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Biomedical subjects

L Anderson

Publications and source records attributed to L Anderson.

At least 37 records · Page 2Linked to original sources
PubMed1999

What do internal medicine residents need to enhance their diabetes care?

OBJECTIVE: To identify areas that should be targeted for improvement in care, we examined internal medicine resident practice patterns and beliefs regarding diabetes in a large urban hospital outpatient clinic. RESEARCH DESIGN AND METHODS: Internal medicine residents were surveyed to assess the frequency at which they performed key diabetes quality of care indicators. Responses were compared with recorded performance derived from chart and laboratory database reviews. Resident attitudes about diabetes were determined using the Diabetes Attitude Survey for Practitioners. Finally, an eight-item scale was used to assess barriers to diabetes care. RESULTS: Both self-described and recorded performance of recommended diabetes services short of national recommendations. For yearly eye examinations and lipid screening, recorded performance levels were similar to trainees' reports. However, documented inquiries about patient self-monitoring of blood glucose, performance of foot examinations, and urine protein screening were lower than trainees' reports. Some 49% of the residents selected a target HbA1c of 6.6-7.5% as an attainable goal, yet half of the patients using oral agents or insulin had HbA1c values > 8.0%. No differences in self-described or recorded performance were found by year of training. Most residents did not perceive themselves to need additional training related to diabetes care, and residents were generally neutral about patient autonomy. Patient nonadherence and time constraints within the clinic were most often cited as barriers to care. CONCLUSIONS: The study identifies several areas that require improvement in resident care of diabetes in the ambulatory setting. Because experience during training contributes to future practice patterns, developing a program that teaches trainees how to implement diabetes practice guidelines and methods to achieve optimal glycemic control may be key to future improvements in the quality of diabetes care.

Adult↗
PubMed1999

Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy-thioguanine.

Thiopurine antimetabolites have been in clinical use for more than 40 years, yet the metabolism of thiopurines remains only partially understood. Data from our previous pediatric phase 1 trial of continuous i.v. infusion of thioguanine (CIVI-TG) suggested that TG was eliminated by saturable mechanism, with conversion of the drug to an unknown metabolite. In this study we have identified this metabolite as 8-hydroxy-thioguanine (8-OH-TG). The metabolite coeluted with the 8-OH-TG standard on HPLC and had an identical UV spectrum, with a lambda(max) of 350 nm. On mass spectroscopy, the positive ion, single quad scan of 8-OH-TG yielded a protonated molecular ion at 184 Da and contained diagnostic ions at m/z 167, 156, 142, and 125 Da. Incubation of TG in vitro with partially purified aldehyde oxidase resulted in 8-OH-TG formation. 8-OH-TG is the predominant circulating metabolite found in patients receiving CIVI-TG and is likely generated by the action of aldehyde oxidase.

Aldehyde Oxidase↗
PubMed1999

Regional hospital improves efficiency with co-generation retrofit.

Feasibility analysis of the co-generation retrofit of the Red Deer Regional Hospital pointed to a reasonable payback of capital cost and increased efficiency in operation of the facility. Budget restrictions nearly stopped the project from proceeding. Innovative construction procedures proposed by the Facility Management Group, in particular, Mr Keith Metcalfe, Director of Maintenance, allowed a worthwhile project to reach successful completion. We feel that this model can perhaps be used by similar facilities in the future to achieve their energy efficiency goals.

Alberta↗
PubMed1998

Ganciclovir chemoablation of herpes thymidine kinase suicide gene-modified tumors produces tumor necrosis and induces systemic immune responses.

