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Karen Smith

Publications and source records attributed to Karen Smith.

At least 19 recordsLinked to original sources
PubMed2006

Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota.

Vertebrates are essentially born germ-free but normally acquire a complex intestinal microbiota soon after birth. Most of these organisms are non-pathogenic to immunocompetent hosts; in fact, many are beneficial, supplying vitamins for host nutrition and filling the available microbiological niche to limit access and consequent pathology when pathogens are encountered. Thus, mammalian health depends on mutualism between host and flora. This is evident in inflammatory conditions such as inflammatory bowel disease, where aberrant responses to microbiota can result in host pathology. Studies with axenic (germ-free) or deliberately colonised animals have revealed that commensal organisms are required for the development of a fully functional immune system and affect many physiological processes within the host. Here, we describe the technical requirements for raising and maintaining axenic and gnotobiotic animals, and highlight the extreme diversity of changes within and beyond the immune system that occur when a germ-free animal is colonized with commensal bacteria.

Animals↗
PubMed2006

Cardiovascular risk estimation by professionally active cardiovascular nurses: results from the Basel 2005 Nurses Cohort.

BACKGROUND: Nurses play a key role in the prevention of cardiovascular disease (CVD) and one would, therefore, expect them to have a heightened awareness of the need for systematic screening and their own CVD risk profile. The aim of this study was to examine personal awareness of CVD risk among a cohort of cardiovascular nurses attending a European conference. METHODS: Of the 340 delegates attending the 5th annual Spring Meeting on Cardiovascular Nursing (Basel, Switzerland, 2005), 287 (83%) completed a self-report questionnaire to assess their own risk factors for CVD. Delegates were also asked to give an estimation of their absolute total risk of experiencing a fatal CVD event in the next 10 years. Level of agreement between self-reported CVD risk estimation and their actual risk according to the SCORE risk assessment system was compared by calculating weighted Kappa (kappa(w)). RESULTS: Overall, 109 responders (38%) self-reported having either pre-existing CVD (only 2%), one or more markedly raised CVD risk factors, a high total risk of fatal CVD (> or =5% in 10 years) or a strong family history of CVD. About half of this cohort (53%) did not know their own total cholesterol level. Less than half (45%) reported having a 10-year risk of fatal CVD of <1%, while 13% reported having a risk > or =5%. Based on the SCORE risk function, the estimated 10-year risk of a fatal CVD event was <1% for 96% of responders: only 2% had a > or =5% risk of such an event. Overall, less than half (46%) of this cohort's self-reported CVD risk corresponded with that calculated using the SCORE risk function (kappa(w)=0.27). CONCLUSION: Most cardiovascular nurses attending a European conference in 2005 poorly understood their own CVD risk profile, and the agreement between their self-reported 10-year risk of a fatal CVD and their CVD risk using SCORE was only fair. Given the specialist nature of this conference, our findings clearly demonstrate a need to improve overall nursing awareness of the role and importance of systematic CVD risk assessment.

Adult↗
PubMed2006

Out-of-hospital cardiac arrest in Victoria: rural and urban outcomes.

OBJECTIVE: To compare the survival rate from out-of-hospital cardiac arrest in rural and urban areas of Victoria, and to investigate the factors associated with these differences. DESIGN: Retrospective case series using data from the Victorian Ambulance Cardiac Arrest Registry. SETTING: All out-of-hospital cardiac arrests occurring in Victoria that were attended by Rural Ambulance Victoria or the Metropolitan Ambulance Service. PARTICIPANTS: 1790 people who suffered a bystander-witnessed cardiac arrest between January 2002 and December 2003. RESULTS: Bystander cardiopulmonary resuscitation was more likely in rural (65.7%) than urban areas (48.4%) (P = 0.001). Urban patients with bystander-witnessed cardiac arrest were more likely to arrive at an emergency department with a cardiac output (odds ratio [OR], 2.92; 95% CI, 1.65-5.17; P < 0.001), and to be discharged from hospital alive than rural patients (urban, 125/1685 [7.4%]; rural, 2/105 [1.9%]; OR, 4.13; 95% CI, 1.09-34.91). Major factors associated with survival to hospital admission were distance of cardiac arrest from the closest ambulance branch (OR, 0.87; 95% CI, 0.82-0.92), endotracheal intubation (OR, 3.46; 95% CI, 2.49-4.80), and the presence of asystole (OR, 0.50; 95% CI, 0.38-0.67) or pulseless electrical activity (OR, 0.73; 95% CI, 0.56-0.95) on arrival of the first ambulance crew. CONCLUSIONS: Survival rates differ between urban and rural cardiac arrest patients. This is largely due to a difference in ambulance response time. As it is impractical to substantially decrease response times in rural areas, other strategies that may improve outcome after cardiac arrest require investigation.

