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Biomedical subjects

K Norris

Publications and source records attributed to K Norris.

At least 19 recordsLinked to original sources
PubMed2006

Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report.

As of January 2005, there were 1020 gene therapy clinical trials ongoing worldwide with 675 or 66.2% devoted to cancer gene therapy. The majority are occurring in the US and Europe (http://www.wiley.co.uk/genetherapy/clinical/). At the present time, to our knowledge there are no trials that employ gene delivery of Fas Ligand (FasL). As an important note, and in contrast to somatic cell therapy trials, there are no reported deaths due to therapeutic vector administration in any cancer gene therapy trial. That said, from our studies and from the published literature, the issue of gene delivery remains the major obstacle to successfully employing gene therapy for cancer treatment. Numerous laboratories are studying this with many different approaches. My co-workers and I have focused on the delivery issue by using various approaches that address tumor targeting and transgene expression. In addition, we are focusing on enhancing tumor cell killing via the bystander effect and through use of small molecules to enhance bystander activity.

Adenoviridae↗
PubMed2003

Phenotypic switching of VEGF and collagen XVIII during hypoxia in head and neck squamous carcinoma cells.

The present study sought to determine the potential role of stress activated MAPK and phosphatidylinositol 3-kinase (PI3K) signaling pathways in mediating phenotypic switching between angiogenic and angiostatic elements among squamous cell carcinoma (SCC) cell lines. In particular, we investigated the effects of hypoxia and those of cobalt chloride (CoCl(2)), which mimics the hypoxic response including the production of reactive oxygen species, on such phenotypic shifts. The expression and production of collagen XVIII, and CBP2/Hsp47 provided a measure of an angiostatic phenotype, while vascular endothelial growth factor (VEGF) expression was used to assess potential angiogenic states. These studies revealed that hypoxia produced a slight up-regulation of collagen XVIII and CBP2/Hsp47 that was inhibited by the stress kinase inhibitor SB203580 but was unaffected by N-acetylcysteine (NAC). In addition, VEGF expression was increased following hypoxia and this effect was reversed with inhibition of by SB203580. Conversely, CoCl(2) significantly diminished the expression of both collagen XVIII and CBP2/Hsp47 and enhanced VEGF expression. These changes were reversed by the PI3K inhibitor wortmannin and by treating cells with NAC. These studies show that phenotypic switching between collagen XVIII and VEGF is controlled by stress activated kinases under hypoxia, and PI3K signaling pathways as well as reactive oxygen species (ROS) following CoCl(2) treatment. Furthermore, modulation of the angiogenic switch is most profound during Akt activation than during activation of stress activated kinases.

Acetylcysteine↗
PubMed2003

Using three-dimensional imaging to assess treatment outcomes in orthodontics: a progress report from the University of the Pacific.

Past research in integrated three-dimensional (3D) craniofacial mapping at the Craniofacial Research Instrumentation Laboratory (CRIL) of the University of the Pacific is summarized in narrative form. The advantages and limitations of recent commercial developments in the application of cone beam geometry volumetric X-ray scanners in dentistry and surface digital mapping of study casts are discussed. The rationale for methods currently in development at CRIL for merging longitudinal information from existing 3D study casts and two-dimensional lateral X-ray cephalograms in studies of orthodontic treatment outcome is presented.

Cephalometry↗
PubMed2003

Targeting of human squamous carcinomas by SPA470-doxorubicin immunoconjugates.

In a quest to identify a favorable target for head and neck cancers and squamous cell carcinoma, we sought to determine if Hsp47/CBP2 could be used as a target and whether the expression of this target was influenced by hypoxia. Moreover, we determined if doxorubicin (DOX) immunoconjugates directed against Hsp47/CBP2 that linked monoclonal antibodies (MAbs) to the 13-keto position of the drug possessed high cytotoxic drug activity and antibody-directed killing of antigen bearing tumor target cells. Experiments were performed using established cell lines of human oral squamous carcinoma cells (SCCs) (SCC-4, -9, -15 and -25) obtained from American Type Culture Collection (ATCC) (Manassas, VA). In addition, the UMB2 cell line is a spontaneous mutant of SCC-9 that does not express Hsp47/CBP2 was also used. Synthesis of the immunoconjugates was accomplished by thiolating the MAbs with 2 IT and reacting the MAbs with the DOX-hydrazone. The binding of MAb-DOX conjugates to SCC cells was determined by indirect immunofluorescence and analyzed using a Becton Dickinson FACS scan with Cell Quest software. Comparison of the cytotoxicity of DOX, MAb-DOX conjugates and MAb+DOX were determined using a limited dilution assay and colony survival assays during normoxia and hypoxia. These studies revealed that SCC cells treated with the SPA470-DOX conjugate for 2 h retained the original binding activity for targeted SCC cells and was significantly more potent that unconjugated DOX, DOX-hydrazone or equivalent MAb protein+DOX. Also, SPA47-DOX produced equal to and at lower concentrations greater cell killing than equivalent dose of free DOX. During hypoxia cells treated with SPA470-DOX demonstrated a small increase in colony survival and a diminishment in cytotoxicity. SPA470-DOX conjugates target SCC cells that express Hsp47/CBP2. The demonstration that SPA470-DOX is effective during hypoxia or conditions that mimic hypoxia presumes the further utility of SPA470-DOX in treating head and neck cancers.