The goal of this work was to identify potential host immune responses to thymidine kinase (TK) suicide gene-modified tumors undergoing chemoablation induced by the prodrug ganciclovir (GCV). The aims were to measure the efficacy and specificity of immunity induced against unmodified tumor, to identify qualitative or quantitative changes in the host response to TK+ tumors undergoing chemoablation that may contribute to the induction of antitumor immunity, and to compare critically the induction of immunity by chemoablation of TK-modified tumors with that of other methods of immunization in this tumor model and in response to other well-defined model antigens. Animals treated with TK+ tumors and GCV developed specific resistance to rechallenge with unmodified tumor. GCV induced significant tumor necrosis, which was associated with a pronounced host cell infiltrate composed of polymorphonuclear cells, both CD4+ and CD8+ T lymphocytes, and increased intratumoral IL-12. Cyclophosphamide-treated mice exhibited no such host response despite the induction of tumor necrosis. CTL responses to defined antigens in TK+ cells were greater in animals treated with prodrug than were those in animals not treated with prodrug but harboring live TK+ cells. Similar degrees of immunity were produced by immunization with irradiated cells.

Animals↗
PubMed1998

High dose rate intraoperative radiation therapy (HDR-IORT) as part of the management strategy for locally advanced primary and recurrent rectal cancer.

PURPOSE: Primary unresectable and locally advanced recurrent rectal cancer presents a significant clinical challenge. Local failure rates are high in both situations. Under such circumstances, there is a significant need to safely deliver tumoricidal doses of radiation in an attempt to improve local control. For this reason, we have incorporated a new approach utilizing high dose rate intraoperative radiation therapy (HDR-IORT). METHODS AND MATERIALS: Between 11/92-12/96, a total of 112 patients were explored, of which 68 patients were treated with HDR-IORT, and 66 are evaluable. The majority of the 44 patients were excluded for unresectable disease or for distant metastases which eluded preoperative imaging. There were 22 patients with primary unresectable disease, and 46 patients who presented with recurrent disease. The histology was adenocarcinoma in 64 patients, and squamous cell carcinoma in four patients. In general, the patients with primary unresectable disease received preoperative chemotherapy with 5-fluorouracil (5-FU) and leucovorin, and external beam irradiation to 4500-5040 cGy, followed by surgical resection and HDR-IORT (1000-2000 cGy). In general, the patients with recurrent disease were treated with surgical resection and HDR-IORT (1000-2000 cGy) alone. All surgical procedures were done in a dedicated operating room in the brachytherapy suite, so that HDR-IORT could be delivered using the Harrison-Anderson-Mick (HAM) applicator. The median follow-up is 17.5 months (1-48 mo). RESULTS: In primary cases, the actuarial 2-year local control is 81%. For patients with negative margins, the local control was 92% vs. 38% for those with positive margins (p = 0.002). The 2-year actuarial disease-free survival was 69%; 77% for patients with negative margins vs. 38% for patients with positive margins (p = 0.03). For patients with recurrent disease, the 2-year actuarial local control rate was 63%. For patients with negative margins, it was 82%, while it was 19% for those with positive margins (p = 0.02). The disease-free survival was 47% (71% for negative margins and 0% for positive margins) (p = 0.04). Prospective data gathering indicated that significant complications occurred in approximately 38% of patients and were multifactorial in nature, and manageable to complete recovery. CONCLUSION: HDR-IORT using our technique is versatile, safe, and effective. The local control rates for primary disease compare quite well with other published series, especially for patients with negative margins. For patients with recurrent disease, locoregional control and survival are especially encouraging in patients with negative resection margins. Further follow-up is needed to see whether these encouraging data will continue.

Adenocarcinoma↗
PubMed1998

A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers.

Genetic and biochemical studies in lower eukaryotes have identified several proteins that ensure accurate segregation of chromosomes. These include the Drosophila aurora and yeast Ipl1 kinases that are required for centrosome maturation and chromosome segregation. We have identified two human homologues of these genes, termed aurora1 and aurora2, that encode cell-cycle-regulated serine/threonine kinases. Here we demonstrate that the aurora2 gene maps to chromosome 20q13, a region amplified in a variety of human cancers, including a significant number of colorectal malignancies. We propose that aurora2 may be a target of this amplicon since its DNA is amplified and its RNA overexpressed, in more than 50% of primary colorectal cancers. Furthermore, overexpression of aurora2 transforms rodent fibroblasts. These observations implicate aurora2 as a potential oncogene in many colon, breast and other solid tumors, and identify centrosome-associated proteins as novel targets for cancer therapy.

