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1.
Pediatr Res ; 91(5): 1049-1056, 2022 04.
Article in English | MEDLINE | ID: mdl-34230621

ABSTRACT

There is no consensus on the optimal pCO2 levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates. A systematic review was conducted in accordance with the PRISMA statement and MOOSE guidelines. Two hundred and ninety-nine studies were screened and 37 studies included. Covidence online software was employed to streamline relevant articles. Hypocapnia was associated with predominantly neurological side effects while hypercapnia was linked with neurological, respiratory and gastrointestinal outcomes and Retinpathy of prematurity (ROP). Permissive hypercapnia did not decrease periventricular leukomalacia (PVL), ROP, hydrocephalus or air leaks. As safe pCO2 ranges were not explicitly concluded in the studies chosen, it was indirectly extrapolated with reference to pCO2 levels that were found to increase the risk of neonatal disease. Although PaCO2 ranges were reported from 2.6 to 8.7 kPa (19.5-64.3 mmHg) in both term and preterm infants, there are little data on the safety of these ranges. For permissive hypercapnia, parameters described for bronchopulmonary dysplasia (BPD; PaCO2 6.0-7.3 kPa: 45.0-54.8 mmHg) and congenital diaphragmatic hernia (CDH; PaCO2 ≤ 8.7 kPa: ≤65.3 mmHg) were identified. Contradictory findings on the effectiveness of permissive hypercapnia highlight the need for further data on appropriate CO2 parameters and correlation with outcomes. IMPACT: There is no consensus on the optimal pCO2 levels in the newborn. There is no consensus on the effectiveness of permissive hypercapnia in neonates. A safe range of pCO2 of 5-7 kPa was inferred following systematic review.


Subject(s)
Hypocapnia , Infant, Premature, Diseases , Carbon Dioxide , Humans , Hypercapnia , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/etiology , Respiration, Artificial/adverse effects
2.
Meas Phys Educ Exerc Sci ; 25(3): 212-226, 2021.
Article in English | MEDLINE | ID: mdl-34326627

ABSTRACT

The purpose of this study was to compare activPAL algorithm-estimated values for time in bed (TIB), wake time (WT) and bedtime (BT) against self-report and an algorithm developed by van der Berg and colleagues. Secondary analyses of baseline data from the Community Activity for Prevention Study (CAPS) were used in which adults ≥ 18 years wore the activPAL for seven days. Mixed-effects models compared differences between TIB, WT, and BT for all three methods. Bland-Altman plots examined agreement and the two-one-sided test examined equivalence. activPAL was not equivalent to self-report or van der Berg in estimating TIB, but was equivalent to self-report for estimating BT, and was equivalent to van der Berg for estimating WT. The activPAL algorithm requires adjustments before researchers can use it to estimate TIB. However, researchers can use activPAL's option to manually enter self-reported BT and WT to estimate TIB and better understand 24-hour movement patterns.

3.
Contemp Clin Trials Commun ; 16: 100482, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31799473

ABSTRACT

OBJECTIVE: To describe and evaluate recruitment approaches for a randomized controlled trial (RCT) of community gardening in Denver, Colorado. (ClinicalTrials.gov: NCT03089177). METHODS: We used community and staff feedback to adapt our recruitment approach from year 1 to year 2 of a multi-year RCT to address health behaviors related to cancer prevention. In year 2, we added a full-time recruitment coordinator, designed and implemented a tracking spreadsheet, and engaged advisory committee members, local garden leaders, and health partners in planning and outreach. Screening and consent rates, staff time and costs for years 1 and 2 are compared. RESULTS: In year 1, recruitment methods yielded 136 initial contacts, 106 screenings and 64 consented participants. In year 2, enhanced staffing and outreach yielded 257 initial contacts, 193 screenings, and 123 consented participants. Personal referrals, health fairs, NextDoor, and fliers yielded the highest percentage of consented participants. School and community meetings yielded the lowest yield for potential participants. Spanish-speaking participants were mostly recruited by direct methods. Compared to year 1 recruitment, which required 707 h of staff time and cost $14,446, year 2 recruitment required 1224 h of staff time and cost $22,992. Average cost for retained participants was $226 (year 1) and $186 (year 2). DISCUSSION: Those planning pragmatic clinical trials with recruitment in multi-ethnic communities can use the results from this study to understand the efficacy of techniques, and to budget costs for recruitment. While our culturally-tailored recruitment methods cost more, they provided more effective and efficient ways to reach recruitment goals.

