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R J Anderson

Publications and source records attributed to R J Anderson.

At least 91 records · Page 5Linked to original sources
PubMed1997

Characterization of recombinant human liver dehydroepiandrosterone sulfotransferase with minoxidil as the substrate.

Biotransformation of xenobiotics and hormones through sulfate conjugation is an important metabolic pathway in humans. The activation of minoxidil, an antihypertensive agent and hair growth stimulator, by sulfation (sulfonation) is carried out by more than one sulfotransferase. Initially only the thermostable form of phenol sulfotransferase was thought to catalyze minoxidil sulfation. We document in this report the new finding that human liver dehydroepiandrosterone sulfotransferase (DHEAST), an hydroxysteroid sulfotransferase distinct from phenol sulfotransferases, also catalyzes the reaction. To characterize more precisely the activity of DHEA ST toward minoxidil, we used COS-1 cells to express DHEA ST from a human liver cDNA clone. The apparent Km values for minoxidil and [35S]3'-phosphoadenosine-5'-phosphosulfate were 3.9 mM and 0.13 microM, respectively. The 50% inactivation temperature of the COS-expressed enzyme was 42 degrees, and the IC50 value for 2,6-dichloro-4-nitrophenol was 1.4 x 10(-4) M. Both the thermal stability behavior and response to DCNP were similar when the cDNA encoded DHEA ST was assayed with DHEA or minoxidil as a substrate. NaCl led to a greater activation of the cDNA expressed DHEA ST when assayed with DHEA (2.5-fold) than when the same preparation was assayed with minoxidil (1.4-fold). These data indicate that DHEA ST catalyzes the sulfate conjugation of minoxidil: DHEA ST activity present in the human gut and liver would be expected to add to the overall sulfate conjugation of orally administered minoxidil. Thus, DHEA ST activity must be considered when determining the human tissue sulfotransferase contribution to minoxidil sulfation.

Animals↗
PubMed1997

Relationship between difficulty in performing daily activities and clinical measures of visual function in patients with retinitis pigmentosa.

OBJECTIVES: To assess the level of perceived difficulty experienced by patients with retinitis pigmentosa (RP) in the performance of everyday activities and to determine the correlation between patients' self-reported difficulty and clinical measures of visual function. METHODS: One hundred sixty-seven patients with typical RP and Usher syndrome type 2, with a wide range of disease severity, rated their difficulty in the performance of 33 activities. We obtained data on visual acuity and visual field area for all patients, and electroretinogram (ERG) recordings on a subgroup of 49 of these patients. Results from the questionnaire were analyzed with factor analysis, and patients' self-reports were compared with their clinical data using correlational analyses and multiple regression. RESULTS: The patients' questionnaire responses clustered into 6 factors: activities involving central vision, miscellaneous activities (no discernible common factor), activities related to mobility, driving, negotiating steps, and eating meals. Of the clinical tests, visual acuity was most strongly related to the patients' ratings of their difficulty in performance. Visual field area also was related to patients' self-assessments but not as strongly as visual acuity. Because visual field area and the ERG measures were correlated, adding ERG information did not improve predictability. CONCLUSIONS: In patients with RP, perceived difficulty in performing common tasks was most strongly related to level of visual acuity and visual fields. Although certain ERG amplitude measures did show positive correlations with some self-reported activities, overall, the ERG amplitude measures showed the least relationship with patients' self-reports. Our results provide insight into RP patients' perceived difficulties in performing everyday activities and the clinical measures of visual function that most highly correlate with these difficulties.

Activities of Daily Living↗
PubMed1997

Stress among package truck drivers.

In 1992, a cross-sectional questionnaire study of package truck drivers in one company was conducted at four widely scattered sites throughout the US; 317 drivers participated, representing 82% of those eligible. The package truck drivers scored significantly above the US working population comparison norm on all summary and individual scales derived from the SCL 90-R, indicating a substantial increase in psychologic distress for this group. The Global Severity Index, the best single summary measure of psychological distress in the SCL 90-R, revealed a mean T score for the drivers of 64.20, 91st percentile of the normative population. The group perceived significantly more daily stressful events than the average working adult, and their sensitivity to these events was also increased. Role overload, a component of the Occupational Stress Inventory, was the most consistent factor associated with symptoms of psychological distress on multiple regression analysis. This study suggests that job stress is a psychological health hazard for these drivers.

Adult↗
PubMed1997

Mechanisms of alcohol impairment of recovery from mechanically denuded areas made within cultured rat hepatocytes.

