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Biomedical subjects

B Bowen

Publications and source records attributed to B Bowen.

At least 19 recordsLinked to original sources
PubMed2003

Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib.

BACKGROUND: Cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs are intended to preserve cyclo-oxygenase-1-mediated gastroprotection and platelet function, whilst inhibiting cyclo-oxygenase-2-mediated inflammation. AIM: To assess the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib vs. non-selective non-steroidal anti-inflammatory drugs. METHODS: Two randomized, double-blind, placebo- and active-controlled studies were performed: (i) daily faecal red blood cell loss was measured in 62 subjects receiving etoricoxib (120 mg once daily), ibuprofen (800 mg t.d.s.) or placebo for 28 days; (ii) the incidence of endoscopically detectable gastric/duodenal ulcers was determined in 742 osteoarthritis or rheumatoid arthritis patients receiving etoricoxib (120 mg once daily), naproxen (500 mg b.d.) or placebo over 12 weeks. RESULTS: In the first study, the between-treatment ratio of faecal blood loss for etoricoxib vs. placebo (1.06) was not significantly different from unity; however, the ratios for ibuprofen vs. placebo (3.26) and etoricoxib (3.08) were significantly greater than unity (P < 0.001). In the second study, the incidence of ulcers of > or = 3 mm with naproxen (25.3%) was significantly higher than that with etoricoxib (7.4%) or placebo (1.4%; P < 0.001); the results were similar for ulcers of > or = 5 mm. CONCLUSIONS: The reduced toxicity of etoricoxib (less faecal blood loss and fewer endoscopically detectable lesions) suggests that use of this drug will may be associated with a reduced incidence of gastrointestinal perforations, ulcers and bleeds.

Adolescent↗
PubMed2001

A review of the reported defects in the human C1 esterase inhibitor gene producing hereditary angioedema including four new mutations.

C1 esterase inhibitor (C1INH) is an important regulatory protein of the classical pathway of complement. Mutations in the gene for this protein cause the autosomal dominant disorder hereditary angioedema (HAE). Approximately 85% of patients with HAE have a Type I defect, characterized by a diminished level of antigenic and functional C1INH. Patients with Type II defects have sufficient protein, but one allele produces dysfunctional protein. We have sequenced the DNA from HAE patients and have discovered four previously unreported mutations. The first mutation is a splice site error at nucleotide 8721, which changes the 3' acceptor splice site AG to GG at the end of intron 5 at nucleotide 8721-8722. The second mutation is a single base insertion in exon 3 between nucleotides 2467 and 2468. The third mutation is a missense error present in the eighth exon of the C1INH; at nucleotide 16867 (amino acid 470), a T to A mutation transforms a Met to a Lys. The fourth mutation closely resembles the third mutation in that it is a missense error occurring in exon 8 in the distal hinge region; a T16827C substitution changes the Phe at amino acid 457 to Leu. This report compiles a list of 97 distinct defects in the C1INH gene that cause hereditary angioedema.

Amino Acid Substitution↗
PubMed2001

Multiple regulators of Ty1 transposition in Saccharomyces cerevisiae have conserved roles in genome maintenance.

Most Ty1 retrotransposons in the genome of Saccharomyces cerevisiae are transpositionally competent but rarely transpose. We screened yeast mutagenized by insertion of the mTn3-lacZ/LEU2 transposon for mutations that result in elevated Ty1 cDNA-mediated mobility, which occurs by cDNA integration or recombination. Here, we describe the characterization of mTn3 insertions in 21 RTT (regulation of Ty1 transposition) genes that result in 5- to 111-fold increases in Ty1 mobility. These 21 RTT genes are EST2, RRM3, NUT2, RAD57, RRD2, RAD50, SGS1, TEL1, SAE2, MED1, MRE11, SCH9, KAP122, and 8 previously uncharacterized genes. Disruption of RTT genes did not significantly increase Ty1 RNA levels but did enhance Ty1 cDNA levels, suggesting that most RTT gene products act at a step after mRNA accumulation but before cDNA integration. The rtt mutations had widely varying effects on integration of Ty1 at preferred target sites. Mutations in RTT101 and NUT2 dramatically stimulated Ty1 integration upstream of tRNA genes. In contrast, a mutation in RRM3 increased Ty1 mobility >100-fold without increasing integration upstream of tRNA genes. The regulation of Ty1 transposition by components of fundamental pathways required for genome maintenance suggests that Ty1 and yeast have coevolved to link transpositional dormancy to the integrity of the genome.