4.
Contemp Clin Trials ; 68: 72-78, 2018 05.
Article in English | MEDLINE | ID: mdl-29563043

ABSTRACT

BACKGROUND: Engaging in health-promoting behaviors (e.g., healthy fruit- and vegetable-rich diet, physical activity) and living in supportive social and built environments are consistently and significantly associated with reductions in cancer, heart disease, diabetes, and other chronic diseases. Interventions to change diet and physical activity behaviors should aim to educate individuals, change the environments in which people live, work and recreate, improve access, availability, and affordability of healthy foods, and create safe places the facilitate active lifestyles. This trial will assess whether community gardening increases fruit and vegetable consumption and physical activity, improves social support and mental health, and reduces age-associated weight gain and sedentary time among a multi-ethnic, mixed-income population. METHODS/DESIGN: A randomized controlled trial of community gardening began in Denver, Colorado in January 2017. Over 3 years, we will recruit 312 consenting participants on Denver Urban Gardens' waitlists and randomize them to garden or remain on the waitlist. At baseline (pre-gardening), harvest time, and post-intervention, study participants will complete three 24-hour dietary recalls, a 7-day activity monitoring period using accelerometry, a health interview and physical anthropometry. DISCUSSION: This project addresses health-promoting behaviors among a multi-ethnic, mixed-income adult population in a large metropolitan area. If successful, this trial will provide evidence that community gardening supports and sustains healthy and active lifestyles, which can reduce risk of cancer and other chronic diseases. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03089177: Registered on 03/17/17.


Subject(s)
Community Participation , Diet Therapy , Gardening/methods , Health Behavior , Health Promotion/methods , Preventive Health Services , Adult , Community Participation/methods , Community Participation/psychology , Diet Therapy/methods , Diet Therapy/psychology , Exercise , Female , Fruit , Healthy Lifestyle , Humans , Male , Mental Health , Preventive Health Services/methods , Preventive Health Services/organization & administration , Social Support , Vegetables
5.
J Nutr Health Aging ; 21(5): 487-491, 2017.
Article in English | MEDLINE | ID: mdl-28448077

ABSTRACT

OBJECTIVE: Chronic inflammation is linked to many chronic conditions. One of the strongest modulators of chronic inflammation is diet. The Dietary Inflammatory Index (DII) measures dietary inflammatory potential and has been validated previously, but not among African Americans (AAs). DESIGN: Cross-sectional analysis using baseline data from the Healthy Eating and Active Living in the Spirit (HEALS) intervention study. SETTING: Baseline data collection occurred between 2009 and 2012 in or near Columbia, SC. PARTICIPANTS: African-American churchgoers. MEASUREMENTS: Baseline data collection included c-reactive protein (CRP) and interleukin-6 from blood draws, anthropometric measures, and numerous questionnaires. The questionnaires included a food frequency questionnaire which was used for DII calculation. The main analyses were performed using quantile regression. RESULTS: Subjects in the highest DII quartile (i.e., more pro-inflammatory) were younger, more likely to be married, and had less education and greater BMI. Individuals in DII quartile 4 had statistically significantly greater CRP at the 75th and 90th percentiles of CRP versus those in quartile 1 (i.e., more anti-inflammatory). CONCLUSION: Construct validation provides support for using the DII in research among AA populations. Future research should explore avenues to promote more anti-inflammatory diets, with use of the DII, among AA populations to reduce risk of chronic disease.