Aged↗
PubMed2006

Mesenteric lymph nodes at the center of immune anatomy.

The surface of the intestinal mucosa is constantly assaulted by food antigens and enormous numbers of commensal microbes and their products, which are sampled by dendritic cells (DCs). Recent work shows that the mesenteric lymph nodes (MLNs) are the key site for tolerance induction to food proteins and that they also act as a firewall to prevent live commensal intestinal bacteria from penetrating the systemic immune system.

Administration, Oral↗
PubMed2006

Pharmacological treatment and perceived health status during 1-year follow up in patients diagnosed with coronary artery disease, but ineligible for revascularization. Results from the Euro Heart Survey on Coronary Revascularization.

BACKGROUND: It has been recognized that a clinically significant portion of patients with coronary artery disease (CAD) continue to experience anginal and other related symptoms that are refractory to the combination of medical therapy and revascularization. The Euro Heart Survey on Revascularization (EHSCR) provided an opportunity to assess pharmacological treatment and outcome in patients with proven CAD who were ineligible for revascularization. METHODS: We performed a secondary analysis of EHS-CR data. After excluding patients with ST-elevation myocardial infarction and those in whom revascularization was not indicated, 4409 patients remained in the analyses. We selected two groups: (1) patients in whom revascularization was the preferred treatment option (n = 3777, 86%), and (2) patients who were considered ineligible for revascularization (n = 632, 14%). RESULTS: Patient ineligible for revascularization had a worse risk profile, more often had a total occlusion (59% vs. 37%, p < 0.001), were treated more often with ACE-inhibitors (65% vs. 55%, p < 0.001) but less likely with aspirin (83% vs. 88%, p < 0.001). Overall, they had higher case-fatality at 1-year (7.0% vs. 3.7%, p < 0.001). Regarding self-perceived health status, measured via the EuroQol 5D (EQ-5D) questionnaire, these same patients reported more problems on all dimensions of the EQ-5D. Furthermore, in the revascularization group we observed an increase between discharge and 1-year follow up (utility score from 0.85 to 1.00) whereas patients ineligible for revascularization did not improve over time (utility score remained 0.80) CONCLUSION: In this large cohort of European patients with CAD, those considered ineligible for revascularization had more co-morbidities and risk factors, and scored worse on self-perceived health status as compared to revascularized patients in the revascularization group. With the exception of ACE-inhibitors and aspirin, there were no major differences regarding drug treatment between the two groups. Given these clinically significant observations, there appears to be a role for nurse-led, multidisciplinary, rehabilitation teams that target clinically vulnerable patients whose symptoms remain refractory to standard medical care.

Activities of Daily Living↗
PubMed2006

Obesity distribution and reproductive hormone levels in women: a report from the NHLBI-sponsored WISE Study.

PURPOSE: Relationships between body weight and disease are not straightforward. Central obesity appears to be a relatively greater cardiovascular risk factor than generalized obesity. The purpose of this study was to evaluate body mass index (BMI) and waist circumference and the association of obesity distribution with blood estrogen levels (estradiol, bioavailable estradiol, and estrone). METHODS: The study cohort consisted of 207 postmenopausal women enrolled in the Women's Ischemia Syndrome Evaluation (WISE) undergoing angiography for evaluation of suspected ischemia. RESULTS: Both BMI and waist circumference were positively associated with all three blood estrogen levels (p < 0.01), with the highest estrogen levels found in the obese women with large waists (p < 0.01). Results from regression analyses confirmed significant associations of BMI and waist circumference with the estrogen levels. CONCLUSIONS: These results demonstrate differing relationships between blood estrogen levels and obesity distribution in a cohort of postmenopausal women with chest pain undergoing coronary angiography. The differing levels by general and central obesity may help explain in part observed epidemiological relationships between obesity and disease.