3T3 Cells↗
PubMed1998

Mycophenolate mofetil reduces the risk of acute rejection less in African-American than in Caucasian kidney recipients.

BACKGROUND: Multicenter clinical trials have shown that mycophenolate mofetil (MMF) reduces the risk of acute rejection, but it is unknown whether African-Americans constitute a subgroup of recipients less likely to benefit from MMF. METHODS: This study compared the acute rejection rates within 6 months of kidney transplantation in MMF-treated transplant patients with those on azathioprine (AZA) at a single center. The study population consisted of 353 consecutive recipients of cadaver or living donor kidney transplants. African-Americans constituted 43% of the patients on AZA and 49% of the patients on MMF. Variables used in a Cox regression analysis included MMF immunosuppression, recipient race, type of transplant, delayed graft function, postoperative immune induction, average cyclosporine trough level, and HLA mismatch. RESULTS: Significantly fewer patients on MMF experienced a biopsy-proven rejection episode than those treated with AZA (24% vs. 42%, respectively; relative risk [RR]=0.57, P=0.001). This decrease in risk was greater in Caucasian transplant recipients (MMF vs. AZA: 16% vs. 46%, RR=0.35, P < 0.001) than in African-American patients (32% vs. 36%, RR=0.88, P=0.6). Within each race stratum, the mean cyclosporine trough levels averaged over 2-week intervals were nearly identical for AZA- compared with MMF-treated patients. In the regression model, the effect of MMF on the incidence of rejection was again less in African-American than in Caucasian patients. CONCLUSIONS: Kidney recipients treated with MMF have a significantly lower risk of acute rejection within 6 months of transplantation than those given AZA. This reduction in risk is significantly less in African-American recipients than Caucasians.

Adult↗
PubMed1998

Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene.

Mutations in the presenilin genes (PS-1 and PS-2) cause early onset autosomal dominant Alzheimer's disease (AD). Eight early-onset, autopsy-documented familial AD kindreds were screened for mutations in PS-1, and seven different mutations were identified. Three of these were new mutations (G209V, A426P, and E120D), two were previously reported mutations in new families, and three mutations were confirmed in previously published families. Two of these new mutations are found within predicted transmembrane domains (TMDs 4, 7, and 8). The A426P mutation is the most C-terminal PS-1 mutation identified to date.

Adult↗
PubMed1998

Tau is a candidate gene for chromosome 17 frontotemporal dementia.

Frontotemporal dementia with parkinsonism, chromosome 17 type (FTDP-17), a recently defined disease entity, is clinically characterized by personality changes sometimes associated with psychosis, hyperorality, and diminished speech output, disturbed executive function and nonfluent aphasia, bradykinesia, and rigidity. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, and amygdala. Neurofibrillary tangles (NFTs) are seen in some but not all families. Inheritance is autosomal dominant and the gene has been regionally localized to 17q21-22 in a 2- to 4-centimorgan (cM) region flanked by markers D17S800 and D17S791. The gene for tau, the primary component of NFTs, is located in the same region of chromosome 17. Tau was evaluated as a candidate gene. Physical mapping studies place tau within 2 megabases or less of D17S791, but it is probably outside the D17S800-D17S791 FTDP-17 interval. DNA sequence analysis of tau coding regions in affected subjects from two FTDP-17 families revealed nine DNA sequence variants, eight of which were also identified in controls and are thus polymorphisms. A ninth variant (Val279Met) was found in one FTDP-17 family but not in the second FTDP-17 family. Three lines of evidence indicate that the Val279Met change is an FTDP-17 causative mutation. First, the mutation site is highly conserved, and a normal valine is found at this position in all three tau interrepeat sequences and in other microtubule associated protein tau homologues. Second, the mutation co-segregates with the disease in family A. Third, the mutation is not found in normal controls.

Chromosome Mapping↗
PubMed1998

Enkephalin-processing oligopeptidases in cobra venom: inhibition by thiorphan and bestatin reveals co-operative actions.