Blotting, Northern↗
PubMed2001

Measuring population health risks using inpatient diagnoses and outpatient pharmacy data.

OBJECTIVE: To examine and evaluate models that use inpatient encounter data and outpatient pharmacy claims data to predict future health care expenditures. DATA SOURCES/STUDY DESIGN: The study group was the privately insured under-65 population in the 1997 and 1998 MEDSTAT Market Scan (R) Research Database. Pharmacy and disease profiles, created from pharmacy claims and inpatient encounter data, respectively, were used separately and in combination to predict each individual's subsequent-year health care expenditures. PRINCIPAL FINDINGS: The inpatient-diagnosis model predicts well for the low-hospitalization under-65 populations, explaining 8.4 percent of future individual total cost variation. The pharmacy-based and in patient-diagnosis models perform comparably overall, with pharmacy data better able to split off a group of truly low-cost people and inpatient diagnoses better able to find a small group with extremely high future costs. The model th at uses both kinds of data performed significantly better than either model alone, with an R2 value of 11.8 percent . CONCLUSIONS: Comprehensive pharmacy and inpatient diagnosis classification systems are each helpful for discriminating among people according to their expected costs. Properly organized and in combination these data are promising predictors of future costs.

Adolescent↗
PubMed2000

Identification of the residues in the Myb domain of maize C1 that specify the interaction with the bHLH cofactor R.

The maize Myb transcription factor C1 depends on the basic helix-loop-helix (bHLH) proteins R or B for regulatory function, but the closely related Myb protein P does not. We have used the similarity between the Myb domains of C1 and P to identify residues that specify the interaction between the Myb domain of C1 and the N-terminal region of R. Substitution of four predicted solvent-exposed residues in the first helix of the second Myb repeat of P with corresponding residues from C1 is sufficient to confer on P the ability to physically interact with R. However, two additional Myb domain amino acid changes are needed to make the P regulatory activity partially dependent on R in maize cells. Interestingly, when P is altered so that it interacts with R, it can activate the Bz1 promoter, normally regulated by C1 + R but not by P. Together, these findings demonstrate that the change of a few amino acids within highly similar Myb domains can mediate differential interactions with a transcriptional coregulator that plays a central role in the regulatory specificity of C1, and that Myb domains play important roles in combinatorial transcriptional regulation.

Amino Acid Sequence↗
PubMed2000

A randomized trial measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects.

PURPOSE: Gastrointestinal microbleeding, as assessed by the measurement of (51)chromium-labeled red blood cells, is a marker of the mucosal injury associated with the use of nonsteroidal anti-inflammatory drugs. This study tested the hypotheses that cyclooxygenase-2 specific inhibition with rofecoxib would cause less fecal blood loss than a therapeutic dose of ibuprofen and would be equivalent to placebo. SUBJECTS AND METHODS: In this randomized, double-blind group study, gastrointestinal blood loss was assessed by measurement of fecal (51)chromium radioactivity during a 1-week placebo baseline period and during 4 weeks of treatment with rofecoxib (25 mg or 50 mg once daily), ibuprofen (800 mg three times daily), or placebo in 67 healthy subjects. Gastrointestinal blood loss during treatment weeks 2 to 4 (versus the baseline period) was expressed as the geometric mean ratio of fecal radioactivity in weeks 2 to 4 compared with baseline. RESULTS: Ibuprofen caused significantly (P <0.001) greater gastrointestinal blood loss (geometric mean ratio of 5.2, 95% confidence interval [CI]: 4.2 to 6.3) than the 25-mg dose of rofecoxib (2.6, 95% CI: 2.2 to 3.1), the 50-mg dose of rofecoxib (2.6, 95% CI: 2.2 to 3.0), or placebo (2.1, 95% CI: 1.8 to 2.5). In contrast, gastrointestinal blood loss with both doses of rofecoxib were equivalent to placebo by a predetermined clinical similarity bound. CONCLUSIONS: In healthy subjects, treatment with rofecoxib, at 2 to 4 times the doses that are currently recommended for the treatment of patients with osteoarthritis, produced significantly less fecal blood loss than a therapeutic dose of ibuprofen and was equivalent to placebo.

Adult↗
PubMed2000

Complex structure of a maize Myb gene promoter: functional analysis in transgenic plants.

