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Biomedical subjects

S R Harris

Publications and source records attributed to S R Harris.

At least 19 recordsLinked to original sources
PubMed2004

A sensitive HPLC-MS-MS assay for quantitative determination of midazolam in dog plasma.

The clinical pharmacokinetics of midazolam have been extensively studied, due to its high clearance by CYP3A4 and sensitivity to drug-drug interactions. In order to investigate the potential to model drug-drug interactions with midazolam in the dog, a selective and sensitive high performance liquid chromatography-tandem mass spectroscopy (HPLC-MS-MS) method has been developed, with sufficient sensitivity to allow analysis of dog plasma samples generated following administration of a clinically relevant dose. The method involves extraction of midazolam and internal standard (flunitrazepam) from dog plasma, using 96-well Oasis MCX solid phase extraction plates. The assay has been validated over a concentration range of 0.1-10 ng/ml and its specificity, accuracy and precision demonstrated. The relative bias of the assay was within +/-15% for all standards with intra- and inter-assay precision (coefficient of variation-%CV) of less than 15%. The assay was applied to the analysis of plasma samples (0.2 ml), generated following intravenous or oral administration of midazolam to male beagle dogs, at a dose level of 0.05 mg/kg, and pharmacokinetic parameters were derived from the resulting data.

Administration, Oral↗
PubMed2001

Clinical practice guidelines for the care and treatment of breast cancer: 11. Lymphedema.

OBJECTIVE: To provide information and recommendations for women and their physicians when making decisions about the management of lymphedema related to breast cancer. OPTIONS: Compression garments, pneumatic compression pumps, massage and physical therapies, other physical therapy modalities, pharmaceutical treatments. OUTCOMES: Symptom control, quality of life, cosmetic results. EVIDENCE: Systematic review of English-language literature retrieved primarily from MEDLINE (1966 to April 2000) and CANCERLIT (1985 to April 2000). Nonsystematic review of breast cancer literature published to October 2000. RECOMMENDATIONS: Pre- and postoperative measurements of both arms are useful in the assessment and diagnosis of lymphedema. Circumferential measurements should be taken at 4 points: the metacarpal-phalangeal joints, the wrists, 10 cm distal to the lateral epicondyles and 15 cm proximal to the lateral epicondyles. Clinicians should elicit symptoms of heaviness, tightness or swelling in the affected arm. A difference of more than 2.0 cm at any of the 4 measurement points may warrant treatment of the lymphedema, provided that tumour involvement of the axilla or brachial plexus, infection and axillary vein thrombosis have been ruled out. Practitioners may want to encourage long-term and consistent use of compression garments by women with lymphedema. One randomized trial has demonstrated a trend in favour of pneumatic compression pumps compared with no treatment. Further randomized trials are required to determine whether pneumatic compression provides additional benefit over compression garments alone. Complex physical therapy, also called complex decongestive physiotherapy, requires further evaluation in randomized trials. In one randomized trial no difference in outcomes was detected between compression garments plus manual lymph drainage versus compression garments alone. Clinical experience supports encouraging patients to consider some practical advice regarding skin care, exercise and body weight. [A patient version of these guidelines appears in Appendix 2.] VALIDATION: An initial draft of this document was developed by a task force sponsored by the BC Cancer Agency. It was updated and revised substantially by a writing committee and then submitted for further review, revision and approval by the Steering Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. SPONSOR: The steering committee was convened by Health Canada. COMPLETION DATE: October 2000.

Bandages↗
PubMed2001

Measurement of upper extremity volume in women after axillary dissection for breast cancer.

OBJECTIVE: To determine if 2 methods of calculating upper extremity volume (using arm circumferences) can substitute for water displacement volumetry. DESIGN: Interrater and test-retest reliability and limits of agreement for volume measures. SETTING: University. PARTICIPANTS: Twenty-five women at risk for lymphedema who had undergone axillary lymph node dissection surgery for breast cancer. INTERVENTIONS: Circumference and volume measurements of both upper extremities were taken by 2 physical therapists at an initial visit and by 1 of the therapists 1 week later. MAIN OUTCOME MEASURES: Intraclass correlation coefficients (ICCs) were calculated to analyze measurement reliability. Pearson's product-moment correlation coefficient (r) was used to evaluate the relationship between volumetry and calculated truncated cone volumes. Limits of agreement were calculated to determine the level of agreement between the 2 measurement methods. RESULTS: Interrater and test-retest reliability ICCs for circumferential and volumetric data were .99 and .99, respectively. Pearson's r values were .93 and .97 for the single truncated cone and the summed truncated cone volume calculations, respectively. Limits of agreement (mean +/- 2 standard deviations) were -52 +/- 334mL and -40 +/- 234mL, respectively, between volumetry and the single truncated cone and summed truncated cone calculations. CONCLUSIONS: Calculated and volumetric measurements in this population are both reliable and closely related, but do not agree with each another, and thus should not be used interchangeably.