Adult↗
PubMed2006

Synthesis and in vitro investigation of cationic 5,15-diphenyl porphyrin-monoclonal antibody conjugates as targeted photodynamic sensitisers.

The synthesis of three cationic 5,15-diphenyl porphyrins, bearing an isothiocyanate group for conjugation to proteins is described. The potential of these compounds as targeted photosensitisers for use in photodynamic therapy (PDT) is demonstrated by their efficient conjugation to monoclonal antibodies and the ability of the bioconjugates to bind and photodynamically inactivate cancer cells that express the corresponding antigen.

Animals↗
PubMed2005

Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington's disease transgenic mice.

Genetic murine models play an important role in the study of human neurological disorders by providing accurate and experimentally accessible systems to study pathogenesis and to test potential therapeutic treatments. One of the most widely employed models of Huntington's disease (HD) is the R6/2 transgenic mouse. To characterize this model further, we have performed behavioral and neuropathological analyses that provide a foundation for the use of R6/2 mice in preclinical therapeutic trials. Behavioral analyses of the R6/2 mouse reveal age-related impairments in dystonic movements, motor performance, grip strength, and body weight that progressively worsen until death. Significant neuropathological sequela, identified as increasing marked reductions in brain weight, are present from 30 days, whereas decreased brain volume is present from 60 days and decreased neostriatal volume and striatal neuron area, with a concomitant reduction in striatal neuron number, are present at 90 days of age. Huntingtin-positive aggregates are present at postnatal day 1 and increase in number and size with age. Our findings suggest that the R6/2 HD model exhibits a progressive HD-like behavioral and neuropathological phenotype that more closely corresponds to human HD than previously believed, providing further assurance that the R6/2 mouse is an appropriate model for testing potential therapies for HD.

Animals↗
PubMed2005

Near IR emitting isothiocyanato-substituted fluorophores: their synthesis and bioconjugation to monoclonal antibodies.

Two near IR emitting fluorophores, based on the phthalocyanine and naphthalocyanine chromophores, which also bear a single isothiocyanato group suitable for conjugation to proteins are reported; their utility as luminescent probes is demonstrated by conjugation to monoclonal antibodies and the ability of these conjugates to selectively bind cells bearing the relevant antigen.

Antibodies, Monoclonal↗
PubMed2005

Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis.

We demonstrate that the histone deacetylase (HDAC) inhibitor drug trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and ameliorates disability in the relapsing phase of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). TSA up-regulates antioxidant, anti-excitotoxicity and pro-neuronal growth and differentiation mRNAs. TSA also inhibits caspase activation and down-regulates gene targets of the pro-apoptotic E2F transcription factor pathway. In splenocytes, TSA reduces chemotactic, pro-Th1 and pro-proliferative mRNAs. A transcriptional imbalance in MS may contribute to immune dysregulation and neurodegeneration, and we identify HDAC inhibition as a transcriptional intervention to ameliorate this imbalance.

Animals↗
PubMed2005

Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice.

Multiple molecular defects trigger cell death in amyotrophic lateral sclerosis (ALS). Among these, altered transcriptional activity may perturb many cellular functions, leading to a cascade of secondary pathological effects. We showed that pharmacological treatment, using the histone deacetylase inhibitor sodium phenylbutyrate, significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice. Phenylbutyrate administration ameliorated histone hypoacetylation observed in G93A mice and induced expression of nuclear factor-kappaB (NF-kappaB) p50, the phosphorylated inhibitory subunit of NF-kappaB (pIkappaB) and beta cell lymphoma 2 (bcl-2), but reduced cytochrome c and caspase expression. Curcumin, an NF-kappaB inhibitor, and mutation of the NF-kappaB responsive element in the bcl-2 promoter, blocked butyrate-induced bcl-2 promoter activity. We provide evidence that the pharmacological induction of NF-kappaB-dependent transcription and bcl-2 gene expression is neuroprotective in ALS mice by inhibiting programmed cell death. Phenylbutyrate acts to phosphorylate IkappaB, translocating NF-kappaB p50 to the nucleus, or to directly acetylate NF-kappaB p50. NF-kappaB p50 transactivates bcl-2 gene expression. Up-regulated bcl-2 blocks cytochrome c release and subsequent caspase activation, slowing motor neuron death. These transcriptional and post-translational pathways ultimately promote motor neuron survival and ameliorate disease progression in ALS mice. Phenylbutyrate may therefore provide a novel therapeutic approach for the treatment of patients with ALS.