Subject(s)
Black or African American , C-Reactive Protein/metabolism , Diet/adverse effects , Feeding Behavior , Inflammation/etiology , Adult , Aged , Chronic Disease , Cross-Sectional Studies , Diet Surveys , Female , Humans , Inflammation/blood , Interleukin-6/blood , Male , Middle Aged , Socioeconomic Factors , Surveys and Questionnaires
6.
Oral Dis ; 23(7): 990-1000, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28434191

ABSTRACT

OBJECTIVES: To describe parotid gland (PG) saliva organic and inorganic composition and flow rate changes, after curative intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC), and analyse the relationship between PG saliva analytes and xerostomia measures. METHODS AND MATERIALS: Twenty-six patients recruited to five prospective phase 2 or 3 trials which assessed toxicity and efficacy of IMRT by HNC subsite, provided longitudinal PG saliva. Salivary flow rate, and subjective and objective xerostomia measures were prospectively collected and saliva tested for inorganic and organic analytes. Statistical comparisons of longitudinal analyte changes and analysis for a relationship between dichotomized xerostomia score and saliva analytes were performed. RESULTS: One hundred and forty-two PG saliva samples from 26 patients were analysed. At 3-6 months after IMRT, stimulated and unstimulated saliva showed significantly decreased flow rate, total protein (TP) secretion rate, phosphate concentration and increased lactoferrin (LF) concentration. Stimulated saliva alone had elevated LF secretion rate and beta-2-microglobulin (B2 M) concentration with decreased calcium (Ca2+ ) and magnesium (Mg2+ ) concentrations and Ca2+ secretion rate. At >12 months, under stimulated and unstimulated conditions, increased LF concentration and decreased Mg2+ and phosphate concentration persisted and, in stimulated saliva, there was decreased potassium (K+ ) and Mg2+ concentration. Unstimulated TP secretion rate was lower in the presence of high-grade xerostomia. Otherwise, no relationship between xerostomia grade and PG salivary flow rate, TP and Ca2+ secretion rate was found. CONCLUSION: Fewer significant differences in PG saliva analytes >12 months after IMRT indicate good functional recovery. Residual xerostomia after IMRT will only be further reduced by addressing the sparing of subsites of the PG or other salivary gland tissues, in addition to the PG.


Subject(s)
Head and Neck Neoplasms/radiotherapy , Organ Sparing Treatments , Parotid Gland/radiation effects , Radiotherapy, Intensity-Modulated/methods , Saliva/chemistry , Saliva/radiation effects , Adult , Aged , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Female , Humans , Male , Middle Aged , Organs at Risk , Radiation Dosage , Radiotherapy, Intensity-Modulated/adverse effects , Saliva/metabolism , Xerostomia/etiology
7.
Biochim Biophys Acta Gen Subj ; 1861(1 Pt A): 3388-3398, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27592162

ABSTRACT

BACKGROUND: Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle. METHODS: Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change. RESULTS: PSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower Km for UDP-glucose, in the presence and absence of G6P, when compared to wild type GS, and despite its phosphorylation. CONCLUSIONS: Elevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state. GENERAL SIGNIFICANCE: This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy.


Subject(s)
Glycogen Storage Disease/enzymology , Glycogen Storage Disease/epidemiology , Glycogen Synthase/genetics , Horses/metabolism , Mutation/genetics , Adenylate Kinase/metabolism , Amino Acid Sequence , Animals , Blotting, Western , Breeding , Enzyme Activation , Glucose Transporter Type 4/metabolism , Glucose-6-Phosphate/metabolism , Glycogen/metabolism , Glycogen Synthase/chemistry , Glycogen Synthase/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Kinetics , Models, Molecular , Muscle, Skeletal/enzymology , Mutant Proteins/metabolism , Phosphorylation , Prevalence , Protein Subunits/metabolism , Structural Homology, Protein , Uridine Diphosphate Glucose/metabolism
8.
Int J Colorectal Dis ; 32(2): 183-192, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27771773

