Biomedical subjects

J Hewett

Publications and source records attributed to J Hewett.

At least 19 recordsLinked to original sources

PubMed2005

Effect of nebulized albuterol on blood glucose in patients with diabetes mellitus with and without cystic fibrosis.

Over 90% of cystic fibrosis (CF) patients are treated with bronchodilators, and 6% have diabetes. Some with asthma also have diabetes, and most are treated with bronchodilators. Systemic administration of adrenergic agents can cause increases in blood glucose, but the effect of inhaled agents is unclear. A double-blind study was performed on 10 patients with type 1 diabetes mellitus (DM) without CF (3 male, 7 female, mean age 25.5 years) and 9 patients with insulin-dependent CF-related diabetes (CFRD) (8 male, 1 female, mean age 21.9 years). On 2 separate days before 9 AM fasting and the morning dose of insulin, 2.5 mg of albuterol or nebulized placebo were given. Blood glucose was measured by finger stick with a glucose reflectance meter before and 15, 30, 45, and 60 min after treatment. No significant changes from baseline or differences between placebo and albuterol occurred in either group. The mean maximum increase from baseline in DM was 20 mg/dl on placebo, and 38 mg/dl on albuterol; in the CFRD, the respective changes were 7 and 7 mg/dl. Two DM patients had a > 50 mg/dl increase on albuterol vs. placebo; no CFRD patients had differences of such magnitude. DM patients had greater increases from baseline than CFRD patients on placebo and albuterol. Differences reached statistical significance at 30 and 45 min on placebo, and 45 min on albuterol. Albuterol 2.5 mg by nebulizer causes no clinically significant increases in blood glucose in DM or CFRD patients. Diabetes patients without CF have a significantly greater increase of glucose with time (placebo or albuterol) than CFRD patients.

Administration, Inhalation↗

PubMed2004

Leptin expression in breast nipple aspirate fluid (NAF) and serum is influenced by body mass index (BMI) but not by the presence of breast cancer.

While obesity is a known risk factor for postmenopausal breast cancer, the molecular mechanisms involved are unclear. Systemic levels of leptin, the product of the ob (obesity) gene, are increased in obese individuals (body mass index, BMI, over 25) and are higher in women than men. Leptin has been found to stimulate the growth of breast cancer cells in vitro. Our goal was to determine whether leptin was 1) present in nipple aspirate fluid (NAF), and 2) whether NAF leptin levels were associated with a) levels in serum, b) obesity, and c) breast cancer. We collected and evaluated NAF specimens from 83 subjects and serum specimens from 49 subjects. NAF leptin was detectable in 16/41 (39 %) of premenopausal and 21/42 (50 %) postmenopausal subjects. NAF leptin was significantly lower (p = 0.042) in premenopausal than postmenopausal women with a BMI < 25, but not in those with a higher BMI. NAF leptin was significantly associated with BMI in premenopausal (p = 0.011) but not in postmenopausal women. Serum leptin was associated with BMI in both premenopausal and postmenopausal women (p = 0.0001 for both). NAF and serum leptin were associated in premenopausal (p = 0.02) but not postmenopausal women. Neither NAF nor serum leptin was associated with premenopausal or postmenopausal breast cancer. Our findings include that 1) leptin is present in the breast and detectable in a subset of NAF samples, 2) NAF leptin in premenopausal but not postmenopausal women parallels serum leptin levels, and 3) neither NAF nor serum levels of leptin were associated with premenopausal or postmenopausal breast cancer.

Adult↗

PubMed2002

Direct evidence for neutrino flavor transformation from neutral-current interactions in the Sudbury Neutrino Observatory.

Observations of neutral-current nu interactions on deuterium in the Sudbury Neutrino Observatory are reported. Using the neutral current (NC), elastic scattering, and charged current reactions and assuming the standard 8B shape, the nu(e) component of the 8B solar flux is phis(e) = 1.76(+0.05)(-0.05)(stat)(+0.09)(-0.09)(syst) x 10(6) cm(-2) s(-1) for a kinetic energy threshold of 5 MeV. The non-nu(e) component is phi(mu)(tau) = 3.41(+0.45)(-0.45)(stat)(+0.48)(-0.45)(syst) x 10(6) cm(-2) s(-1), 5.3sigma greater than zero, providing strong evidence for solar nu(e) flavor transformation. The total flux measured with the NC reaction is phi(NC) = 5.09(+0.44)(-0.43)(stat)(+0.46)(-0.43)(syst) x 10(6) cm(-2) s(-1), consistent with solar models.