Antibodies, Monoclonal↗
PubMed2003

The relationship between body mass index, blood pressure and pulse rate among normotensive and hypertensive participants in the third National Health and Nutrition Examination Survey (NHANES).

Obesity is associated with high insulin and leptin levels. Studies also suggest that high levels of insulin and leptin increase sympathetic nervous system (SNS) activity and engender increased chronotropy, vasoconstriction and antinatriuresis that may contribute to the pathogenesis of obesity related hypertension. Sympathetic modulation of cardiovascular responses requires good baroreceptor sensitivity and optimal vascular compliance. The vascular changes associated with isolated systolic hypertension (ISH) have been shown to modify baroreceptor sensitivity and vascular compliance and may mitigate sympathetic modulation of cardiovascular responses and attenuate the hypertensive effect of obesity. The purpose of this study is to examine the differences in the relationship between body mass index, pulse rate (PR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) among participants with normal blood pressure and ISH using data from the third National Health and Nutrition Examination Survey. Data from 13,761 non-institutionalized adults 18 years and older not receiving antihypertensive therapy were analyzed. Results showed that PR, SBP and DBP increase with increasing BMI. The rise in PR, SBP and DBP with BMI is higher among participants with normal blood pressure than among those with ISH. We concluded that increasing level of obesity is associated with a rise in pulse rate and blood pressure but the effect of obesity on blood pressure and pulse rate might be weaker among participants with ISH.

Adolescent↗
PubMed2001

The use of the Hospital Anxiety and Depression Scale (HADS) in patients with chronic obstructive pulmonary disease: a pilot study.

AIMS: To investigate the use of the Hospital Anxiety and Depression Scale (HADS) with recuperating chronic obstructive pulmonary disease (COPD) patients. To study prevalence rates and changes in clinically relevant anxiety and depression during rehabilitation. METHODS: Consecutive patients admitted to a non acute respiratory ward over a twelve week period were asked to complete a HADS questionnaire on three occasions. Nurses recorded basic demographic information on admission. Additional demographic, medical and psychiatric data were obtained by retrospective review of medical records. RESULTS: Of 93 consecutive inpatients, 79 (85%) completed the admission HADS. 72 patients were eligible to complete the day three HADS and 60 the discharge HADS. Clinically relevant anxiety (HADS score of > or =8) was indicated in 39 patients (50%) and depression in 22 (28%). HADS anxiety (p=0.05) and total scores (anxiety+depression) (p=0.03) decreased between admission and discharge. A larger proportion of patients scored within the normal or mild psychopathology range by discharge. More severe COPD (FEV1% predicted) correlated with higher HADS anxiety scores (r=-0.39, p<0.001) and HADS depression scores (r=-0.34, p<0.005). Patients with a recorded history of anxiety (p<0.0001) and depression (p<0.02) had higher WADS scores. Females (n=37) when compared to males (n=42), recorded significantly higher HADS anxiety scores throughout (p<0.005). CONCLUSIONS: Clinically relevant anxiety, indicated by higher HADS scores, was more common in patients with severe COPD, a past history of anxiety or depression and females. Anxiety and total mood improved during inpatient rehabilitation. The use of this instrument with New Zealand COPD patients may improve identification and treatment of anxious and depressed patients.

Age Distribution↗
PubMed2001

The buffer effect and large-scale population regulation in migratory birds.