Acetylation↗
PubMed2005

Use of ecotoxicological tools to evaluate the health of New Bedford Harbor sediments: a microbial biomarker approach.

We have been investigating microbial communities in sediments from New Bedford Harbor (NBH), Massachusetts, USA, for a number of years. NBH is a U.S. Environmental Protection Agency-designated Superfund site heavily contaminated with polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and heavy metals. Microorganisms are thought to contribute to the fate and distribution of contaminants in NBH through a variety of mechanisms, including direct transformations and formation of soluble and insoluble species. Our more recent research has focused on changes in microbial community structure and function in response to exposure to toxic contaminants, with the ultimate goal of using microbes as ecotoxicological tools. Microbial diversity, as measured by restriction fragment-length polymorphism analysis, changes along pollution gradients, with an apparent increase in diversity at the most contaminated sites, concomitant with an increase in genetic relatedness. Current work on microbial communities examines the presence of arsenic-resistance genes in NBH isolates. In collaboration with the Plymouth Environmental Research Center, Plymouth University, United Kingdom, we have also used more conventional ecotoxicological approaches to examine the health of the NBH biota.

Animals↗
PubMed2005

Ethnic disparities in adjuvant chemotherapy for breast cancer are not caused by excess toxicity in black patients.

BACKGROUND: Black patients with breast cancer may be at greater risk for chemotherapy-related hematologic toxicity than white patients because of lower baseline blood cell counts. We hypothesize that these baseline differences could lead to excess hematologic toxicity and greater modification of chemotherapy dosing in black patients and that this may contribute to the poorer survival observed in black patients with breast cancer compared with white patients with breast cancer. PATIENTS AND METHODS: We performed a retrospective cohort study of black and white patients with breast cancer treated with adjuvant chemotherapy at an academic medical center over an 18-month period. Clinical chart review and pharmacy records were used to collect data on the following: modification of chemotherapy dose or administration; hematologic toxicity; blood cell counts before, during, and after therapy; occurrence of febrile neutropenia; use of prophylactic antibiotics; and use of granulocyte colony-stimulating factor in order to determine whether ethnicity was an independent predictor of these outcomes. RESULTS: Among 23 black patients and 98 white patients with breast cancer treated with adjuvant chemotherapy, modification of chemotherapy administration occurred in 56 patients (46%). Modification was more common among black patients (65.2% vs. 41.8%; relative risk [RR], 1.56; P = 0.04). Black patients were more likely to receive reduced cumulative doses of adjuvant chemotherapy (RR, 2.49; P = 0.03). CONCLUSION: Our findings suggest that hematologic tolerability of adjuvant chemotherapy is similar in black and white patients. Strategies aimed at improving psychosocial barriers to adjuvant therapy and at reducing surgical complications in black patients may improve overall breast cancer outcomes in this group.

Black or African American↗
PubMed2004

Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington's disease.

Huntington's disease (HD) is a fully penetrant autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in the Huntingtin gene. Transcriptional dysfunction, excitotoxicity, and oxidative stress have all been proposed to play important roles in the pathogenesis of HD. This study was designed to explore the therapeutic potential of mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic. Pharmacological treatment of a transgenic mouse model of HD (R6/2) with mithramycin extended survival by 29.1%, greater than any single agent reported to date. Increased survival was accompanied by improved motor performance and markedly delayed neuropathological sequelae. To identify the functional mechanism for the salubrious effects of mithramycin, we examined transcriptional dysfunction in R6/2 mice. Consistent with transcriptional repression playing a role in the pathogenesis of HD, we found increased methylation of lysine 9 in histone H3, a well established mechanism of gene silencing. Mithramycin treatment prevented the increase in H3 methylation observed in R6/2 mice, suggesting that the enhanced survival and neuroprotection might be attributable to the alleviation of repressed gene expression vital to neuronal function and survival. Because it is Food and Drug Administration-approved, mithramycin is a promising drug for the treatment of HD.