Journal Article↗

PubMed2002

Measurement of day and night neutrino energy spectra at SNO and constraints on neutrino mixing parameters.

The Sudbury Neutrino Observatory (SNO) has measured day and night solar neutrino energy spectra and rates. For charged current events, assuming an undistorted 8B spectrum, the night minus day rate is 14.0%+/-6.3%(+1.5%)(-1.4%) of the average rate. If the total flux of active neutrinos is additionally constrained to have no asymmetry, the nu(e) asymmetry is found to be 7.0%+/-4.9%(+1.3%)(-1.2%). A global solar neutrino analysis in terms of matter-enhanced oscillations of two active flavors strongly favors the large mixing angle solution.

Journal Article↗

PubMed2001

Measurement of the rate of nu(e) + d --> p + p + e(-) interactions produced by (8)B solar neutrinos at the Sudbury Neutrino Observatory.

Solar neutrinos from (8)B decay have been detected at the Sudbury Neutrino Observatory via the charged current (CC) reaction on deuterium and the elastic scattering (ES) of electrons. The flux of nu(e)'s is measured by the CC reaction rate to be straight phi(CC)(nu(e)) = 1.75 +/- 0.07(stat)(+0.12)(-0.11)(syst) +/- 0.05(theor) x 10(6) cm(-2) s(-1). Comparison of straight phi(CC)(nu(e)) to the Super-Kamiokande Collaboration's precision value of the flux inferred from the ES reaction yields a 3.3 sigma difference, assuming the systematic uncertainties are normally distributed, providing evidence of an active non- nu(e) component in the solar flux. The total flux of active 8B neutrinos is determined to be 5.44+/-0.99 x 10(6) cm(-2) s(-1).

Journal Article↗

PubMed2001

Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin.

PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of (99m)Tc-sestamibi, a P-gp and MRP1 substrate, was also evaluated. PATIENTS AND METHODS: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m(2)/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m(2) was administered. Cycles were repeated every 21 to 28 days. (99m)Tc-sestamibi scans were performed before and during administration of VX-710 alone. RESULTS: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m(2)/h or less. Among seven patients receiving VX-710 160 mg/m(2)/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m(2)/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of (99m)Tc-sestamibi in all patients. CONCLUSION: A 96-hour infusion of VX-710 at 120 mg/m(2)/h plus doxorubicin 45 mg/m(2) has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

A close association of torsinA and alpha-synuclein in Lewy bodies: a fluorescence resonance energy transfer study.

TorsinA, a novel protein in which a mutation causes dominant, early onset torsion dystonia, may serve as a chaperone for misfolded proteins that require refolding or degradation. It has been hypothesized that misfolded alpha-synuclein, a protein in which two mutations cause autosomal dominantly inherited Parkinson's disease, serves as a nidus for the development of a Lewy body. We hypothesized that torsinA plays a role in the cellular processing of alpha-synuclein. We demonstrate that anti-torsin antibodies stain Lewy bodies and Lewy neurites in the substantia nigra and cortex. Using sensitive fluorescent resonance energy transfer (FRET) techniques, we find evidence of a close association between torsinA and alpha-synuclein in Lewy bodies.

Carrier Proteins↗

PubMed2001

The application of a compact multispectral imaging system with integrated excitation source to in vivo monitoring of fluorescence during topical photodynamic therapy of superficial skin cancers.

A novel, compact and low-cost multispectral fluorescence imaging system with an integrated excitation light source is described. Data are presented demonstrating the application of this method to in vivo monitoring of fluorescence before, during and after topical 5-aminolevulinic acid photodynamic therapy of superficial skin cancers. The excitation source comprised a fluorescent tube with the phosphor selected to emit broadband violet light centered at 394 nm. The camera system simultaneously captured spectrally specific images of the fluorescence of the photosensitizer, protoporphyrin IX, the illumination profile and the skin autofluorescence. Real-time processing enabled images to be manipulated to create a composite image of high contrast. The application and validation of this method will allow further detailed studies of the characteristics and time-course of protoporphyrin IX fluorescence, during topical photodynamic therapy in human skin in vivo.

Aminolevulinic Acid↗

PubMed2001

Criminals' explanations of their criminal behavior, III: the effects of time and context.