The maize P gene encodes a Myb-like transcription factor that regulates synthesis of red flavonoid pigments in floral organs. To study the transcriptional regulation of the P gene, candidate regulatory sequences of the P1-rr gene promoter were identified by Ac insertional mutagenesis and subjected to functional testing in transgenic maize plants. The results indicate that a 561 bp fragment (Pb) encompassing the transcription start site (-235 to +326) supports weak expression of a GUS reporter gene in floral organs, including husk, silk, kernel pericarp, cob and male inflorescence. Two other fragments, located approximately 1 and 5 kb 5' of the transcription start site, increased the levels of GUS activity in floral tissues and thus appear to contain enhancer elements. All of the tested constructs gave similar patterns of GUS expression, suggesting that the 561 bp Pb fragment that is common among the transgene constructs contains regulatory elements that promote activation in floral organs. The basal promoter and proximal enhancer fragments contain putative binding sites for bZip regulatory factors, and a complex arrangement of palindromes including a large inverted repeat of two tRNA-like genes. Possibly, interconversions between linear and cruciform conformations of the palindromes may affect protein/DNA interactions and thereby modulate P1-rr expression.

Base Sequence↗
PubMed2000

Expression profiling of the maize flavonoid pathway genes controlled by estradiol-inducible transcription factors CRC and P.

To determine the scope of gene expression controlled by the maize transcription factors C1/R and P, which are responsible for activating flavonoid synthesis, we used GeneCalling, an open-ended, gel-based, mRNA-profiling technology, to analyze cell suspension lines of the maize inbred Black Mexican Sweet (BMS) that harbored estradiol-inducible versions of these factors. BMS cells were transformed with a continually expressed estrogen receptor/maize C1 activator domain fusion gene (ER-C1) and either a fusion of C1 and R (CRC), P, or luciferase genes regulated by a promoter containing four repeats of an estrogen receptor binding site. Increasing amounts of luciferase activity, anthocyanins, and flavan-4-ols were detected in the respective cell lines after the addition of estradiol. The expression of both known and novel genes was detected simultaneously in these BMS lines by profiling the mRNA isolated from replicate samples at 0, 6, and 24 hr after estradiol treatment. Numerous cDNA fragments were identified that showed a twofold or greater difference in abundance at 6 and 24 hr than at 0 hr. The cDNA fragments from the known flavonoid genes, except chalcone isomerase (chi1), were induced in the CRC-expressing line after hormone induction, whereas only the chalcone synthase (c2) and flavanone/dihydroflavonol reductase (a1) genes were induced in the P-expressing line, as was expected. Many novel cDNA fragments were also induced or repressed by lines expressing CRC alone, P alone, or both transcription factors in unique temporal patterns. The temporal differences and the evidence of repression indicate a more diverse set of regulatory controls by CRC or P than originally expected. GeneCalling analysis was successful in detecting members of complex metabolic pathways and uncovering novel genes that were either coincidentally regulated or directly involved in such pathways.

Artificial Gene Fusion↗
PubMed2000

Electromyography during stereotactic pallidotomy for Parkinson's disease.

In stereotactic pallidotomy for Parkinson's disease, care must be taken to avoid internal capsule injury while maximizing improvement of rigidity and tremor. In 21 patients, intraoperative electromyography (EMG) was used to assess stimulation thresholds required for capsular responses and to monitor muscle tone and tremor. Surface EMG electrodes were placed on the face and multiple muscle groups of the extremities. The stimulation and lesion electrode was introduced via MRI-guided stereotaxis toward a point 2-3 mm anterior to the midcommissural point, 5-6 mm inferior to the AC-PC plane, and 21-22 mm lateral to the midline. Exact targets were modified according to MRI-visualized anatomy. With stimulation at 5 and 50 Hz, thresholds for detection of EMG responses were usually seen at 4-5 mA. EMG responses were consistently seen prior to visual observation of muscle activity. Timing of EMG response relative to stimulus aided in differentiating stimulus-related movement from spontaneous tremor. Resting spontaneous EMG activity was seen to decrease as rigidity was improved by incremental lesion production. EMG activity related to tremor was recorded; tremor decrease by lesion production was documented by EMG recording. Patient cooperation with physiologic testing during stimulation and lesion production may become limited. Intraoperative EMG monitoring provides an adjunct to improve reliability of assessment of capsular stimulation and rigidity while providing documentation of lesion impact on rigidity and tremor.

