites, and independent of type of catheter. CONCLUSION: Microdialysis catheters with high cut-off membranes can be used in routine clinical practice in the NSICU, adding the possibility of macro-molecule sampling from the extracellular space during monitoring.

Brain Chemistry↗
PubMed2006

A high sugar content, low caffeine drink does not alleviate sleepiness but may worsen it.

Although the ingestion of high levels of glucose might have a short acting alerting effect, there is evidence of an ensuing enhancement of sleepiness in people already sleepy. Some 'energy drinks' contain large quantity of sugars. We compared 250 ml of a well known 'energy drink' (42 g sugars, containing a low [30 mg] level of caffeine for 'flavouring') with a nil sugar nil caffeine, similar tasting control. These were given a week apart, in a repeated measures, double blind, balanced design, to 10 participants sleep restricted to 5 h the prior night. They had a light lunch, consumed a drink at 13:50 h, and 10 min later underwent 3 x 30 min consecutive periods at a reaction time (RT) task (the Psychomotor Vigilance Test), separated by 3 min breaks when self-ratings of sleepiness were made. The energy drink did not counteract sleepiness, and led to slower RTs and more lapses during the final 30 min session, around 80 min after consumption.

Adolescent↗
PubMed2005

Correlation between mouse potency and in vitro relative potency for human papillomavirus Type 16 virus-like particles and Gardasil vaccine samples.

An in vitro relative potency (IVRP) assay has been developed as an alternative to the mouse potency assay used to release Merck's human papillomavirus (HPV) vaccine, Gardasil, for early phase clinical trials. The mouse potency assay is a classical, in vivo assay, which requires 4-6 weeks to complete and exhibits variability on the order of 40% relative standard deviation (RSD). The IVRP assay is a sandwich-type immunoassay that is used to measure relative antigenicity of the vaccine product. The IVRP assay can be completed in three days, has a variability of approximately 10% RSD and does not require the sacrifice of live animals. Because antigen detection is achieved using H16.V5, a neutralizing monoclonal antibody, which binds to a clinically-relevant epitope, the relative antigenicity measured by the IVRP assay is believed to be a good predictor of in vivo potency. In this study, the relationship between immunogenicity, as measured by the mouse potency assay and antigenicity as measured by the IVRP assay, is demonstrated. Freshly manufactured and aged samples produced using two different manufacturing processes were tested using both methods. The results demonstrate that there is an inverse correlation between the IVRP and mouse potency assays. Additionally, clinical results indicate IVRP is predictive of human immunogenicity. Thus, antigenicity, as defined by the H16.V5 epitope, can be used as a surrogate for immunogenicity and the IVRP assay is suitable for use as the sole potency test for Gardasil samples.

Animal Testing Alternatives↗
PubMed2005

Community pharmacy supply of emergency hormonal contraception: a structured literature review of international evidence.

BACKGROUND: We could find no previous published review of the evidence relating to pharmacy supply of emergency hormonal contraception (EHC). Our objectives were to review, summarize and evaluate the peer-reviewed evidence relating to community pharmacy supply of EHC both in the UK and internationally. METHODS: Systematic searches were conducted for peer-reviewed international research from January 1990 to January 2005. The UK Health Development Agency's Evidence Base 2000 standards and the evidence categories used by the UK Department of Health were applied to each paper. RESULTS: We included 24 peer-reviewed papers. There was one randomized controlled trial (RCT); the remainder of the studies were qualitative or observational studies. Pharmacy supply of EHC enables most women to receive it within 24 h of unprotected sexual intercourse. Services were highly rated by women. One RCT showed that improving access to EHC did not reduce the use of other contraceptives, lead to an increase in risky sexual behaviour or increase the incidence of sexually transmitted infections (STIs). Users expressed some concerns about the appropriateness of receiving additional pharmacist advice regarding future contraception use and STIs. One study found pharmacy supply had led to a decrease in attendances at accident and emergency departments. CONCLUSION: There is good evidence that community pharmacy EHC services provide timely access to treatment and are highly rated by women.