ABSTRACT

PURPOSE: Colorectal cancer (CRC) is one of the most common and preventable forms of cancer but remains the second leading cause of cancer-related death. Colorectal adenomas are precursor lesions that develop in 70-90 % of CRC cases. Identification of peripheral biomarkers for adenomas would help to enhance screening efforts. This exploratory study examined the methylation status of 20 candidate markers in peripheral blood leukocytes and their association with adenoma formation. METHODS: Patients recruited from a local endoscopy clinic provided informed consent and completed an interview to ascertain demographic, lifestyle, and adenoma risk factors. Cases were individuals with a histopathologically confirmed adenoma, and controls included patients with a normal colonoscopy or those with histopathological findings not requiring heightened surveillance (normal biopsy, hyperplastic polyp). Methylation-specific polymerase chain reaction was used to characterize candidate gene promoter methylation. Odds ratios (ORs) and 95 % confidence intervals (95% CIs) were calculated using unconditional multivariable logistic regression to test the hypothesis that candidate gene methylation differed between cases and controls, after adjustment for confounders. RESULTS: Complete data were available for 107 participants; 36 % had adenomas (men 40 %, women 31 %). Hypomethylation of the MINT1 locus (OR 5.3, 95% CI 1.0-28.2) and the PER1 (OR 2.9, 95% CI 1.1-7.7) and PER3 (OR 11.6, 95% CI 1.6-78.5) clock gene promoters was more common among adenoma cases. While specificity was moderate to high for the three markers (71-97 %), sensitivity was relatively low (18-45 %). CONCLUSION: Follow-up of these epigenetic markers is suggested to further evaluate their utility for adenoma screening or surveillance.


Subject(s)
Adenomatous Polyps/genetics , DNA Methylation/genetics , Genetic Association Studies , Aged , Case-Control Studies , Female , Humans , Male , Middle Aged , Odds Ratio , Promoter Regions, Genetic/genetics
9.
Oncogene ; 34(18): 2297-308, 2015 Apr 30.
Article in English | MEDLINE | ID: mdl-24954508

ABSTRACT

Cancer cells form three-dimensional (3D) multicellular aggregates (or spheroids) under non-adherent culture conditions. In ovarian cancer (OC), spheroids serve as a vehicle for cancer cell dissemination in the peritoneal cavity, protecting cells from environmental stress-induced anoikis. To identify new targetable molecules in OC spheroids, we investigated gene expression profiles and networks upregulated in 3D vs traditional monolayer culture conditions. We identified ALDH1A1, a cancer stem cell marker as being overexpressed in OC spheroids and directly connected to key elements of the ß-catenin pathway. ß-Catenin function and ALDH1A1 expression were increased in OC spheroids vs monolayers and in successive spheroid generations, suggesting that 3D aggregates are enriched in cells with stem cell characteristics. ß-Catenin knockdown decreased ALDH1A1 expression levels and ß-catenin co-immunoprecipitated with the ALDH1A1 promoter, suggesting that ALDH1A1 is a direct ß-catenin target. Both short interfering RNA-mediated ß-catenin knockdown and A37 ((ethyl-2-((4-oxo-3-(3-(pryrrolidin-1-yl)propyl)-3,4-dihydrobenzo [4,5]thioeno [3,2-d]pyrimidin-2-yl)thio)acetate)), a novel ALDH1A1 small-molecule enzymatic inhibitor described here for the first time, disrupted OC spheroid formation and cell viability (P<0.001). ß-Catenin knockdown blocked tumor growth and peritoneal metastasis in an OC xenograft model. These data strongly support the role of ß-catenin-regulated ALDH1A1 in the maintenance of OC spheroids and propose new ALDH1A1 inhibitors targeting this cell population.