The effect of ethanol on the ability of a denuded hepatocyte cell surface to recover is unknown. We therefore determined the effect of ethanol on the rate of renewal of mechanical wounds made in near-confluent monolayers of primary cultures of rat hepatocytes. We found that ethanol exerted a dose-dependent effect to impair rat hepatocyte recovery and that at least 12 hours of exposure to ethanol was required to induce this impairment. The effect of ethanol to impair recovery of denuded areas of epithelium was not seen in two established renal tubular epithelial cell lines. Ethanol impairment of rat hepatocyte recovery could be blocked by an alcohol dehydrogenase inhibitor (4-methyl pyrazole) and potentiated by an inhibitor of aldehyde dehydrogenase (pargyline). The effect of ethanol to inhibit rat hepatocyte recovery of denuded areas was not associated with any change in hepatocyte cell surface expression of the beta1 integrin subunit as determined by flow cytometry. These results suggest that acetaldehyde is responsible for ethanol inhibition of hepatocyte recovery from mechanical injury and that this impairment occurs independent of cell surface expression of the beta1 integrin subunit.

Animals↗
PubMed1997

Rate of visual field loss in retinitis pigmentosa.

PURPOSE: The authors quantitate the rate of visual field loss in patients with retinitis pigmentosa as it relates to different clinical field phenotypes. PATIENTS AND METHODS: Goldmann visual fields were obtained with target V4e in 77 patients and with target II4e in 71 patients who had either isolated or various genetic types of retinitis pigmentosa and who met certain entrance criteria. The visual fields were categorized into five distinct clinical field phenotypes on the basis of their pattern of field loss. Mixed-model methods for the analysis of longitudinal data were used to model the natural logarithm of the visual field area as a function of patient age and clinical field phenotype. The average half-life (time over which half of the remaining field area would be lost) of the visual field area for each phenotype was computed from the results of this analysis. Visual field data were not analyzed for patients with a normal clinical field phenotype (type 1). RESULTS: Independent of the field phenotype, average half-life values were 7.3 years for target V4e and 6.8 years for target II4e, which were not statistically different (P = 0.16). Visual fields with partial or complete midperipheral ring scotomas (type 2) and those with only a residual central field (type 4) had a half-life of 9.5 and 9.4 years, respectively, for target V4e, and 8.9 and 8.0 years, respectively, for target II4e. Patients with partial peripheral restriction (type 5) lost visual fields with a half-life of 9.5 years for target V4e and 7.3 years for target II4e. None of these differences in the half-lives between the different phenotypes were statistically significant for either targets V4e or II4e. Fields with a residual central area and remaining temporal and/or nasal islands (type 3) had a half-life of 4.8 years for target V4e and 6.0 years for target II4e. The differences in half-lives between type 3 and each of the other field phenotypes were statistically significant for the V4e target, but not for the II4e target. CONCLUSIONS: The results of this study can be useful for counseling patients with retinitis pigmentosa and various visual field phenotypes as to their potential rate of visual field loss.

Half-Life↗
PubMed1997

Familial neuroendocrine tumors as a model of hereditary cancer.

Familial neuroendocrine tumors are reviewed. The most dramatic advances have been in the application of molecular genetic techniques to define the affected genes and to develop predictive testing for patients with multiple endocrine neoplasia syndromes. Germline mutations at specific loci of the RET proto-oncogene have been demonstrated in patients with multiple endocrine neoplasia types IIA, IIB, and familial medullary thyroid carcinoma not associated with multiple endocrine neoplasia. This has led to direct DNA testing for these mutations in patients at risk for these syndromes. The approach to predictive testing, diagnosis, and early treatment of these patients is discussed as a model for the approach to hereditary cancers. Linkage testing with DNA markers is still required for patients with multiple endocrine neoplasia type I because the responsible gene has not yet been isolated. Efforts to clarify the etiologies of other familial neuroendocrine tumors not associated with multiple endocrine neoplasia continue. Familial pheochromocytoma, neuroblastoma, and carcinoid also are reviewed. The use of molecular genetic techniques as a powerful tool for the early identification and treatment of susceptible individuals is emphasized.

Algorithms↗
PubMed1997

How medical schools can maintain quality while adapting to resource constraints.

To gain a better understanding of the effects on medical schools of ongoing transformations in medical practice, science, and public expectations, the Association of American Medical Colleges (AAMC) formed the Advisory Panel on the Mission and Organization of Medical Schools (APMOMS) in 1994. Six working groups were appointed to address different issues of importance. This article is a report of the findings and recommendations of the Working Group on Adapting to Resource Constraints. That group was charged to consider how leaders in academic medicine can respond to the challenges of external forces and the anticipated diminishing of resources, and to focus on medical schools and how they can maintain quality while reengineering to effect needed changes. The group members developed their thinking within four categories: size of the academic enterprise; organizational models and their relationships to the clinical enterprise; faculty tenure and compensation; and partnerships with capital-intensive entities. Three recommendations for action, to which the APMOMS unanimously agreed, were made to the AAMC, which has already acted upon them in ways described in the article. The group also developed a series of "ideas for consideration," which represent a range of the members' perspectives. The working group did not seek (and probably could not have obtained) unanimous agreement on many of the issues that these ideas focus upon. The ideas are presented as a series of resolutions designed to stimulate discussion and foster better-informed planning.