Buffer effects occur when sites vary in quality and fluctuations in population size are mirrored by large changes in animal numbers in poor-quality sites but only small changes in good-quality sites. Hence, the poor sites 'buffer' the good sites, a mechanism that can potentially drive population regulation if there are demographic costs of inhabiting poor sites. Here we show that for a migratory bird this process can apply on a country-wide scale with consequences for both survival and timing of arrival on the breeding grounds (an indicator of reproductive success). The Icelandic population of the black-tailed godwit, Limosa limosa islandica, wintering in Britain has increased fourfold since the 1970s (ref. 5) but rates of change within individual estuaries have varied from zero to sixfold increases. In accordance with the buffer effect, rates of increase are greater on estuaries with low initial numbers, and godwits on these sites have lower prey-intake rates, lower survival rates and arrive later in Iceland than godwits on sites with stable populations. The buffer effect can therefore be a major process influencing large-scale population regulation of migratory species.

Animals↗
PubMed2001

Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.

CONTEXT: Incidence of end-stage renal disease due to hypertension has increased in recent decades, but the optimal strategy for treatment of hypertension to prevent renal failure is unknown, especially among African Americans. OBJECTIVE: To compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a beta-blocker (metoprolol) on hypertensive renal disease progression. DESIGN, SETTING, AND PARTICIPANTS: Interim analysis of a randomized, double-blind, 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease (glomerular filtration rate [GFR] of 20-65 mL/min per 1.73 m(2)) enrolled between February 1995 and September 1998. This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000. INTERVENTIONS: Participants were randomly assigned to receive amlodipine, 5 to 10 mg/d (n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d (n = 441), with other agents added to achieve 1 of 2 blood pressure goals. MAIN OUTCOME MEASURES: The primary outcome measure was the rate of change in GFR; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50% or 25 mL/min per 1.73 m(2), end-stage renal disease, or death. RESULTS: Among participants with a urinary protein to creatinine ratio of >0.22 (corresponding approximately to proteinuria of more than 300 mg/d), the ramipril group had a 36% (2.02 [SE, 0.74] mL/min per 1.73 m(2)/y) slower mean decline in GFR over 3 years (P =.006) and a 48% reduced risk of the clinical end points vs the amlodipine group (95% confidence interval [CI], 20%-66%). In the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups (P =.38). However, compared with the amlodipine group, after adjustment for baseline covariates the ramipril group had a 38% reduced risk of clinical end points (95% CI, 13%-56%), a 36% slower mean decline in GFR after 3 months (P =.002), and less proteinuria (P<.001). CONCLUSION: Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria.

Adrenergic beta-Antagonists↗
PubMed2001

Depletion models can predict shorebird distribution at different spatial scales.

Predicting the impact of habitat change on populations requires an understanding of the number of animals that a given area can support. Depletion models enable predictions of the numbers of individuals an area can support from prey density and predator searching efficiency and handling time. Depletion models have been successfully employed to predict patterns of abundance over small spatial scales, but most environmental change occurs over large spatial scales. We test the ability of depletion models to predict abundance at a range of scales with black-tailed godwits, Limosa limosa islandica. From the type II functional response of godwits to their prey, we calculated the handling time and searching efficiency associated with these prey. These were incorporated in a depletion model, together with the density of available prey determined from surveys, in order to predict godwit abundance. Tests of these predictions with Wetland Bird Survey data from the British Trust for Ornithology showed significant correlations between predicted and observed densities at three scales: within mudflats, within estuaries and between estuaries. Depletion models can thus be powerful tools for predicting the population size that can be supported on sites at a range of scales. This greatly enhances our confidence in predictions of the consequences of environmental change.

Animals↗
PubMed2001

Combating diabetic nephropathy with drug therapy.

Diabetes mellitus is the leading cause of end-stage renal disease and also increases the risk of atherosclerotic vascular disease. Hypertension amplifies both problems. Detection of microalbuminuria, a common and early manifestation of diabetic nephropathy and a marker for cardiovascular risk, permits early treatment to reduce progression of nephropathy and vascular disease in diabetes. Although optimal glycemic control is essential to reduce the risk of nephropathy, aggressive blood pressure lowering to a level of 130/80 mg Hg or below in hypertensive diabetic patients is as important as glycemic control. Initial drug therapy for nephropathy should include an angiotensin-converting enzyme inhibitor (or if contra-indicated, an angiotensin receptor blocker), as several large randomized double-blinded multicenter clinical trials have demonstrated an independent renoprotective effect with renin angiotensin system inhibition. The role of advanced glycation end products in the pathogenesis of renal and vascular disease in diabetes is becoming more clearly established. However, the use of therapeutic strategies directed at blocking their effect still awaits further investigation. A multifaceted intervention program that combines optimal glycemic control, lifestyle modification/cardiovascular prevention guidelines such as lipid control and smoking cessation, with appropriate antihypertensive therapy when indicated, will prevent or delay both the occurrence and progression of diabetic nephropathy.