Subject(s)
Aldehyde Dehydrogenase/metabolism , Cell Culture Techniques/methods , Ovarian Neoplasms/pathology , Spheroids, Cellular/metabolism , beta Catenin/metabolism , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase 1 Family , Animals , Cell Line, Tumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Neoplasm Transplantation , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolism , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/metabolism , RNA, Small Interfering/pharmacology , Retinal Dehydrogenase , Spheroids, Cellular/drug effects , Wnt Signaling Pathway/drug effects , beta Catenin/genetics
11.
Bioresour Technol ; 114: 399-405, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22459956

ABSTRACT

Spent mushroom compost (SMC), a byproduct of commercial mushroom cultivation, poses serious environmental problems that have hampered the growth of this important agro-industry. In an effort to develop new applications for SMC, we explored its use as a feedstock for bioethanol production. SMC constitutes approximately 30%w/w polysaccharides, 66% of which is glucan. Following dilute-acid pretreatment and enzymatic hydrolysis, both in the presence of PEG 6000, 97% of glucan and 44% of xylan in SMC were converted into the corresponding monosaccharides. Incorporation of PEG 6000 reduced the cellulase requirement by 77%. Zwittergent 3-12 and 3-14 also significantly increased the efficacy of acid pretreatment and enzymatic hydrolysis. The use of SMC in bioethanol production represents a potential mitigation solution for the critical environmental issues associated with the stockpiling of the major byproduct of the mushroom industry.


Subject(s)
Agaricales/chemistry , Agaricales/metabolism , Ethanol/metabolism , Monosaccharides/biosynthesis , Multienzyme Complexes/chemistry , Soil Microbiology , Hydrolysis , Refuse Disposal/methods
12.
J Inherit Metab Dis ; 30(3): 404, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17508265

ABSTRACT

The mtDNA mutation 8993T > G is associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) and Leigh syndrome. There are few reported cases of prenatal testing for mtDNA disorders. Specifically for 8993T > G, there are six cases in which prenatal diagnosis has been reported. We describe prenatal diagnosis in a 36-year-old G3P1 woman with 33% heteroplasmy in white blood cells. She had a previous child who died from Leigh disease (92% heteroplasmy). She underwent prenatal testing by both CVS and amniocentesis of the 8993T > G heteroplasmy levels. This is the first reported case in which both procedures were used. Heteroplasmy was similar in both tissues (58.6% CVS and 55% amniocentesis), in support of the theory that this testing is reliable and may be considered in prenatal cases where this mutation is known in the mother. To date, her child is 20 months old and developing normally. Heteroplasmy determination in the child was refused. Although the infant is developmentally normal, consistent with the observation that levels of heteroplasmy below 60% are compatible with a mild phenotype, this conclusion must be tempered by the limited period of observation and the fact that patients with the NARP phenotype often present later than 20 months of age.


Subject(s)
Amniocentesis/methods , Chorionic Villi/pathology , Polymorphism, Single Nucleotide , Prenatal Diagnosis , Adult , Biopsy , Female , Humans , Muscular Diseases/genetics , Pregnancy , Retinitis Pigmentosa/genetics
13.
Neurotoxicology ; 28(1): 76-82, 2007 Jan.
Article in English | MEDLINE | ID: mdl-16956664

ABSTRACT

Recent evidence indicates a role for oxidative stress and resulting products, e.g. 4-hydroxy-2-nonenal (4HNE) in the pathogenesis of Parkinson's disease (PD). 4HNE is a known inhibitor of mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme very important to the dopamine (DA) metabolic pathway. DA undergoes monoamine oxidase-catalyzed oxidative deamination to 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4-dihydroxyphenylacetic acid (DOPAC) via ALDH2. The biotransformation of DOPAL is critical as previous studies have demonstrated this DA-derived aldehyde to be a reactive electrophile and toxic to dopaminergic cells. Therefore, 4HNE produced via oxidative stress may inhibit ALDH2-mediated oxidation of the endogenous neurotoxin DOPAL. To test this hypothesis, ALDH2 in various model systems was treated with 4HNE and activity toward DOPAL measured. Incubation of human recombinant ALDH2 with 4HNE (1.5-30 microM) yielded inhibition of activity toward DOPAL. Furthermore, ALDH2 in rat brain mitochondrial lysate as well as isolated rat brain mitochondria was also sensitive to the lipid peroxidation product at low micromolar, as evident by a decrease in the rate of DOPAL to DOPAC conversion measured using HPLC. Taken together, these data indicate that 4HNE at low micromolar inhibits mitochondrial biotransformation of DOPAL to DOPAC, and generation of the lipid peroxidation product may represent a mechanism yielding aberrant levels of DOPAL, thus linking oxidative stress to the uncontrolled production of an endogenous neurotoxin relevant to PD.