Education, Medical↗
PubMed1997

Reproducibility of visual acuity measurements in patients with retinitis pigmentosa.

PURPOSE: To establish the normal short-term range of variation in the measurement of visual acuity in patients with retinitis pigmentosa. METHODS: Sixteen patients (31 eyes) with retinitis pigmentosa, whose visual acuity ranged from 20/25 to 20/200, participated in this prospective clinical study. The best-corrected visual acuity in undilated and in dilated conditions was recorded independently by two masked observers on two visits of each patient within a 2-week interval by means of the Early Treatment Diabetic Retinopathy Study charts (The Lighthouse, Long Island City, NY). RESULTS: Using mixed-model analysis, a reasonable upperbound for intervisit (intraobserver) variability of 6.0 letters for the visual acuity of patients with undilated pupils and 6.3 letters for the visual acuity of patients with dilated pupils and the corresponding maximum interobserver variability of visual acuity of 5.7 letters in patients with either undilated or dilated pupils on the Early Treatment Diabetic Retinopathy Study charts were computed. The overall average interobserver and intraobserver variability in visual acuity ranged from 1.3-2.3 letters. CONCLUSIONS: A change in visual acuity of seven letters or more on the standardized Early Treatment Diabetic Retinopathy Study charts may be considered important in patients with retinitis pigmentosa. For these patients with minor lens opacity, visual acuity measurements obtained with undilated and dilated pupils were similar. These findings help to establish guidelines for monitoring the response of visual acuity during any future therapeutic intervention trials or for determining substantial changes in visual acuity over time when the course of visual acuity loss in such patients is monitored.

Adult↗
PubMed1997

Detection of adeno-associated virus type 2 in sorted human bone marrow progenitor cells.

Wild-type adeno-associated virus (wtAAV) is a helper-dependent human parvovirus which has the ability to integrate into the genome of a wide variety of human cells, including those of the hemopoietic lineages. Recombinant adeno-associated virus (rAAV) is becoming a good candidate for virally mediated gene therapy. rAAV is likely to be a safe vector in clinical gene transfer, as it has never been associated with any disease despite previous studies showing that up to 70% of adults are seropositive for wtAAV. Seroconversion appears to occur early in life. wtAAV is an upper respiratory tract virus that is gut secreted, but little is known about the integration of latent wtAAV in hemopoietic lineages. Unlike retroviruses, which have been the most common vehicles for gene transfer to date, wtAAV appears to have a preferred integration site in the target cell which has been termed AAVS1. Several studies have shown that wtAAV can only integrate into only one of the pair of chromosome 19 in a cell. This may have implications for the use of rAAV in gene transfer because patients with latent virus would be refractory to further infection with rAAV. We used a polymerase chain reaction (PCR) assay to detect the presence of wtAAV in the bone marrow samples from 106 patients who presented at our institution. We were able to detect the presence of integrated virus in 18 whole marrow samples. Subsequently CD34+ and CD3+ cell subsets were sorted from the cryopreserved marrow of three PCR-positive individuals to assess integration of virus in these cell lineages. In all three samples tested, we were unable to detect wtAAV virus in the CD34+ hematological precursor cells, but a detectable level of integrated viral DNA was demonstrated in the CD3+ cell fraction. Our findings therefore suggest that CD34+ cells might remain a good target for rAAV-mediated gene transfer despite previous wtAAV infection.

Adolescent↗
PubMed1996

Refined crystal structure of adenylosuccinate synthetase from Escherichia coli complexed with hydantocidin 5'-phosphate, GDP, HPO4(2-), Mg2+, and hadacidin.

A crystal structure of adenylosuccinate synthetase from Escherichia coli, complexed with 5'-phosphate, GDP, HPO4(2-), Mg2+, and hadacidin at 100 K, has been refined to an Rfactor of 0.195 against data to 2.6 A resolution. Bond lengths and angles deviate from expected values by 0.012 A and 1.86 degrees, respectively. Lys 16 and backbone amides 15-17 and 42 interact with the phosphates of GDP, while Ser 414, Asp 333, and backbone amides 331 and 416 interact with the base. Mg2+ is octahedrally coordinated. Oxygen atoms from GDP, phosphate, and hadacidin define the equatorial plane of coordination of the Mg2+, while backbone carbonyl 40 and the side chain of Asp 13 are the apical ligands. HPO4(2-) hydrogen bonds with Lys 16, His 41, backbone amides 13, 40, and 224, and the base moiety of the hydantocidin inhibitor. The carboxylate of hadacidin interacts with Arg 303 and Thr 301; its N-formyl group coordinates to Mg2+, and its hydroxyl group hydrogen bonds with Asp 13. The 5'-phosphate of the hydantocidin inhibitor interacts with Asn 38, Thr 129, and Thr 239 but is approximately 3.5 A from Arg 143 (related by molecular 2-fold symmetry). The base moiety of hydantocidin 5'-phosphate hydrogen bonds to Gln 224 and participates in a hydrogen-bonded network that includes the phosphate molecule, several water molecules, and Asp 13. Hydantocidin 5'-phosphate, GDP, HPO4(2-), and Mg2+ may represent a set of synergistic inhibitors even more effective than the combination of IMP, GDP, NO3-, and Mg2+.