Antihypertensive Agents↗
PubMed2001

Improving end-of-life experience and care in the community: a conceptual framework.

End-of-life research and interventions have mostly focused on patients and family. There are compelling reasons for studying end-of-life experience and care from a community perspective. "Whole community" approaches to end-of-life care have been endorsed by the Institute of Medicine Committee on Care at End of Life. Building on the model developed by Stewart and colleagues, which integrates quality of life and quality of health indicators, a conceptual framework is presented that describes pertinent whole-community characteristics, structures, processes, and outcomes. The framework offers a map for whole-community research, intervention, and evaluation with the goal of changing the community culture related to life's end and thereby improving the quality of life for dying people and their families.

Community Health Services↗
PubMed2001

Behavioral treatment of hypertensive heart disease in African Americans: rationale and design of a randomized controlled trial.

African Americans experience higher morbidity and mortality than Whites do as a result of hypertension and associated cardiovascular disease. Chronic psychosocial stress has been considered an important contributing factor to these high rates. The authors describe the rationale and design for a planned randomized controlled trial comparing Transcendental Meditation, a stress-reduction technique, with lifestyle education in the treatment of hypertension and hypertensive heart disease in urban African Americans. They pretested 170 men and women aged 20 to 70 years over a 3-session baseline period, with posttests at 6 months. Outcomes included clinic and ambulatory blood pressure, quality of life, left ventricular mass measured by M-mode echocardiography, left ventricular diastolic function measured by Doppler, and carotid atherosclerosis measured by beta-mode ultrasound. This trial was designed to evaluate the hypothesis that a selected stress reduction technique is effective in reducing hypertension and hypertensive heart disease in African Americans.

Adult↗
PubMed2001

Pharmacokinetics of a transdermal testosterone system in men with end stage renal disease receiving maintenance hemodialysis and healthy hypogonadal men.

Androgen deficiency is common in men with end stage renal disease (ESRD) on maintenance hemodialysis. Pharmacokinetics of transdermal testosterone in men receiving maintenance hemodialysis have not been studied. Our objective was to compare the pharmacokinetics of a transdermal testosterone system in healthy hypogonadal men and in men with ESRD on maintenance hemodialysis. We recruited 10 healthy hypogonadal men and 8 medically stable men on maintenance hemodialysis, 18--70 yr old, who had serum testosterone less than 300 ng/dL. After baseline sampling during a 24-h control period, two testosterone patches were applied daily for 28 days, to achieve a nominal delivery of 10-mg testosterone daily. In addition to single, pooled samples on days 7, 14, and 21, blood was drawn at 0, 2, 4, 6, 8, and 24 h on day 28 in healthy hypogonadal men and on an interdialytic day (day 21 or 28) as well as a dialysis day (day 21 or 28) in men on hemodialysis. On the dialysis day (day 21 or 28), serum free and total testosterone levels were measured hourly for 4 h before hemodialysis and for 4 h during hemodialysis. The dialysate was sampled for testosterone measurement. Baseline mean + SD total (92 +/- 82 vs. 222 +/- 50 ng/dL) and free (11 +/- 9 vs. 27 +/- 6 pg/mL) testosterone concentrations were lower in healthy hypogonadal men than in men with ESRD. After application of two testosterone patches, serum total and free testosterone concentrations rose into the midnormal range in both groups of men. Time-average, steady state (total testosterone, 506 +/- 88 vs. 516 +/- 86 ng/dL; free testosterone, 55 +/- 9 vs. 67 +/- 11 pg/mL), minimum, and maximum total and free testosterone concentrations were not significantly different between the two groups of men during treatment. Increments in total and free testosterone concentrations above baseline, baseline-subtracted areas under the total and free testosterone curves, and half-life of testosterone elimination (t(1/2), 2.1 +/- 0.1 vs. 2.1 +/- 0.2 h, P = not significant) were not significantly different between the two groups. In men receiving hemodialysis, time-average, steady state, and maximal total and free testosterone concentrations and baseline-subtracted areas under the total and free testosterone curves were higher on dialysis day than on an interdialytic day. On the day of hemodialysis, time-average total and free testosterone concentrations were not significantly different during the 4 h before or during hemodialysis. The amount of testosterone removed in the dialysate (8.4 +/- 1.6 microg during 4 h of hemodialysis) was small compared with the daily testosterone production rates in healthy young men. Serum dihydrotestosterone and estradiol concentrations increased into the normal male range and were not significantly different between the two groups. Percent suppression of LH was greater in men with ESRD than in healthy hypogonadal men. A regimen of two Testoderm TTS testosterone patches (Alza Corp., Mountain View, CA) daily can maintain serum concentrations of total and free testosterone and its metabolites dihydrotestosterone and estradiol in the midnormal range in healthy hypogonadal men and men on hemodialysis. The amount of testosterone cleared by hemodialysis is small, and hemodialysis does not significantly affect serum total and free testosterone concentrations in men treated with the testosterone patch.