Subject(s)
3,4-Dihydroxyphenylacetic Acid/analogs & derivatives , Aldehydes/toxicity , Dopamine/metabolism , 3,4-Dihydroxyphenylacetic Acid/metabolism , 3,4-Dihydroxyphenylacetic Acid/toxicity , Aldehyde Dehydrogenase/metabolism , Aldehyde Reductase/metabolism , Animals , Chromatography, High Pressure Liquid , Half-Life , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Oxidation-Reduction , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley
14.
J Pharmacol Exp Ther ; 313(3): 1011-6, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15687373

ABSTRACT

Capecitabine is an oral prodrug of 5-fluorouracil that is indicated for the treatment of breast and colorectal cancers. A three-step in vivo-targeted activation process requiring carboxylesterases, cytidine deaminase, and thymidine phosphorylase converts capecitabine to 5-fluorouracil. Carboxylesterases hydrolyze capecitabine's carbamate side chain to form 5'-deoxy-5-fluorocytidine (5'-DFCR). This study examines the steady-state kinetics of recombinant human carboxylesterase isozymes carboxylesterase (CES) 1A1, CES2, and CES3 for hydrolysis of capecitabine with a liquid chromatography/mass spectroscopy assay. Additionally, a spectrophotometric screening assay was utilized to identify drugs that may inhibit carboxylesterase activation of capecitabine. CES1A1 and CES2 hydrolyze capecitabine to a similar extent, with catalytic efficiencies of 14.7 and 12.9 min(-1) mM(-1), respectively. Little catalytic activity is detected for CES3 with capecitabine. Northern blot analysis indicates that relative expression in intestinal tissue is CES2 > CES1A1 > CES3. Hence, intestinal activation of capecitabine may contribute to its efficacy in colon cancer and toxic diarrhea associated with the agent. Loperamide is a strong inhibitor of CES2, with a K(i) of 1.5 muM, but it only weakly inhibits CES1A1 (IC(50) = 0.44 mM). Inhibition of CES2 in the gastrointestinal tract by loperamide may reduce local formation of 5'-DFCR. Both CES1A1 and CES2 are responsible for the activation of capecitabine, whereas CES3 plays little role in 5'-DFCR formation.


Subject(s)
Antimetabolites, Antineoplastic/metabolism , Carboxylesterase/metabolism , Deoxycytidine/analogs & derivatives , Deoxycytidine/metabolism , Isoenzymes/metabolism , Loperamide/pharmacology , Prodrugs/metabolism , Capecitabine , Carboxylesterase/antagonists & inhibitors , Carboxylesterase/genetics , Fluorouracil/analogs & derivatives , Gastrointestinal Tract/enzymology , Humans , Hydrolysis , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics
15.
Pharmacogenomics J ; 4(5): 307-14, 2004.
Article in English | MEDLINE | ID: mdl-15224082

ABSTRACT

Significant variability in the antitumor efficacy and systemic toxicity of gemcitabine has been observed in cancer patients. However, there are currently no tools for prospective identification of patients at risk for untoward events. This study has identified and validated single-nucleotide polymorphisms (SNP) in genes involved in gemcitabine metabolism and transport. Database mining was conducted to identify SNPs in 14 genes involved in gemcitabine metabolism. Pyrosequencing was utilized to determine the SNP allele frequencies in genomic DNA from European and African populations (n=190). A total of 14 genetic variants (including 12 SNPs) were identified in eight of the gemcitabine metabolic pathway genes. The majority of the database variants were observed in population samples. Nine of the 14 (64%) polymorphisms analyzed have allele frequencies that were found to be significantly different between the European and African populations (P<0.05). This study provides the first step to identify markers for predicting variability in gemcitabine response and toxicity.