Attitude of Health Personnel↗
PubMed2005

Sunscreen penetration of human skin and related keratinocyte toxicity after topical application.

Sunscreen skin penetration and safety assessment should be considered together in order to ensure that in vitro cytotoxicity studies examine relevant doses of these organic chemical UV filters to which viable epidermal cells are realistically exposed. In this study, we sought to determine whether sufficient topically applied sunscreens penetrated into human viable epidermis to put the local keratinocyte cell populations at risk of toxicity. The penetration and retention of five commonly used sunscreen agents (avobenzone, octinoxate, octocrylene, oxybenzone and padimate O) in human skin was evaluated after application in mineral oil to isolated human epidermal membranes. Sunscreen concentration-human keratinocyte culture response curves were then defined using changes in cell morphology and proliferation (DNA synthesis using radiolabelled thymidine uptake studies) as evidence of sunscreens causing toxicity. Following 24 h of human epidermal exposure to sunscreens, detectable amounts of all sunscreens were present in the stratum corneum and viable epidermis, with epidermal penetration most evident with oxybenzone. The concentrations of each sunscreen found in human viable epidermis after topical application, adjusting for skin partitioning and binding effects, were at least 5-fold lower, based on levels detected in viable epidermal cells, than those appearing to cause toxicity in cultured human keratinocytes. It is concluded that the human viable epidermal levels of sunscreens are too low to cause any significant toxicity to the underlying human keratinocytes.

Cells, Cultured↗
PubMed2005

Successful sons or superior daughters: sex-ratio variation in springbok.

Mothers would often benefit from producing more offspring of one sex than the other. Although some species show an astonishing ability to skew their sex ratio adaptively, the trends found in many studies on vertebrates have proved inconsistent. Furthermore, evidence for a mechanism by which such a bias is achieved is equivocal at best. Here, we examine sex-ratio variation over 30 years, both at an individual and a population level, in the highly polygynous, size-dimorphic springbok (Antidorcas marsupialis). Many previous studies of similar species have shown that mothers in superior condition preferentially produce sons, whereas those in poorer condition produce more daughters. We found the opposite to be true in springbok, perhaps because daughters provide mothers in superior condition with a more rapid and secure fitness return. This theory was supported by the findings that earlier-conceived offspring tended to be female and that an increased proportion of daughters were produced with increasing rainfall (which was likely to reduce nutritional stress). We also show that selective reabsorption of embryos is unlikely to be the main mechanism by which deviations from an equal sex ratio are achieved. Hence, either differential implantation occurs or females are able to influence the sex of the sperm fertilizing an egg.

Age Factors↗
PubMed2005

Rationale and design of the cardiac magnetic resonance imaging substudy of The ONTARGET Trial Programme.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve cardiovascular disease outcomes in high-risk patients, but evidence for the cardio-protective effects of angiotensin II receptor blockers (ARBs) is less extensive. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the parallel Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease (TRANSCEND)--which together form The ONTARGET Trial Programme--are long-term, large-scale, double-blind, multinational outcome studies with the primary objectives of determining if the combination of the ARB telmisartan 80 mg and the ACE inhibitor ramipril 10 mg is more effective than ramipril 10 mg alone, and if telmisartan is at least as effective as ramipril (in the case of ONTARGET), and if telmisartan is superior to placebo (in the case of TRANSCEND), in providing cardiovascular protection for high-risk patients. A pre-defined substudy is being conducted within The ONTARGET Trial Programme to compare the effects of these agents, alone and in combination, on cardiac structure and function. The substudy overcomes criticisms of many previous studies, which have been performed in small numbers of patients using suboptimal methodology, by evaluating changes in left ventricular structure and function using sophisticated technology provided by magnetic resonance imaging (MRI). Some 300 randomized patients within ONTARGET, recruited from selected centres in Australia, Canada, Germany, Hong Kong, New Zealand and Thailand, will have MRI undertaken at baseline and at 2-year follow-up. As this method of assessing left ventricular dysfunction is somewhat timeconsuming, expensive and complex, and in the light of current interest in the role of B-type natriuretic peptide (BNP) as a simple, inexpensive diagnostic and prognostic tool, the substudy will also examine whether changes in BNP during follow-up correlated with changes in left ventricular dysfunction.