The peptidase inhibitors thiorphan and bestatin were tested for their ability to inhibit the actions of the oligopeptidases contained in the venom of the Taiwan cobra (Naja naja atra). With methionine enkephalin (TyrGlyGlyPheMet) as substrate, thiorphan was an effective inhibitor of cleavage of the GlyPhe peptide bond while bestatin inhibited cleavage of the TyrGly peptide bond. Thiorphan and bestatin also inhibited subsequent cleavage of the fragments GlyGlyPheMet and TyrGlyGly respectively. These inhibitors reveal an interplay between the venom oligopeptidases in which the enzymes provide additional substrates for each other following their initial competitive attack on the neuropeptide. A possible explanation is that the system is intended to ensure a steady release of Tyr, GlyGly and PheMet over time. Significantly, Tyr is the favoured substrate of the L-amino acid oxidase present in the venom, which rapidly transforms this aromatic amino acid into phenolic derivatives. The efficacies of these inhibitors also suggest that there are similarities between the venom oligopeptidases and the peptidases associated with the processing of enkephalin in its normal contexts.

Aminopeptidases↗
PubMed1998

Conversion of tyrosine to phenolic derivatives by Taiwan cobra venom.

We have examined the ability of Taiwan cobra (Naja naja atra) venom to transform in vitro the amino acid tyrosine to phenolic oxidation products via 4-hydroxyphenylpyruvate. This amino acid can be released from neuropeptide substrates by oligopeptidases present in the venom. Using a variety of analytical techniques to probe a complicated series of reactions, we confirm that the L-amino acid oxidase present in the venom initially releases the keto form of 4-hydroxyphenylpyruvic acid and hydrogen peroxide after reacting with the tyrosine. Thereafter, there is evidence that a tautomerase in the venom promotes a partial conversion of the keto-form 4-hydroxyphenylpyruvic acid into an enol form. The enol is oxidised primarily to 4-hydroxybenzaldehyde and 4-hydroxyphenol (hydroquinone). The keto form is oxidised through to 4-hydroxyphenylacetic acid by the hydrogen peroxide co-released by the L-amino acid oxidase. The venom promotes both these spontaneous oxidation routes and also generates traces of other phenolics, some of which are as yet unidentified. We propose that reactions between the precursors of the major oxidation products may be responsible for generating unusual short-lived phenolics, possibly giving rise to special bioactivities that are relevant to venom action.

Amino Acid Sequence↗
PubMed1998

Development and evaluation of a new alcohol-based surgical hand scrub formulation with persistent antimicrobial characteristics and brushless application.

BACKGROUND: Since the introduction in the 1970s of surgical hand scrub formulations that contain 4% chlorhexidine gluconate (CHG), new surgical scrub formulations that have improved efficacy, persistence, or significantly improved use characteristics have not been forthcoming. In addition, the manufacturer's labeling for popular hand scrub products generally requires scrub times in excess of 6 minutes, whereas current practical needs call for products with substantially shorter scrub times. A new alcohol-based surgical scrub formulation, which has ingredients that provide emollient, surfactant, and antimicrobial persistence characteristics to complement the rapid and broad-spectrum antiseptic qualities of alcohol, has been developed in an effort to address these current practical needs. METHODS: The relative efficacy of a new alcohol-based surgical scrub formulation that contains ingredients that provide surfactant and antimicrobial persistence characteristics was compared with that of commercial 4% CHG and 7.5% povidone iodine (PVPI) formulations with use of human subjects. Hand antimicrobial count sampling was performed by using standardized "glove juice" methodology. RESULTS: The efficacy and persistence results of the new formulation showed statistically significant improvement over both CHG and PVPI at a substantially lessened scrub time (3 minutes). In addition, use of the new formulation without a scrub brush produced results statistically similar to 3-minute applications with either a brush or a sponge. CONCLUSIONS: The new alcohol-based formulation demonstrates promise as a new surgical hand scrub formulation with antimicrobial and use characteristics that are significantly improved over current CHG and PVPI formulations. These studies demonstrate the suitability of this formulation for use as a surgical hand scrub and for brushless application.

Administration, Topical↗
PubMed1998

A comparison of midazolam co-induction with propofol predosing for induction of anaesthesia.