Animals↗
PubMed2004

A population-based evaluation of the thrombolysis in myocardial infarction risk score for unstable angina and non-ST elevation myocardial infarction.

BACKGROUND: The Thrombolysis in Myocardial Infarction risk score (TIMI-RS) for unstable angina/non-ST elevation myocardial infarction (MI) was developed in patients presenting with unstable angina accompanied by high-risk features or non-ST elevation MI to determine early risk stratification. HYPOTHESIS: The validity in patients presenting for emergency care with symptoms suggestive of acute coronary syndrome (ACS) has not been well established, and the present study sought to do so by evaluating the TIMI-RS in a prospective fashion. METHODS: A prospective TIMI-RS using seven variables was calculated in 245 patients admitted to the hospital with symptoms suggestive of ACS: (1) age > 65, (2) three or more cardiac risk factors, (3) ST deviation, (4) aspirin use within 7 days, (5) two or more anginal events over 24 h, (6) history of coronary stenosis, and (7) elevated troponin. Patients were contacted at 30 days and data were collected concerning major adverse cardiac events. RESULTS: In patients presenting with chest pain, a higher TIMI-RS was associated with an increase in major adverse cardiac events within 30 days. We found that the 30-day event rate was 0% for a score of 1, 20% for a score of 2, 24% for a score of 3, 42% for a score of 4, 52% for a score of 5, and 70% for a score of 6 or 7 (p < 0.0001). CONCLUSIONS: The TIMI-RS successfully differentiates early risk for major adverse cardiac events in a general population presenting with symptoms suggestive of acute coronary syndrome. A simple bedside calculation of the TIMI-RS provides rapid risk stratification, allowing facilitation of therapeutic decision making in patients with symptoms suggestive of ACS.

Aged↗
PubMed2004

Validation of the accuracy of pretest and exercise test scores in women with a low prevalence of coronary disease: the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) study.

BACKGROUND: Recently revised American College of Cardiology/American Heart Association guidelines have suggested that exercise test scores be used in decisions concerning patients with suspected coronary artery disease (CAD). Pretest and exercise test scores derived for use in women without known CAD have not been tested in women with a low prevalence of CAD. METHODS: Within the Women's Ischemia Syndrome Evaluation (WISE) study, we evaluated 563 women undergoing coronary angiography for suspected myocardial ischemia. The prevalence of angiographic CAD was 26%. Overall, 189 women underwent treadmill exercise testing. Prognostic end points included death, myocardial infarction, stroke, and revascularization. RESULTS: Each score stratified women into 3 probability groups (P <.001) according to the prevalence of coronary disease: Pretest: low 20/164 (12%), intermediate 53/245 (22%), high 75/154 (49%); Exercise test: low 11/83 (13%), intermediate 22/74 (30%), high 17/32 (53%). However, the Duke score did not stratify as well: low 7/46 (15%), intermediate 36/126 (29%), high 6/17 (35%); P =.44. When pretest and exercise scores were considered together, the best stratification with the exercise test score was in the intermediate pretest group (P <.03). The Duke score did not stratify this group at all (P =.98). Pretest and exercise test scores also stratified women according to prognostic end points: pretest--low 7/164 (4.3%), intermediate 28/245 (11.4%), high 27/154 (17.5%), P <.01; exercise test--low 4/83 (4.8%) and intermediate-high 17/106 (16%), P =.014. CONCLUSION: Both pretest and exercise test scores performed better than the Duke score in stratifying women with a low prevalence of angiographic CAD. The exercise test score appears useful in women with an intermediate pretest score, consistent with American College of Cardiology/American Heart Association guidelines.

Coronary Angiography↗