Subject(s)
Deoxycytidine/analogs & derivatives , Deoxycytidine/metabolism , Genetic Variation/genetics , Polymorphism, Single Nucleotide/genetics , Antimetabolites, Antineoplastic/metabolism , Antimetabolites, Antineoplastic/therapeutic use , Chi-Square Distribution , Databases, Genetic/statistics & numerical data , Deoxycytidine/therapeutic use , Gene Frequency/genetics , Humans , Gemcitabine
16.
Genesis ; 37(2): 84-90, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14595844

ABSTRACT

The sex of most mammals is determined by the action of SRY. Its presence initiates testis formation resulting in male differentiation, its absence results in ovary formation and female differentiation. We have used suppression subtraction hybridisation between 12.0-12.5 days postcoitum (dpc) mouse testes and ovaries to identify genes that potentially lie within the Sry pathway. Normalised urogenital ridge libraries comprising 8,352 clones were differentially screened with subtracted probes. A total of 272 candidate cDNAs were tested for qualitative differential expression and localisation by whole mount in situ hybridisation; germ cell-dependent or -independent expression was further resolved using busulfan. Fifty-four genes were identified that showed higher expression in the testis than the ovary. One novel gene may be a candidate for interactions with WT1, based on its localisation to Sertoli cells and map position (16q24.3).


Subject(s)
Gonads/embryology , Gonads/metabolism , Sex Differentiation , Animals , Female , Gene Expression Regulation, Developmental , In Situ Hybridization , Male , Mice , Ovary/embryology , Ovary/metabolism , Sex Determination Processes
17.
Curr Hypertens Rep ; 3(6): 481-7, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11734093

ABSTRACT

Hypertension is often poorly controlled despite its importance and despite the availability of very effective treatments. Many factors contribute to poor control, including failure of patients to attend physicians, failure of physicians to detect and adequately treat hypertension to goal levels, and failure of patients to persist with prescribed therapy. An under-recognized problem is the failure, both in writing and in the application by third party payers, of consensus guidelines to recognize the important difference between efficacy in clinical trials and effectiveness in clinical practice. The issue of applicability of guidelines to actual practice was studied in the context of a Canadian Family Medicine teaching practice. At the time of the study, consensus guidelines for management of hypertension recommended that drug therapy be initiated with a beta-blocker or diuretic, except for patients with complicated hypertension for whom these drug classes are relatively contraindicated. It was generally assumed that widespread use of other classes of drugs represented inappropriate and wasteful use of resources. By a retrospective chart audit, we determined the proportion of patients in a family practice for whom therapy with a beta-blocker or diuretic was contraindicated, and examined the compliance of the physicians in the practice with guidelines. We found that about half of hypertensives had conditions for which recommended therapy is not a beta-blocker or diuretic. Thus, failure of physicians to follow guidelines is apparently less inappropriate than is widely perceived.


Subject(s)
Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Patient Compliance , Blood Pressure/physiology , Guideline Adherence , Humans , Hypertension/complications , Hypertension/psychology , Retrospective Studies , Time Factors , Treatment Outcome
18.
Ann Epidemiol ; 11(6): 417-27, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11454501