Administration, Cutaneous↗
PubMed2001

High blood pressure knowledge in an urban African-American community.

OBJECTIVE: To determine the level and determinants of knowledge of the risks for hypertension and the potential for its prevention in an urban African-American community. METHODS: In a survey of 397 African-American adults (18-73 years of age) at an urban community fair, we measured high blood pressure knowledge using a 12-item questionnaire designed at NIH for the assessment of high blood pressure knowledge among non-medical persons. RESULTS: The mean high blood pressure knowledge score for the overall sample was 83.1%. There were subgroup differences in the scores with significant associations between high blood pressure knowledge score and level of education (P = .002) and a personal history of hypertension (P = .009). CONCLUSION: We concluded that the participants exhibited a high, but variable, level of high blood pressure knowledge with a higher level of education and/or a personal history of hypertension having a significant association with greater blood pressure knowledge. The effects of the magnitude and mode of acquisition of high blood pressure knowledge on the control of high blood pressure and its related outcomes need to be examined in further studies.

Adolescent↗
PubMed2001

The effect of gender on age-related blood pressure changes and the prevalence of isolated systolic hypertension among older adults: data from NHANES III.

OBJECTIVE: To examine gender differences in age-related blood pressure changes and the prevalence of isolated systolic hypertension. DESIGN: Third National Health and Nutrition Examination Survey, 1988-1994. SETTING: 89 mobile examination centers and household questionnaire. PARTICIPANTS: 6635 men and 7189 women over the age of 18 years who were not under treatment for high blood pressure. MAIN OUTCOME MEASURES: Levels of systolic blood pressure, diastolic blood pressure, and pulse pressure by age and gender; prevalence of isolated systolic hypertension (ISH). RESULTS: Systolic blood pressures (SBP) and pulse pressures (PP) were higher in males than in females among adults less than 45 years old. After age 45, SBP and PP were higher in females. Diastolic blood pressures were lower among adult females across all age categories. The prevalence of stages 1 and 2/3 ISH were higher among females after age 44 years. The magnitude of the gender differences in the prevalence of ISH was also age-dependent. CONCLUSIONS: ISH was higher in elderly women than men. These age-related blood pressure changes may account in part for the higher cardiovascular mortality reported among elderly females compared with elderly males and should be considered an important target for cardiovascular preventive strategy, particularly in elderly females.

Adolescent↗
PubMed2000

Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B.

Several protein-tyrosine phosphatases (PTPs) have been proposed to act as negative regulators of insulin signaling. Recent studies have shown increased insulin sensitivity and resistance to obesity in PTP1B knockout mice, thus pointing to this enzyme as a potential drug target in diabetes. Structure-based design, guided by PTP mutants and x-ray protein crystallography, was used to optimize a relatively weak, nonphosphorus, nonpeptide general PTP inhibitor (2-(oxalyl-amino)-benzoic acid) into a highly selective PTP1B inhibitor. This was achieved by addressing residue 48 as a selectivity determining residue. By introducing a basic nitrogen in the core structure of the inhibitor, a salt bridge was formed to Asp-48 in PTP1B. In contrast, the basic nitrogen causes repulsion in other PTPs containing an asparagine in the equivalent position resulting in a remarkable selectivity for PTP1B. Importantly, this was accomplished while retaining the molecular weight of the inhibitor below 300 g/mol.

Animals↗