Adult↗
PubMed2001

Reliability and validity of the Harris Infant Neuromotor Test.

OBJECTIVE: To examine the reliability and validity of the Harris Infant Neuromotor Test (HINT), a screening tool that can be administered and scored in <30 minutes, with the goal of identifying neuromotor differences in infants aged 3 to 12 months. STUDY DESIGN: Infants, aged 3 to 12 months (n = 54), were assessed in 2 high-risk infant follow-up programs in Vancouver, British Columbia. Inter-rater, test-retest, and intra-rater reliability were examined. Concurrent and predictive validity of the HINT with the Bayley Scales of Infant Development-II (BSID-II) were evaluated by using the Pearson product-moment correlation. RESULTS: Intraclass correlation coefficients for reliability for the Total HINT Score ranged from 0.98 to 0.99. Concurrent validity of the HINT with the BSID-II Mental Scale during the first year was r = -0.73 (P <.01), and with the BSID-II Motor Scale, r = -0.89 (P <.01). The predictive relationships between the HINT and the BSID-II at 17 to 22 months were r = -0.11 for the BSID-II Mental Scale and r = -0.49 (P <.01) for the BSID-II Motor Scale. CONCLUSIONS: The HINT is reliable for screening infant neuromotor performance and has strong concurrent validity with the Bayley-II Mental and Motor Scales. HINT scores during the first year accounted for 24% of the variance of Bayley-II Motor scores at 17 to 22 months.

British Columbia↗
PubMed2000

Challenging the myth of exercise-induced lymphedema following breast cancer: a series of case reports.

Women who have had axillary lymph nodes removed for the management of breast cancer are at increased risk of developing upper extremity lymphedema. Physical therapists, surgeons, and other health professionals have warned these women to avoid vigorous, repetitive, or excessive upper body exercise, believing that such types of exercise might actually induce lymphedema. The purpose of this series of case reports was to challenge that belief by systematically measuring the arm circumferences, across three points in time, of 20 women who had received axillary dissection and who were competing in the vigorous, upper body sport of Dragon Boat racing. Measurably different change was defined as an increase in circumference of the ipsilateral upper extremity at any of the four landmarks of >0.5 inches between Time 1 and Time 2 or between Time 1 and Time 3; only two women showed a measurably different change (5/8 in). Furthermore, none of the women showed a clinically significant difference in arm circumference between the ipsilateral and contralateral extremities at Time 3.

Adult↗
PubMed2000

The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells.

Protease inhibitors are very effective in treating patients infected with HIV. However, many drugs in this class penetrate poorly into the central nervous system (CNS) and may permit this site to be a sanctuary from which resistant virus can emerge. Previous studies have shown that the protease inhibitor saquinavir (SQV) interacts with the multidrug transport system, P-glycoprotein (P-gp), expressed in epithelial cells in the gut mucosa and at the blood-brain barrier, and thus might affect both the oral absorption and the penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue and plasma was also investigated in rats and in normal and P-gp-deficient mdr1a(-/-) mice. The distribution ratio of SQV in plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bolus i.v. injection of [(14)C]SQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from mdr1a(-/-) mice. Similarly, oral administration of [(14)C]SQV (500 mg/kg) resulted in a 5-fold increase in systemic exposure and a 10-fold increase in brain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiting oral absorption and CNS exposure to this protease inhibitor.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Teachers' Use of the MABC Checklist to Identify Children with Motor Coordination Difficulties.

Children with motor coordination problems often have difficulty succeeding in the classroom. No previous research could be located in which classroom teachers used screening tools to determine the severity of the children's motor coordination problems or their need for consultation from occupational and physical therapists. The purposes of this study were: 1) to examine the relationship between teachers' scores on the Movement Assessment Battery for Children (MABC) checklist and the physical therapist's scores on the MABC test; and 2) to examine the degree of concordance in decision making by determining if the teachers and physical therapist, using these two measures independently, identified the same children with motor difficulties and those without motor difficulties. Teachers completed the MABC checklist and the physical therapist administered the MABC test to 103 children. The relationship between the teachers' and physical therapist's scores was examined using the Pearson product-moment correlation. Sensitivity and specificity of the checklist were assessed with the MABC test scores as the criterion measure. The correlation between the teachers' scores and the physical therapist's scores was r = 0.51. The sensitivity of the checklist at the 15th percentile cutoff point was 14.3%, and specificity was 97.8%. The sensitivity of the MABC checklist was so low that many children at risk for motor problems based on the MABC test were not identified. Thus, the independent use of this checklist by teachers to identify children with motor coordination problems is not recommended.