In a double-blind, placebo-controlled study of 90 ASA 1 and 2 patients scheduled for elective surgery we compared the effect of pre-administering midazolam 2 mg or propofol 30 mg on the dose of propofol subsequently required to induce anaesthesia. Using loss of response to verbal command and tolerance to placement of a facemask as end-points, the dose of propofol required to induce anaesthesia was significantly smaller in the patients given propofol (1.87 mg.kg-1) or midazolam (1.71 mg.kg-1) when compared to the control group (2.38 mg.kg-1). Although the decrease in blood pressure following induction was no difference between the two study groups and the decrease was felt not to be of clinical significance in this group of patients. As propofol is presented ' ... for use in a single patient only' and the technique of predosing with propofol allowed induction of all patients with less than 200 mg (a single ampoule), we question on a cost basis whether midazolam co-induction is necessary to reduce propofol induction doses.

Adjuvants, Anesthesia↗
PubMed1998

The effects of coital lubricants on sperm motility in vitro.

Infertility affects approximately 15% of couples, and in about one-third the primary cause is a male factor. Patients undergoing infertility investigations frequently experience sexual dysfunction, which often is due to inadequate vaginal lubrication. This can lead to increased use of coital lubricants. The effects of such lubricants on sperm motility have not been widely studied, although sperm motility is one of the best prognostic indicators of fertilization. Using a prospective longitudinal control-based study, we analysed the effect of adding four lubricants: KY jelly, baby oil, olive oil and saliva on sperm motion in 16 samples from patients undergoing infertility investigations. Sperm samples were prepared by density gradient centrifugation prior to mixing with lubricants. Motility parameters were determined using computer-assisted semen analysis after 5, 15 and 30 min. All lubricants except baby oil significantly decreased percentage progressive motility, progressive velocity, curvilinear velocity and lateral head displacement at 12.5% concentration. At a lower concentration of 6.25%, both olive oil and saliva still significantly reduced progressive motility parameters, while KY jelly diminished head movement parameters. Hence, even at these very low concentrations, coital lubricants impair sperm motility and thus may adversely affect fertility.

Cellulose↗
PubMed1998

Concomitant irradiation and dose-escalating carboplatin for locally advanced carcinoma of the uterine cervix: an updated report.

The combination of radiotherapy and carboplatin is associated with high response rates among women who have cervical cancer. To improve control rates for patients who have locally advanced carcinoma of the uterine cervix, oncologists have explored combinations of radiotherapy and chemotherapy. Carboplatin is an analogue of cisplatin, with similar efficacy against cervix cancer and a toxicity profile that is theoretically appealing for this group of patients because it is not nephrotoxic. Fifteen women with International Federation of Gynecology and Obstetrics (FIGO) stages IB2 through IIIB or recurrent carcinoma of the cervix were treated with megavoltage irradiation and weekly intravenous carboplatin (7 women, 60 mg/m2; 8 women, 90 mg/m2). Response was documented among all patients treated at 60 mg/m2 (three complete responses, four partial responses) and in 6 women treated with 90 mg/m2 (four complete responses, two partial responses). The two nonresponders in the series presented with recurrent glassy cell carcinoma of the cervix. All patients completed the planned course of therapy without the need for treatment interruption. At 60 mg/m2, one dose of carboplatin was withheld because of grade 2 thrombocytopenia. At 90 mg/m2, one case of grade 2 leukopenia was documented. The leukocyte counts remained within normal limits for all 3 patients who were irradiated through extended portals that encompassed the paraaortic nodes (2 women, 60 mg/m2; 1 woman, 90 mg/m2). To date, 2 of 7 patients treated at the lower dose level have died of disease (one local progression and distant failure at 11 months, one distant failure alone at 6 months). The remaining patients treated at 60 mg/m2 are alive at a median of 24 months (range, 21-37 months). Among those treated at the higher dose level, 1 patient is alive with local and distant failure at 14 months, and 1 woman succumbed to local and distant disease at 4 months. The remainder are alive at a median follow-up of 6 months (range, 2-10 months). The regimen was unsuccessful in salvaging women with recurrent glassy cell carcinoma. We conclude that the combination of radiotherapy and carboplatin can be safely delivered at both of the chemotherapy schedules studied. The regimen should not be offered to women who have recurrent glassy cell tumors. To prove the efficacy of this approach, phase III testing should be considered that compares the combination of agents to irradiation alone.

