Level of nicotine replacement during a quit-smoking attempt.
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Cotinine↗
Biomedical subjects
Karen Brown
Publications and source records attributed to Karen Brown.
Tamoxifen DNA damage detected in human endometrium using accelerator mass spectrometry.
This study was aimed to establish whether tamoxifen binds irreversibly to uterine DNA when given to women. Patients were given a single therapeutic dose of [(14)C]tamoxifen citrate orally (20 mg, 0.37 or 1.85 MBq) approximately 18 h prior to hysterectomy or breast surgery. Nonmalignant uterine tissue was separated into myometrium and endometrium. DNA and protein were isolated and bound radiolabel determined by the sensitive technique of accelerator mass spectrometry. Levels of irreversible DNA binding of tamoxifen in the endometrium of treated patients were 237 +/- 77 adducts/10(12) nucleotides (mean +/- SE, n = 10). In myometrial tissues, a similar extent of DNA binding was detected (492 +/- 112 adducts/10(12) nucleotides). Binding of tamoxifen to endometrial and myometrial proteins was 10 +/- 3 and 20 +/- 4 fmol/mg, respectively. In breast tissue, sufficient DNA could not be extracted but protein binding was an order of magnitude higher than that seen with endometrial proteins (358 +/- 81 fmol/mg). These results demonstrate that after oral administration, tamoxifen forms adducts in human uterine DNA but at low numbers relative to those previously reported in women after long-term tamoxifen treatment where levels, when detected, ranged from 15000 to 130000 adducts/10(12) nucleotides. Our findings support the hypothesis that the low level of DNA adducts in human uterus is unlikely to be involved with endometrial cancer development.
Adult↗
Correspondence regarding M. Sharma et al., "Antioxidant inhibits tamoxifen-DNA adducts in endometrial explant culture".
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Antioxidants↗
Take note(s): differential EHR satisfaction with two implementations under one roof.
OBJECTIVE: The aim of this study was to rigorously evaluate perceived differences in satisfaction with an electronic health record (EHR) between residents of two medical specialties who share the same health record, practice location, administration, and information technology support. DESIGN: A cross-sectional survey was used comparing user satisfaction between pediatrics residents and internal medicine residents in an academic practice. MEASUREMENTS: The survey was designed to measure baseline demographic characteristics, attitudes toward computers, general satisfaction with an EHR, and perceived practicality of use, variation from familiar practice, organizational support, and impact on delivery of care. RESULTS: Medicine subjects were similar to pediatrics subjects in baseline demographic characteristics. Satisfaction with the EHR implementation was very high for both sets of subjects, but internal medicine residents were significantly less likely to be satisfied with the EHR implementation (relative risk [RR]=0.84, 95% confidence interval [CI]=0.73-0.98) and considerably less likely to believe that their colleagues were satisfied with it (RR=0.56, 95% CI=0.41-0.77). The only surveyed characteristic independently predicting satisfaction was medical specialty (p=0.04). Medicine subjects were less likely to believe template-based documentation improved their efficiency (RR=0.64, 95% CI=0.46-0.88). They were significantly more likely to believe the system had been designed to improve billing (RR=1.50, 95% CI=1.05-2.04) and not to improve patient care (RR=0.61, 95% CI=0.44-0.85). CONCLUSION: The authors found a difference in satisfaction between internal medicine and pediatrics users of an EHR. Although many potential factors that influence satisfaction were similar between subjects in the two specialties, differences in previous experience may have influenced the results. Medicine residents had more previous experience with a different EHR implementation, which they may have perceived as superior to the one involved in this study. Pediatric residents had more previous experience with structured data entry prior to EHR implementation and more preventive care patient encounters for which structured data entry may be well suited. Since successful implementations generally require satisfied users, understanding what factors affect satisfaction can improve chances of a system's success.
Adult↗
Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study.