Journal Article↗
PubMed1999

Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells.

Flavone acetic acid (FAA) is a synthetic flavonoid that demonstrated extraordinary anti-tumour properties in murine models but was not effective in clinical trials. In an effort to better understand the molecular mechanisms by which FAA asserts its tumouricidal activities, we have examined the effect of FAA on the cell cycle. We observed FAA-mediated G2/M cell cycle arrest in mammary carcinoma cells at a concentration previously demonstrated to have anti-tumour effects in rodent models. The cell cycle arrest was accompanied by an increase in the P34cdc2 (cdc2) cyclin-dependent kinase activity. Morphological cytogenetic analysis demonstrated a colcemid-like effect of FAA on cytokinesis by causing accumulation of condensed C-metaphases of a sustained mitotic block. The cell cycle effect was blocked by the antioxidants ADPC and ascorbate, the superoxide scavenger Tiron, and the sphingosine kinase inhibitor L-cycloserine, but not by inhibitors of nitric oxide synthase. Based on these data, we propose that FAA may induce cell cycle arrest by stimulating the activity of acidic sphingomyelinase leading to the generation of reactive oxygen species.

Animals↗
PubMed1998

Stimulatory effect of endogenous tissue inhibitor of metalloproteinases-1 (TIMP-1) overexpression on type IV collagen and laminin gene expression in rat mammary carcinoma cells.

We recently reported enhanced tumor growth and stimulation of vascular endothelial growth factor (VEGF) expression in rat mammary carcinoma cells transfected with a human tissue inhibitor of metalloproteinases-1 (hTIMP-1) cDNA (1). In the present study, we examined if the composition of the stroma was altered in the tumors with the highest hTIMP-1 production. Immunohistological examination revealed increased amounts of the basement membrane (BM) components, type IV collagen and laminin, in the hTIMP-1 overexpressing tumors compared to that of the control. In vitro studies also revealed upregulation of type IV collagen and laminin gene expression associated with the hTIMP-1 overexpression. Endogenous RNA levels of rat TIMP-1 and the rat matrix metalloproteinases (MMPs), MMP-2, MMP-3, and MMP-9, were not affected by the hTIMP-1 transfection, suggesting that the increase in BM deposition was not a result of decreased collagenolytic activity. This is the first report to show an association between overexpression of TIMP-1 and increased tumor BM matrix production through stimulation of type IV collagen and laminin gene expression.

Animals↗
PubMed1998

Mammary carcinoma cells over-expressing tissue inhibitor of metalloproteinases-1 show enhanced vascular endothelial growth factor expression.

The tissue inhibitor of metalloproteinases-1 (TIMP-1) has at least 2 independent functions, i.e., regulation of matrix metalloproteinases and erythroid-potentiating activity. We investigated the effects of TIMP-1 over-expression on tumor growth, using cloned lines derived from a TIMP-1-transfected rat breast carcinoma cell line. The in vitro growth rate of the TIMP-1-transfected clones was indistinguishable from that of the control. In contrast, the highest TIMP-1-producing clone (159.0 ng/ml), designated as T-H, formed 4.6-fold larger s.c. tumors than did the control after 14 days. Tumors derived from an intermediate TIMP-1-producing clone (45.4 ng/ml), designated as T-M, were 1.9-fold larger than the control. TIMP-1 over-expression was associated with increased vascular endothelial growth factor (VEGF) expression, vascularization and proliferative activity of the s.c. tumors. Similar to the rat breast carcinoma cells, transfection of TIMP-1 cDNA into the human breast carcinoma cell line MCF-7 resulted in up-regulation of VEGF, with a linear relationship between TIMP-1 and VEGF production in 9 cell clones examined. There was, however, no change in VEGF expression when the rat and human breast carcinoma cell lines were exposed to exogenous recombinant TIMP-1. Our findings suggest that over-expression of TIMP-1 confers growth advantage on breast carcinoma cells in vivo and that up-regulation of VEGF expression may play an important role in this TIMP-1-mediated, growth-stimulating effect.

Animals↗
PubMed1998

Physical therapist management of lymphedema following treatment for breast cancer: a critical review of its effectiveness.

The purpose of this review is to analyze the research literature that has examined the effectiveness of physical therapy in the management of lymphedema following treatment for breast cancer. Thirteen studies met the criteria for experimental research, which were then categorized according to Sackett's levels of evidence. One study was graded at level II, 5 studies were graded at level III, and the remaining 7 studies were graded at level V. One grade B recommendation and 6 grade C recommendations were developed from the levels of evidence. The 13 selected studies were also graded according to 6 criteria to evaluate scientific rigor. Clinical recommendations and future research directions are provided.

Breast Neoplasms↗
PubMed1997

Vascular endothelial growth factor is essential for initial but not continued in vivo growth of human breast carcinoma cells.