The authors looked at the explanations for their index of violent crimes as given by 69 incarcerated violent male offenders, respectively. We then examined the extent to which those explanations changed with the passing of time and with change in context. We found that explanations of impaired internal control increased with the passing of time, and that such explanation was given more often to mental health professionals rather than law enforcement professionals. Finally, we found that our subjects tended to give mental health professionals fewer explanations involving external control with the passing of time.

Adult↗

PubMed2000

Mutant torsinA, responsible for early-onset torsion dystonia, forms membrane inclusions in cultured neural cells.

Early-onset torsion dystonia is a hereditary movement disorder thought to be caused by decreased release of dopamine into the basal ganglia, without apparent neuronal degeneration. Recent cloning of the gene responsible for this disease, TOR1A (DYT1), identified the encoded protein, torsinA, as a member of the AAA+ superfamily of chaperone proteins and revealed highest levels of expression in dopaminergic neurons in human brain. Most cases of this disease are caused by a deletion of one glutamic acid residue in the C-terminal region of the protein. Antibodies generated against torsinA revealed expression of a predominant immunoreactive protein species similar to the predicted size of 37.8 kDa in neural, glial and fibroblastic lines by western blot analysis. This protein is N-glycosylated with high mannose content and not, apparently, phosphoryl-ated. Overexpression of torsinA in mouse neural CAD cells followed by immunocytochemistry, revealed a dramatically different pattern of distribution for wild-type and mutant forms of the protein. The wild-type protein was found throughout the cytoplasm and neurites with a high degree of co-localization with the endoplasmic reticulum (ER) marker, protein disulfide isomerase. In contrast, the mutant protein accumulated in multiple, large inclusions in the cytoplasm around the nucleus. These inclusions were composed of membrane whorls, apparently derived from the ER. If disrupted processing of the mutant protein leads to its accumulation in multilayer membranous structures in vivo, these may interfere with membrane trafficking in neurons.

Animals↗

PubMed1999

Inducible nitric oxide synthase expression in cultures enriched for mature oligodendrocytes is due to microglia

Hewett JA, Hewett SJ, Winkler S, Pfeiffer SE. 1999. Inducible nitric oxide synthase expression in cultures enriched for mature oligodendrocytes is due to microglia. J Neurosci Res 56:189-198. In the article referenced above, the LPS concentration employed in all studies was 1 &mgr;g/ml, not 1 mg/ml as published. This correction appears: in the Materials and Methods section on page 190, column 1, line 47; in the Results section on page 191, column 2, legend to Figure 1, line 3; on page 192, column 2, legend to Figure 2, line 3; on page 194, column 2, legend to Figure 5, line 4; on page 195, column 1, legend to Figure 6, line 3; and in the Discussion section on page 196, column 1, line 9. The publisher regrets this error.

Journal Article↗

PubMed1999

Functional coexpression of HSV-1 thymidine kinase and green fluorescent protein: implications for noninvasive imaging of transgene expression.

Current gene therapy technology is limited by the paucity of methodology for determining the location and magnitude of therapeutic transgene expression in vivo. We describe and validate a paradigm for monitoring therapeutic transgene expression by noninvasive imaging of the herpes simplex virus type 1 thymidine kinase (HSV-1-tk) marker gene expression. To test proportional coexpression of therapeutic and marker genes, a model fusion gene comprising green fluorescent protein (gfp) and HSV-1-tk genes was generated (tkgfp gene) and assessed for the functional coexpression of the gene product, TKGFP fusion protein, in rat 9L gliosarcoma, RG2 glioma, and W256 carcinoma cells. Analysis of the TKGFP protein demonstrated that it can serve as a therapeutic gene by rendering tkgfp transduced cells sensitive to ganciclovir or as a screening marker useful for identifying transduced cells by fluorescence microscopy or fluorescence-activated cell sorting (FACS). TK and GFP activities in the TKGFP fusion protein were similar to corresponding wild-type proteins and accumulation of the HSV-1-tk-specific radiolabeled substrate, 2'-fluoro-2'-deoxy-1beta-D-arabinofuranosyl-5-iodo-uracil (FIAU), in stability transduced clones correlated with gfp-fluorescence intensity over a wide range of expression levels. The tkgfp fusion gene itself may be useful in developing novel cancer gene therapy approaches. Valuable information about the efficiency of gene transfer and expression could be obtained by non-invasive imaging of tkgfp expression with FIAU and clinical imaging devices (gamma camera, positron-emission tomography [PET], single photon emission computed tomography [SPECT]), and/or direct visualization of gfp expression in situ by fluorescence microscopy or endoscopy.