Adenylosuccinate Synthase↗
PubMed1996

Distinct but related human immunodeficiency virus type 1 variant populations in genital secretions and blood.

For a HIV vaccine to be effective, it will be essential that it protect against the virus variants to which individuals are most frequently exposed. HIV-1 is predominantly a sexually acquired virus, thus, variants in genital secretions are a potentially important reservoir of viruses that are transmitted. Because there are no data available on variants in the genital mucosa, we analyzed this provirus population and compared it to the proviruses in the blood of individuals chronically infected with HIV-1. A major genetic difference between variants within a patient were insertions, which were apparently created by duplication of adjacent sequences, that resulted in acquisition of new potential glycosylation sites in V1 and V2. Comparisons of mucosal and PBMC variants suggest that these tissues harbor distinct, but related populations of HIV-1 variants. In two of three patients, the mucosal variants were most closely related to a minor variant genotype in blood. In a third individual, viruses in both tissues were surprisingly homogeneous, but the majority of variants in the cervix encoded a V1 sequence with a predicted glycosylation pattern similar to a minor variant in blood. The V3 sequence patterns of the mucosal isolates indicate they may be predominantly macrophage-tropic viruses.

Adolescent↗
PubMed1996

N-[4-hydroxyphenyl] retinamide in rheumatoid arthritis: a pilot study.

OBJECTIVE: To evaluate the efficacy and tolerability of N-[4 hydroxyphenyl] retinamide (4-HPR), a synthetic retinoid, in the treatment of rheumatoid arthritis (RA). METHODS: An uncontrolled, open clinical trial with synovial biopsy pre- and postmedication to evaluate the clinical effects of 4-HPR as well as its effects on metalloproteinase gene expression. RESULTS: Twelve patients with severe, longstanding RA were enrolled in this study. Six patients withdrew before study completion, 2 because of drug toxicity, 2 because of a flare of RA, and 2 because of intercurrent medical problems. No patient met predetermined Paulus criteria treatment response, and there was no improvement in the laboratory parameters, except for a modest decrease in C-reactive protein. No decrease in messenger RNA for the metalloproteinases collagenase and stromelysin was seen in the 2 patients in whom paired synovial biopsies were obtained. CONCLUSION: No beneficial clinical effect was observed with the retinoid 4-HPR in the treatment of severe, longstanding RA at the 300 mg/day dosage studied. The use of higher dosages is precluded by the observed toxicities. The effect of this drug in patients with early or mild disease was not studied. Although this particular retinoid was not effective in this pilot study, the use of other retinoids in RA should still be considered.

Antineoplastic Agents↗
PubMed1996

Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active ankylosing spondylitis (AS) that is not controlled with nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred sixty-four patients with AS were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on morning stiffness, back pain, and physician and patient global assessments. RESULTS: While longitudinal analysis revealed a trend favoring SSZ in the middle of treatment, no difference was seen at the end of treatment. Response rates were 38.2% for SSZ and 36.1% for placebo (P = 0.73). The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). AS patients with associated peripheral arthritis showed improvement that favored SSZ (P = 0.02). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints. CONCLUSION: SSZ at a dosage of 2,000 mg/day does not seem to be more effective than placebo in the treatment of AS patients with chronic, longstanding disease. SSZ is well tolerated and may be more effective than placebo in the treatment of AS patients with peripheral joint involvement. This effect is more pronounced in treatment of the peripheral arthritis in this subgroup of AS patients.

Adult↗
PubMed1996

Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active psoriatic arthritis (PsA) resistant to nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred twenty-one patients with PsA were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on joint pain/ tenderness and swelling scores and physician and patient global assessments. RESULTS: Longitudinal analysis revealed a trend favoring SSZ treatment (P = 0.13). At the end of treatment, response rates were 57.8% for SSZ compared with 44.6% for placebo (P = 0.05). The Westergren erythrocyte sedimentation rate declined more in the PsA patients taking SSZ than in those taking placebo (P < 0.0001). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints, including dyspepsia, nausea, vomiting, and diarrhea. CONCLUSION: SSZ at a dosage of 2,000 mg/day is well tolerated and may be more effective than placebo in the treatment of patients with PsA.

Adult↗