BACKGROUND: Stratification for risk of recurrence after a first episode of venous thromboembolism (VTE) would affect the duration of anticoagulant therapy. We aimed to determine the incidence of recurrence of VTE in relation to clinical risk factors and standard laboratory testing for heritable thrombophilic defects. METHODS: We established a database to prospectively follow-up a cohort of unselected patients who had had a first episode of objectively proven VTE. We excluded patients with malignant disease and antiphospholipid syndrome. All patients were offered testing for heritable thrombophilia. FINDINGS: At 2 years, the cumulative recurrence rate in 570 patients was 11%. Incidence was lowest after surgery-related VTE (0%) and highest after unprecipitated VTE (19.4%) (p<0.001). 85% of patients were tested for heritable thrombophilic defects. Recurrence rates were not related to presence or absence of laboratory evidence of heritable thrombophilia (hazard ratio 1.50 [95% CI 0.82-2.77]; p=0.187). In patients with a first event that was unprecipitated or was associated with a non-surgical trigger, recurrence rates did not differ in patients with or without thrombophilia (1.34 [0.73-2.46]; p=0.351). INTERPRETATION: In unselected patients who have had a first episode of VTE, testing for heritable thrombophilia does not allow prediction of recurrent VTE in the first 2 years after anticoagulant therapy is stopped. However, assessment of clinical risk factors associated with the first episode of VTE does predict risk of recurrence. Patients with postoperative VTE have a very low rate of recurrence.
Adult↗
Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans.
In animals, effective immune responses against malignancies and against several infectious pathogens, including malaria, are mediated by T cells. Here we show that a heterologous prime-boost vaccination regime of DNA either intramuscularly or epidermally, followed by intradermal recombinant modified vaccinia virus Ankara (MVA), induces high frequencies of interferon (IFN)-gamma-secreting, antigen-specific T-cell responses in humans to a pre-erythrocytic malaria antigen, thrombospondin-related adhesion protein (TRAP). These responses are five- to tenfold higher than the T-cell responses induced by the DNA vaccine or recombinant MVA vaccine alone, and produce partial protection manifest as delayed parasitemia after sporozoite challenge with a different strain of Plasmodium falciparum. Such heterologous prime-boost immunization approaches may provide a basis for preventative and therapeutic vaccination in humans.
Animals↗
Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand.
The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.
Administration, Oral↗
Structural characterization of carcinogen-modified oligodeoxynucleotide adducts using matrix-assisted laser desorption/ionization mass spectrometry.
The aim of this study was to determine the chemical structure of in vitro 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-modified oligodeoxynucleotides (ODNs) by exonuclease digestion and matrix-assisted laser desorption/ionization mass spectrometry. A single-stranded 11-mer ODN, 5'-d(CCATCGCTACC), was reacted with N-acetoxy-PhIP, resulting in the formation of one major and eight minor PhIP-ODN adducts. A 10 min treatment of the major and one minor PhIP-ODN adduct with a 3'-exonuclease, bovine intestinal mucosa phosphodiesterase (BIMP), and a 5'-exonuclease, bovine spleen phosphodiesterase, results in inhibition of the primary exonuclease activity at deoxyguanosine (dG) producing 5'-d(CCATCG(PhIP)) and 5'-d(G(PhIP)CTACC) product ions, respectively. Post-source decay (PSD) of these enzymatic end products identifies dG as the sole modification site in two 11-mer ODN-PhIP adducts. PSD of the minor PhIP-ODN adduct digestion end product, 5'-d(CCATCG(PhIP)), also reveals that the PhIP adducted guanine moiety is in an oxidized form. Prolonged treatment of the PhIP-ODN adducts at 37 degrees C with BIMP induces a non-specific, or endonuclease, enzymatic activity culminating in the formation of deoxyguanosine 5'-monophosphate-PhIP (5'-dGMP-PhIP). The PSD fragmentation pattern of the 5'-dGMP-PhIP [M + H](+) ion of the major adduct confirms PhIP binds to the C-8 position of dG. For the minor adduct, PSD results suggest that PhIP binds to the C-8 position of an oxidized guanine, supporting the hypothesis that this adduct arises from oxidative degradation, resulting in a spirobisguanidino structure.