Adult↗
PubMed1998

Agonist-induced endocytosis and recycling of the gonadotropin-releasing hormone receptor: effect of beta-arrestin on internalization kinetics.

This study examined the dynamics of endocytotic and recycling events associated with the GnRH receptor, a unique G protein-coupled receptor (GPCR) without the intracellular carboxyl-terminal tail, after agonist stimulation, and investigated the role of beta-arrestin in this process. Subcellular location of fluorescently labeled epitope-tagged GnRH receptors stably expressed in HEK 293 cells was monitored by confocal microscopy, and the receptor/ligand internalization process was quantified using radioligand binding and ELISA. Agonist stimulation resulted in reversible receptor redistribution from the plasma membrane into the cytoplasmic compartment, and colocalization of internalized GnRH receptors with transferrin receptors was observed. Internalization experiments for the GnRH receptor and another GPCR possessing a carboxy-terminal tail, the TRH receptor, showed that the rate of internalization for the GnRH receptor was much slower than for the TRH receptor when expressed in both HEK 293 and COS-7 cells. TRH receptor internalization could be substantially increased by coexpression with beta-arrestin in COS-7 cells, while GnRH receptor internalization was not affected by coexpression with beta-arrestin in either cell type. Coexpression of the GnRH receptor with the dominant negative beta-arrestin (319-418) mutant did not affect its ability to internalize, and activated GnRH receptors did not induce time-dependent redistribution of beta-arrestin/green fluorescent protein to the plasma membrane. However, the beta-arrestin mutant impaired the internalization of the TRH receptor, and activated TRH receptors induced the beta-arrestin/green fluorescent protein translocation. This study demonstrates that, despite having no intracellular carboxy-terminal tail, the GnRH receptor undergoes agonist-stimulated internalization displaying distinctive characteristics described for other GPCRs that internalize via a clathrin-dependent mechanism and recycle through an acidified endosomal compartment. However, our data indicate that the GnRH receptor may utilize a beta-arrestin-independent endocytotic pathway.

Animals↗
PubMed1998

Mechanisms of progressive glomerular injury in membranous nephropathy.

Glomerular function and structure were serially evaluated in 15 patients with membranous nephropathy who exhibited relapsing nephrosis and chronic depression of GFR. GFR declined from 56+/-8 (mean+/-SEM) at onset to 31+/-4 ml/min per 1.73 m2 after a 2- to 5-yr period of observation (P < 0.05). An analysis of filtration dynamics suggested persistent elevation of net ultrafiltration pressure. To examine a possible role for declining intrinsic glomerular filtration capacity as the basis for the observed hypofiltration, glomeruli in the baseline and a repeat biopsy (performed after a median of 28 mo) were subjected to morphometric analysis and mathematical modeling. Analysis of the baseline biopsy revealed a reduction in filtration slit frequency and thickening of the glomerular basement membrane, lowering computed hydraulic permeability by 66% compared with normal kidney donors. In contrast, filtration surface area was increased by 37% as a result of glomerular hypertrophy. The repeat biopsy revealed persistent depression of hydraulic permeability, primarily owing to foot process broadening. An additional finding was a decrease in filtration surface area from baseline in patent glomeruli, possibly due to encroachment on the capillary lumen of an increasingly widened basement membrane. Also, a striking increase in the prevalence of global glomerulosclerosis from 7+/-2% to 23+/-4% was found between the two biopsies, suggesting a significant loss of functioning nephrons. It is concluded that hypofiltration in membranous nephropathy is the consequence of a biphasic loss of glomerular ultrafiltration capacity, initially owing to impaired hydraulic permeability that is later exacerbated by a superimposed loss of functioning glomeruli and of filtration surface area.

Adult↗