Administration, Oral↗
PubMed2004

Policy implications associated with the socioeconomic and health system impact of telehealth: a case study from Canada.

This research was undertaken to inform future telehealth policy directions regarding the socioeconomic impact of telehealth. Fifty-seven sources were identified and analyzed through a comprehensive literature search of electronic databases, the Internet, journals, conference proceedings, as well as personal communication with consultants in the field. The review revealed a focus on certain socioeconomic indicators such as cost, access, and satisfaction. It also identified areas of opportunity for further research and policy analysis and development (e.g., social isolation, life stress, poverty), along with various barriers and challenges to the advancement of telehealth. These included confidentiality, reimbursement, and legal and ethical considerations. To become fully integrated into the health care system, telehealth must be viewed as more than an add-on service. This paper offers 19 general and 20 subject-specific telehealth recommendations, as well as seven policy strategies.

Alberta↗
PubMed2004

Assessment of pigmented skin lesions in terms of blood perfusion estimates.

BACKGROUND/AIMS: Cutaneous malignant melanoma is a disease of increasing clinical and economical importance. The prognosis is good with early diagnosis. The chief differential diagnosis is benign melanocytic naevus, a common lesion in Caucasians. Attempts have been made to use bioengineering techniques to aid in the initial diagnosis. The present study proposes a method of extracting possibly discriminative blood perfusion properties in pigmented skin lesions by combining information on the lesions' blood perfusion with optical or visual information of their spatial extent. METHODS: A total of 46 blood perfusion measurements were performed on 22 pigmented skin lesions, the ultimate diagnosis of which was three histologically proven malignant melanomas, four histologically proven benign naevi and fifteen naevi assessed by two specialist dermatologists as being benign. Laser Doppler perfusion imaging gave two different types of two-dimensional data sets (64x64 pixels), one representing the total backscattered light intensity at each measurement point (TLI image) and the second corresponding to perfusion values. The boundaries of each examined lesion were derived from the TLI image employing greyscale thresholding, thus resulting in an estimated region of interest (ROI) approximating the optical extent of the lesion. The ROI was superimposed on the perfusion image and extraction of perfusion features was then performed. RESULTS: The processing of the TLI images was successful in delineating the lesions' boundaries. The first hypothesis that the mean perfusion quotients in MM and benign naevi are equal could not be rejected at the chosen 5% level of significance. The second hypothesis that the mean percent-age of elevated perfusion values (image pixels) within the ROI shows no difference between MM and benign naevi could be rejected at a 5% level of significance. CONCLUSIONS: This study has presented a method of extracting blood perfusion parameters of pigmented skin lesions by combining blood perfusion information with information on the lesion's optical extent. The proposed method of presenting data could prove to be a useful discriminative adjunct in the assessment of pigmented skin lesions.

Adult↗
PubMed2003

Early embryonic death of glutamate carboxypeptidase II (NAALADase) homozygous mutants.

Glutamate carboxypeptidase II (EC 3.4.17.21) catalyzes the hydrolysis (Km = 0.2 microM) of the neuropeptide N-acetylaspartylglutamate to yield N-acetylaspartate and glutamate and also serves as a high-affinity folate hydrolase in the gut, cleaving the polyglutamate chain to permit the absorption of folate. N-acetylaspartylglutamate is an agonist at the mGluR3 metabotropic receptor and a source of extracellular glutamate through hydrolysis by glutamate carboxypeptidase II. Given the important role of glutamate in brain development and function, we were interested in the effects of a null mutation of glutamate carboxypeptidase II that would potentiate the effects of N-acetylaspartylglutamate. The PGK-Neomycin cassette was inserted to delete exons 9 and 10, which we previously demonstrated encode for the zinc ligand domain essential for enzyme activity. Successful germline transmission was obtained from chimeras derived from embryonic stem cells with the targeted mutation of glutamate carboxypeptidase II. Homozygous null mutants did not survive beyond embryonic day 8. Folate supplementation of the heterozygous mothers did not rescue the homozygous embryos. Mice heterozygous for the null mutation appeared grossly normal and expressed both mutated and wild-type mRNA but the activity of glutamate carboxypeptidase II is comparable to the wild-type mice. The results indicate that the expression of glutamate carboxypeptidase II is upregulated when one allele is inactivated and that its activity is essential for early embryogenesis.