In this study, we used a self-contained tetracycline-regulated retroviral vector system to elucidate the role of vascular endothelial growth factor (VEGF) in controlling s.c. growth of human T-47D breast carcinoma cells. VEGF expression was tightly regulated by this system, both in vitro and in nude mouse xenografts. A 2.4-fold increase in tumor volume was associated with VEGF overexpression. Tumor growth was almost completely inhibited when VEGF was suppressed from the time of T-47D cell inoculation, and a 6-fold reduction in tumor volume was observed when VEGF suppression was started in 175-mm3 tumors. However, no growth inhibition was observed when VEGF suppression was started in 820-mm3 tumors. In these tumors, basic fibroblast growth factor and transforming growth factor alpha RNA expression was detected after VEGF was switched off. These findings demonstrate that VEGF is critical for the initial s.c. growth of T-47D breast carcinoma cells, whereas other angiogenic factors can compensate for the loss of VEGF after the tumors have reached a certain size.

Animals↗
PubMed1997

Flavone acetic acid stimulates nitric oxide and peroxynitrite production in subcutaneous mouse tumors.

Flavone acetic acid (FAA) has powerful anti-tumor activity against many types of solid murine tumors, but its biochemical mechanism of action is not understood. The present study examined the role of tumor vasculature and nitric oxide in mediating the anti-tumor effects of FAA. Athymic nude mice bearing subcutaneous RJ2-14 tumors were treated with a single dose of FAA, 200 mg/kg i.p., and euthanized at various times. Apoptosis within tumors was apparent during the first six hours of FAA treatment. We found that Type III, endothelial nitric oxide synthase (NOS) activity was significantly increased in tumors, but not in other tissues, as early as two hours after FAA dosing. FAA also stimulated the formation of the toxic peroxynitrite radical in tumors within two hours of treatment as assessed by immunostaining for nitrotyrosine. Staining was observed in dilated tumor vessels and surrounding tumor cells and correlated with the presence of apoptosis. Tumor endothelium may therefore be a critical target for FAA activity via stimulation of the nitric oxide pathway.

Adenocarcinoma↗
PubMed1997

Single-subject research in rehabilitation: a review of studies using AB, withdrawal, multiple baseline, and alternating treatments designs.

OBJECTIVE: To review the "methodologic rules" for using single-subject research designs (SSRDs) and to review the use of SSRDs in rehabilitation research of the past decade. DATA SOURCES: CINAHL and MEDLINE searches using "single subject" and "single system" as key words for the period 1985-1995 yielded 61 articles related to rehabilitation. STUDY SELECTION: Studies were selected for review if they described one of four commonly used SSRDs, specifically AB, withdrawal, multiple baseline, or alternating treatments. DATA EXTRACTION: Studies cited were identified by consensus and either exemplify adherence to the experimental rules of SSRDs or illustrate errors that result in threats to the validity of stated findings. DATA SYNTHESIS: All four types of SSRDs have been reported in rehabilitation studies, sometimes incorrectly. CONCLUSIONS: SSRDs, with their client-centered focus, are ideally suited for researching human behavior in the rehabilitation practice environment. Although numerous sources clearly identify the methodologic requirements for single-subject experiments, several studies violate the basic rules, threatening the validity of the results of these studies. Other properly applied SSRDs illustrate the strengths of this approach, which can produce empirical support for rehabilitation interventions.

Humans↗
PubMed1997

Metabolism of the calcium antagonist, mibefradil (POSICOR, Ro 40-5967). Part III. Comparative pharmacokinetics of mibefradil and its major metabolites in rat, marmoset, cynomolgus monkey and man.

1. The metabolism of mibefradil has been examined in rat, marmoset, cynomolgus monkey and man after single and multiple oral administration. 2. Metabolites typically represent between 50 and 80% of the circulating drug-related material after single oral doses of mibefradil to man, rat and marmoset. They arise by a combination of enzymatic processes: cytochrome P450-mediated oxidation at saturated and unsaturated carbon atoms, cytochrome P450-catalysed dealkylation and hydrolysis of the ester side-chain. 3. Plasma levels of mibefradil in the cynomolgus monkey are extremely low as a result of very efficient first-pass hydrolysis of its side-chain to give the corresponding alcohol. Steady-state concentrations of this metabolite are comparable with those of the parent drug in man and marmoset, but are relatively low in rat plasma. 4. Hydroxylation at the benzylic carbon of the tetrahydronaphthyl ring leads to further important metabolites in primates, whereas the products of O- and N-demethylation are found in small amounts in all four species. 5. Estimates of the exposure of the various species to the principal metabolites indicate that the choice of the rat, marmoset and cynomolgus monkey for the toxicological assessment of mibefradil was appropriate.

Adult↗