ABSTRACT

PURPOSE: To evaluate the effect of social desirability trait, the tendency to respond in a manner consistent with societal expectations, on self-reported fruit, vegetable, and macronutrient intake. METHODS: A 61-item food frequency questionnaire (FFQ), 7-item fruit and vegetable screener, and a single question on combined fruit and vegetable intake were completed by 132 female employees at five health centers in eastern Massachusetts. Intake of fruit and vegetables derived from all three methods and macronutrients from the FFQ were fit as dependent variables in multiple linear regression models (overall and by race/ethnicity and education); independent variables included 3-day mean intakes derived from 24-hour recalls (24HR) and score on the 33-point Marlowe-Crowne Social Desirability scale (the regression coefficient for which reflects its effect on estimates of dietary intake based on the comparison method relative to 24HR). RESULTS: Results are based on the 93 women with complete data and FFQ-derived caloric intake between 450 and 4500 kcal/day. In women with college education, FFQ-derived estimates of total caloric were associated with under-reporting by social desirability trait (e.g., the regression coefficient for total caloric intake was -23.6 kcal/day/point in that group versus 36.1 kcal/day/point in women with education less than college) (difference = 59.7 kcal/day/point, 95% confidence interval (CI) = 13.2, 106.2). Except for the single question on which women with college education tended to under-report (difference =.103 servings/day/point, 95% CI = 0.003, 0.203), there was no association of social desirability trait with self-reported fruit and vegetable intake. CONCLUSIONS: The effect of social desirability trait on FFQ reports of macronutrient intake appeared to differ by education, but not by ethnicity or race. The results of this study may have important implications for epidemiologic studies of diet and health in women.


Subject(s)
Diet/psychology , Self Concept , Social Desirability , Adult , Body Composition , Diet Surveys , Energy Intake , Ethnicity , Female , Fruit , Humans , Linear Models , Mental Recall , Nutrition Assessment , Reproducibility of Results , Vegetables
19.
Pediatrics ; 107(6): 1463-9, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11389278

ABSTRACT

The use of condoms as part of the prevention of unintended pregnancies and sexually transmitted diseases (STDs) in adolescents is evaluated in this policy statement. Sexual activity and pregnancies decreased slightly among adolescents in the 1990s, reversing trends that were present in the 1970s and 1980s, while condom use among adolescents increased significantly. These trends likely reflect initial success of primary and secondary prevention messages aimed at adolescents. Rates of acquisition of STDs and human immunodeficiency virus (HIV) among adolescents remain unacceptably high, highlighting the need for continued prevention efforts and reflecting the fact that improved condom use can decrease, but never eliminate, the risk of acquisition of STDs and HIV as well as unintended pregnancies. While many condom education and availability programs have been shown to have modest effects on condom use, there is no evidence that these programs contribute to increased sexual activity among adolescents. These trends highlight the progress that has been made and the large amount that still needs to be accomplished.


Subject(s)
Adolescent Behavior/psychology , Condoms/statistics & numerical data , Adolescent , Age Factors , Condoms/trends , Female , Health Education/methods , Humans , Male , Pediatrics/organization & administration , Pediatrics/standards , Physician's Role , Practice Guidelines as Topic , Pregnancy , Pregnancy in Adolescence , Safe Sex/psychology , Sexual Behavior/psychology , Sexually Transmitted Diseases/prevention & control
20.
Pediatrics ; 107(6): 1476-9, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11389281

ABSTRACT

Sexual assault is a broad-based term that encompasses a wide range of sexual victimizations, including rape. Since the American Academy of Pediatrics published its last policy statement on this topic in 1994, additional information and data have emerged about sexual assault and rape in adolescents, the adolescent's perception of sexual assault, and the treatment and management of the adolescent who has been a victim of sexual assault. This new information mandates an updated knowledge base for pediatricians who care for adolescent patients. This statement provides that update, focusing on sexual assault and rape in the adolescent population.


Subject(s)
Patient Care/standards , Pediatrics/standards , Rape/psychology , Sex Offenses/psychology , Adolescent , Adult , Age Factors , Attitude , Coercion , Delivery of Health Care/standards , Female , Humans , Male , Pediatrics/organization & administration , Physician's Role , Practice Guidelines as Topic , Rape/rehabilitation , Rape/statistics & numerical data , Sex Factors , Sex Offenses/statistics & numerical data , Terminology as Topic , United States/epidemiology , Violence/psychology
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