Carcinogens↗
DNA adducts formed from 4-hydroxytamoxifen are more mutagenic than those formed by alpha-acetoxytamoxifen in a shuttle vector target gene replicated in human Ad293 cells.
The drug tamoxifen, used to treat breast cancer, causes liver cancer in rats and endometrial cancer in women. Tamoxifen forms liver DNA adducts in both short- and long-term dosing of rodents, and DNA adducts have also been reported in tissues of women undergoing tamoxifen therapy. It is not known if the induction of endometrial cancer in women is through these DNA adducts or through the estrogenic nature of the drug. In this study, we have investigated the mutagenicity of two model reactive intermediates of tamoxifen, alpha-acetoxytamoxifen and 4-hydroxytamoxifen quinone methide (4-OHtamQM). These form the same DNA adducts as those found in tamoxifen-treated rats. The two compounds were used to treat the pSP189 plasmid containing the supF gene, which was replicated in Ad293 cells before being screened in indicator bacteria. Plasmid reacted with 4-OHtamQM was more likely to be mutated (2-7-fold increase) than that reacted with alpha-acetoxytamoxifen, despite having a lower level of DNA damage (12-20-fold less), as assayed by (32)P-postlabeling. The two compounds induced statistically different mutation spectra in the supF gene. The majority of mutations in alpha-acetoxytamoxifen-treated plasmid were GC -->TA transversions while GC-->AT transitions were formed in 4-OHtamQM-treated plasmid. 4-OHTamQM-treated DNA induced a larger proportion of multiple mutations and large deletions compared to alpha-acetoxytamoxifen. Sites of mutational hotspots were observed for both compounds. In conclusion, the quantitatively minor DNA adduct of tamoxifen (dG-N(2)-4-hydroxytamoxifen) is more mutagenic than the major tamoxifen DNA adduct (dG-N(2)-tamoxifen).
Adenosine Triphosphate↗
Benzimidazoles and isosteric compounds as potent and selective factor Xa inhibitors.
Benzimidazoles and their isosteric compounds as factor Xa inhibitors are discussed.
Animals↗
An audit of results of a no-drainage practice policy after hepatectomy.
BACKGROUND: It was hypothesized that routine operative drainage is unnecessary for elective hepatic resection. METHODS: A review was made of the clinical records of patients undergoing liver resection at a tertiary referral hepatobiliary surgery center since the conclusion in April of 1994 of our previous randomized drainage trial. The main outcome measures were operative drainage versus no operative drainage assessed for possible association with diagnoses, extent of hepatectomy, hospital course, and postoperative radiologic percutaneous drainage procedures. RESULTS: Of 1,165 patients, 184 were operatively drained with closed drains according to specific practice criteria and 981 were not subject to operative drainage. Patients who were not operatively drained had length of stay (10.1 days), mortality (2%), and complication rate (34%) comparable with the nondrained patients in the previous randomized trial. Ten percent of these patients required postoperative percutaneous drainage. Patients who were operatively drained were a group who were at higher risk for biliary leakage or infections and consequently had a significantly longer hospital stay, greater mortality, higher complication rate, and required a greater number of percutaneous abdominal drainages. CONCLUSIONS: The 84% of patients not operatively drained had no greater adverse outcome. After hepatic resection, routine drainage of the abdomen is unnecessary.
Adult↗
Strain differences in the response to the 5-HT1A receptor agonist, 8-OH-DPAT.