Aging↗
PubMed2003

Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS Trial.

BACKGROUND AND PURPOSE: The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed that blood pressure lowering reduced stroke risk in patients with a history of cerebrovascular events. Here, we report the consistency of treatment effects across different stroke subtypes and among major clinical subgroups. METHODS: PROGRESS was a randomized, double-blind trial among 6105 people with a prior history of cerebrovascular events. Participants were assigned to active treatment (perindopril for all participants and indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo(s). RESULTS: During a mean of 3.9 years of follow-up, active treatment reduced the absolute rates of ischemic stroke from 10% to 8% (relative risk reduction [RRR], 24%; 95% confidence interval [CI], 10 to 35) and the absolute rates of intracerebral hemorrhage from 2% to 1% (RRR, 50%; 95% CI, 26 to 67). The relative risk of any stroke during follow-up was reduced by 26% (95% CI, 12 to 38) among patients whose baseline cerebrovascular event was an ischemic stroke and by 49% (95% CI, 18 to 68) among those whose baseline event was an intracerebral hemorrhage. There was no evidence that treatment effects were modified by other drug therapies (antiplatelet or other antihypertensive agents), residual neurological signs, atrial fibrillation, or the time since the last cerebrovascular event. CONCLUSIONS: Beneficial effects of a perindopril-based treatment regimen were observed for all stroke types and all major clinical subgroups studied. These data suggest that effective blood pressure-lowering therapy should be routinely considered for all patients with a history of cerebrovascular events.

Aged↗
PubMed2003

Effects of a perindopril-based blood pressure-lowering regimen on disability and dependency in 6105 patients with cerebrovascular disease: a randomized controlled trial.

BACKGROUND AND PURPOSE: We sought to quantify the effects of blood pressure lowering on long-term disability and dependency among patients with cerebrovascular disease. METHODS: We performed a randomized, double-blind, placebo-controlled trial. A total of 6105 participants with a history of stroke or transient ischemic attack in the past 5 years were recruited from 172 hospital outpatient clinics in 10 countries. Subjects were randomly assigned to the following groups: active treatment (angiotensin-converting enzyme inhibitor perindopril [4 mg/d] for all patients, with the diuretic indapamide added at the discretion of treating physicians) or matching placebo(s). Measurements were disability (defined as a Barthel Index score < or =99/100) and dependency (a positive response to the following question: "In the last 2 weeks has the patient required regular help with everyday activities?"). RESULTS: The median duration of follow-up was 4 years. At the last available assessment, 19% of the active treatment group and 22% of the placebo group were disabled (adjusted odds ratio, 0.76; 95% CI, 0.65 to 0.89; P<0.001). Twelve percent of the active treatment group and 14% of the placebo group were dependent (adjusted odds ratio, 0.84; 95% CI, 0.71 to 0.99; P=0.04). The effects of treatment appeared to be mediated primarily through the prevention of disability and dependency associated with recurrent stroke. Four-year treatment with the study drug regimen would be expected to result in the avoidance of 1 case of long-term disability for every 30 (95% CI, 19 to 79) patients. CONCLUSIONS: Among individuals with cerebrovascular disease, a perindopril-based blood pressure-lowering regimen not only reduced the risk of stroke and major vascular events but also substantially reduced the risks of associated long-term disability and dependency.

Activities of Daily Living↗