Aged↗
PubMed1999

Targeted manipulation of maize genes in vivo using chimeric RNA/DNA oligonucleotides.

Site-specific heritable mutations in maize genes were engineered by introducing chimeric RNA/DNA oligonucleotides. Two independent targets within the endogenous maize acetohydroxyacid synthase gene sequence were modified in a site-specific fashion, thereby conferring resistance to either imidazolinone or sulfonylurea herbicides. Similarly, an engineered green fluorescence protein transgene was site-specifically modified in vivo. Expression of the introduced inactive green fluorescence protein was restored, and plants containing the modified transgene were regenerated. Progeny analysis indicated Mendelian transmission of the converted transgene. The efficiency of gene conversion mediated by chimeric oligonucleotides in maize was estimated as 10(-4), which is 1-3 orders of magnitude higher than frequencies reported for gene targeting by homologous recombination in plants. The heritable changes in maize genes engineered by this approach create opportunities for basic studies of plant gene function and agricultural trait manipulation and also provide a system for studying mismatch repair mechanisms in maize.

Acetolactate Synthase↗
PubMed1999

Characterization of the regulatory elements of the maize P-rr gene by transient expression assays.

The maize P-rr gene conditions floral-specific flavonoid pigmentation, especially in the kernel pericarp and cob. We analyzed the P-rr promoter by transient expression assays, in which segments of the P-rr promoter were fused to the GUS reporter gene and introduced into maize cells by particle bombardment. A basal P-rr promoter fragment (-235 to +326) gave low, but significant, levels of GUS reporter gene expression. Interestingly, two widely spaced segments containing enhancer-like activity were found. When tested individually, both the proximal (-1252 to -236) and distal (-6110 to -4842) segments boosted expression of the basal P-rr promoter::GUS construct about five-fold. A 1.6 kb segment of the P-rr promoter (-1252 to +326) containing the proximal enhancer and the 5'-untranslated leader driving the GUS reporter gene showed preferential expression in BMS and embryogenic suspension cell cultures vs. endosperm-derived suspension cell cultures. These results demonstrate the application of transient assay techniques for the identification of regulatory elements responsible for floral-specific regulation of the complex P-rr gene promoter in maize.

DNA, Plant↗
PubMed1999

Estimation of pulmonary deposition of aerosol using gamma scintigraphy.

Following delivery of technetium 99m-labeled aerosols through a ventilator circuit, the amount of radioactivity in the lungs of 58 ventilated rabbits was estimated first by gamma scintigraphy via gamma camera and later by direct counting of the excised lungs (n = 116 specimens) with a gamma counter. The in situ radioactivity measured via scintigraphy was closely correlated with the gamma counter ex vivo tissue counts of the radioactivity (R2 = 0.997, P < 0.001). Overall, gamma scintigraphy gave slightly lower values of activity than the tissue counts from the gamma counter, but the limits of agreement between the two measurements were narrow enough for us to consider that the tissue and scintigraphy methods were in agreement. We conclude that gamma scintigraphy provides a convenient and noninvasive means for the accurate estimation of aerosol deposition in the lungs of small animals and possibly in small infants.

Aerosols↗
PubMed1999

Maize R2R3 Myb genes: Sequence analysis reveals amplification in the higher plants.

Transcription factors containing the Myb-homologous DNA-binding domain are widely found in eukaryotes. In plants, R2R3 Myb-domain proteins are involved in the control of form and metabolism. The Arabidopsis genome harbors >100 R2R3 Myb genes, but few have been found in monocots, animals, and fungi. Using RT-PCR from different maize organs, we cloned 480 fragments corresponding to a 42-44 residue-long sequence spanning the region between the conserved DNA-recognition helices (Myb(BRH)) of R2R3 Myb domains. We determined that maize expresses >80 different R2R3 Myb genes, and evolutionary distances among maize Myb(BRH) sequences indicate that most of the amplification of the R2R3 Myb gene family occurred after the origin of land plants but prior to the separation of monocots and dicots. In addition, evidence is provided for the very recent duplication of particular classes of R2R3 Myb genes in the grasses. Together, these findings render a novel line of evidence for the amplification of the R2R3 Myb gene family in the early history of land plants and suggest that maize provides a possible model system to examine the hypothesis that the expansion of Myb genes is associated with the regulation of novel plant cellular functions.

Amino Acid Sequence↗