Fischer and Sprague-Dawley ovariectomized rats were hormonally primed with estradiol benzoate (EB) and progesterone, and the ability of the 5-HT(1A) receptor agonist, (+/-) 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), to inhibit lordosis behavior was examined. Both strains showed rapid inhibition of lordosis behavior following either intraperitoneal or subcutaneous treatment with 8-OH-DPAT. Similarly, in both strains, pretreatment with EB (1 week prior to estrogen and progesterone priming) attenuated the lordosis-inhibiting effects of 8-OH-DPAT. However, Sprague-Dawley females showed a greater decline in lordosis behavior with a lower dose of 8-OH-DPAT than did Fischer females. The strain difference was present in females that had been preprimed with EB as well as in females receiving a single estrogen and progesterone priming. Moreover, strain differences were present across different priming doses of EB. Sprague-Dawley females were also more likely to show flat body posture after injection with 8-OH-DPAT so that the greater sensitivity of this strain to the 5-HT(1A) receptor agonist was not restricted to the drug's effect on lordosis behavior. These findings lead to the suggestion that, relative to Fischer rats, Sprague-Dawley females are more responsive to the 5-HT(1A) receptor agonist. Possible explanations for this strain difference are discussed.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Retropharyngeal hematoma--a rare complication of anticoagulant therapy.
Anticoagulation is routinely employed in cardiac surgery following mechanical valve replacement. Warfarin is the most common agent used for anticoagulation. Bleeding, internal or external, remains the major complication with anticoagulant therapy. The risk is known to be higher with INR levels above 4.5. We report a case of a retropharyngeal hematoma following trivial blunt trauma to a patient whose INR had shot up to 6.8 and also discuss its management.
Anticoagulants↗
Visualizing nuclear proteins together with transcribed and inactive genes in structurally preserved cells.
Recent data support the idea that the mammalian nucleus is organized in a functionally significant way. Immunocytochemistry has revealed the existence of diverse nuclear "bodies" and compartments. Fluorescence in situ hybridization (FISH) has shown that chromosomes change their spatial relationships during dynamic cell cycle progression and that nuclear organization can change during development and differentiation when patterns of gene expression are established or modified. To determine the relationship between nuclear organization and genome function is an important goal for biology. This article describes an immunoFISH technique, which is a useful tool for investigating the functional organization of the nucleus. It combines immunocytochemistry with FISH to allow associations between proteins, DNA, and RNA to be visualized in a single-step analysis using confocal microscopy. Immunocytochemistry and FISH were thought incompatible since cell preparation flattens nuclei and the harsh DNA denaturation treatment required for FISH destroys proteins. The immunoFISH technique successfully overcomes these problems and can reveal interactions between nuclear components not readily detectable using other experimental approaches. The interactions of single-copy, endogenous loci with nuclear proteins or bodies can be seen, as can spatial compartmentalization of these loci, in cells preserved in three dimensions, representative of the situation in vivo. Allelic differences in transcription can be related to nuclear location and protein interactions of the individual alleles since genes, RNA and proteins can be visualized together. Chromosome behavior can be followed through mitosis to investigate centromere activity or vector segregation efficiency, for example. Visual data obtained using the immunoFISH technique have provided insight into the functional significance of nuclear organization and its role in cell biology.
DNA-Binding Proteins↗
Reversible coma in children after improper baclofen pump insertion.
We report the occurrence of delayed postoperative coma in five of nine consecutive children following surgery for insertion of baclofen infusion pumps. We suspect that improper technique resulted in an inadvertent administration of an intrathecal baclofen bolus. We suggest ways to minimize this risk.
Analgesics, Opioid↗
Identification of human CYP forms involved in the activation of tamoxifen and irreversible binding to DNA.
This study investigates which CYP forms are responsible for the conversion of tamoxifen to its putative active metabolite alpha-hydroxytamoxifen and irreversible binding to DNA. We have used eight different baculovirus expressed recombinant human CYP forms and liquid chromatography-mass spectrometry to show that only CYP3A4 is responsible for the NADPH-dependent alpha-hydroxylation of tamoxifen. Surprisingly, this CYP did not catalyse the formation of 4-hydroxytamoxifen. We demonstrate for the first time, by means of accelerator mass spectrometry, that CYP3A4 also catalysed the activation of [(14)C]tamoxifen to intermediates that irreversibly bind to exogenous DNA. Incubation of [(14)C]tamoxifen (20.6 kBq, 100 micro M) with CYP3A4, in the presence of NADPH for 60 min led to levels of DNA binding of 39.0+/-9.0 adducts/10(8) nucleotides (mean +/- SE, n = 6). While CYP3A4 converted tamoxifen to N-desmethyltamoxifen (38.3 +/- 7.20 pmol/20 min/pmol CYP, n = 4), the polymorphic CYP2D6 showed the highest activity for producing this metabolite (48.6+/-1.52pmol/20 min/pmol CYP). CYP2D6 was also the most active in catalysing 4-hydroxylation of tamoxifen, although an order of magnitude lower level was also detected with CYP2C19. With tamoxifen as substrate, no 3,4-dihydroxytamoxifen could be detected with any CYP form. CYP2B6 did not catalyse the metabolism or the binding of tamoxifen to DNA. It is concluded that CYP3A4 is the only P450 of those tested that converts tamoxifen to alpha-hydroxytamoxifen and the only one that results in appreciable levels of irreversible binding of tamoxifen to DNA.
Biotransformation↗
Can assessment for obstructive sleep apnea help predict postadenotonsillectomy respiratory complications?
BACKGROUND: The aim of this study was to determine the frequency and type of respiratory complications after adenotonsillectomy in children. A second aim was to assess the ability of preoperative sleep studies to identify children at risk for respiratory complications. METHODS: Children referred for sleep studies between 1992 and 1998, who underwent adenotonsillectomy within 6 months of the preoperative study, were reviewed. The study focused on two variables: the obstructive apnea and hypopnea index and the oxygen saturation nadir. Medical charts were reviewed for postoperative respiratory complications. RESULTS: Three hundred forty-nine children were referred for sleep studies, and 163 met the inclusion criteria. Thirty-four children (21%) had postoperative respiratory complications requiring a medical intervention. Children experiencing respiratory complications were younger (aged < 2 yr; adjusted odds ratio, 4.3; 95% confidence interval, 1.7-11) and had an associated medical condition (odds ratio, 3; 95% confidence interval, 1.4-6.5). A preoperative obstructive apnea and hypopnea index of 5 or more events per hour increased the chance of postoperative respiratory complications (odds ratio, 7.2; 95% confidence interval, 2.7-19.3), as did a preoperative oxygen saturation nadir of 80% or less (odds ratio, 6.4; 95% confidence interval, 2.8-14.5). A preoperative oxygen saturation nadir of 80% or less had a likelihood ratio of 3.1, increasing the probability of postoperative respiratory complications from 20 to 50%. CONCLUSIONS: The data suggest, but do not prove, that preoperative nocturnal oximetry could be a useful preoperative test to identify children who are at increased risk for postoperative respiratory complications.
Adenoidectomy↗
Awareness of genetic testing for colorectal cancer predisposition among specialists in gastroenterology.
OBJECTIVES: Adult gastroenterologists practicing in New York State were surveyed to determine their practice with regard to identifying family histories consistent with inherited forms of colorectal cancer, and to assess their awareness of cancer genetic counseling and molecular genetic testing for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: A closed-ended questionnaire was mailed to 815 gastroenterologists identified through the membership Directory of the American Gastroenterological Association (1998). Two mailings resulted in a response rate of 35%. RESULTS: In all, 99% of the gastroenterologists obtained a family history from their patients, and 95% were aware of cancer genetic counseling. However, only 51% would routinely refer patients for genetic counseling before providing cancer predisposition testing. In addition, only 52% were aware of the availability of genetic tests for FAP and 34% for HNPCC. Presented with a family history consistent with HNPCC, 79% could identify the syndrome, 26% recommended genetic counseling for the consultand, and 16% advised appropriate screening, according to current recommendations. CONCLUSIONS: The majority of gastroenterologists do obtain a family history on their patients. However, there is a need for physician education regarding the recognition of pedigrees consistent with inherited colorectal cancer, the genetic counseling process, and the availability of mutation testing for FAP and HNPCC.
Adenomatous Polyposis Coli↗