Animals↗

PubMed1997

Fine localization of the torsion dystonia gene (DYT1) on human chromosome 9q34: YAC map and linkage disequilibrium.

The DYT1 gene, which maps to chromosome 9q34, appears to be responsible for most cases of early-onset torsion dystonia in both Ashkenazic Jewish (AJ) and non-Jewish families. This disease is inherited in an autosomal dominant mode with reduced penetrance (30%-40%). The abnormal involuntary movements associated with this disease are believed to be caused by unbalanced neural transmission in the basal ganglia. Previous linkage disequilibrium studies in the AJ population placed the DYT1 gene in a 2-cM region between the loci D9S62a and ASS. A YAC contig has now been created spanning 600 kb of this region including D9S62a. The location of the DYT1 gene has been refined within this contig using several new polymorphic loci to expand the linkage disequilibrium analysis of the AJ founder mutation. The most likely location of the DYT1 gene is within a 150 kb region between the loci D9S2161 and D9S63.

Adult↗

PubMed1995

The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study.

We compared omeprazole and mephenytoin as probes for the CYP2C19 metabolic polymorphism. Single oral doses of omeprazole (20 mg) or mephenytoin (100 mg) were administered at least 1 week apart to 167 healthy volunteers. Mephenytoin metabolism was measured using the amount of 4'-hydroxymephenytoin and the S/R ratio of mephenytoin in an 8-hour urine collection. Omeprazole hydroxylation was measured using the ratio of omeprazole to 5'-hydroxyomeprazole in serum 2 hours after dosing. All three methods separated poor- or extensive-metabolizer phenotypes with complete concordance. Omeprazole hydroxylation correlated with the S/R ratio of mephenytoin in extensive metabolizers (r2 = 0.681; p < 0.001). Genotyping tests showed that six poor metabolizers of omeprazole were homozygous for a single base pair mutation in exon 5 of CYP2C19. These results support the hypothesis that omeprazole 5'-hydroxylation cosegregates with the CYP2C19 metabolic polymorphism.

Adult↗

PubMed1995

Comparing clinical vocabularies using coding system fidelity.

Much effort has been directed toward the development of an ideal multipurpose controlled medical vocabulary for use in human and veterinary medicine. SNOMED International is one effort that has resulted in a larger and more complex nomenclature system. Although it was able to code more concepts, SNOMED International failed to statistically improve vocabulary fidelity when compared with the 30+ year old SNVDO vocabulary. We found that SNOMED has a lower intercoder consistency than SNVDO and that a greater number of codes were necessary to represent an individual concept. Our study shows a significant Coder-Vocabulary interaction which suggests that more emphasis should be placed on coding guidelines and coder training. Clinician data entry and coding may be necessary for maximum vocabulary fidelity.

Abstracting and Indexing↗

PubMed1994

Weather, beliefs about weather, and disease severity among patients with fibromyalgia.

OBJECTIVE: This investigation 1) examined the relationships among actual weather, disease severity, and symptoms for individuals with fibromyalgia, 2) assessed subjects' beliefs about weather affecting their symptoms, and 3) examined differences between individuals with high and low "weather sensitivity." METHODS: Eighty-four individuals meeting Yunus' criteria for the diagnosis of fibromyalgia participated. Subjects completed the Weather and Pain Questionnaire (WPQ), the Arthritis Impact Measurement Scales (AIMS), the Symptom Checklist-90-Revised (SCL-90-R), and a Visual Analog Scale (VAS) assessing pain. A tender point index and a myalgic score were also obtained. RESULTS: Subjects reported that weather affected musculoskeletal symptoms predominantly. The strongest relationship was found between weather beliefs and self-reported pain scores. Subjects with high weather sensitivity tended to have more functional impairment and psychological distress.

Activities of Daily Living↗

PubMed1994

Pharmacogenetic characteristics of the eosinophilia-myalgia syndrome.

This study tested the hypothesis that patterns of xenobiotic metabolism in patients with eosinophilia-myalgia syndrome (EMS) differed from healthy control subjects. We determined the genotypes of 27 EMS patients with EMS and 114 control subjects for the cytochrome P450 CYP2D6 polymorphism. The metabolic phenotypes of patients with EMS for S-mephenytoin hydroxylation (n = 17) and dapsone acetylation (n = 19) were determined and compared with 29 healthy control subjects. The incidence of the CYP2D6 poor metabolizer genotype (mutant/mutant) was 0.185 in patients with EMS and 0.061 in control subjects (Mantel-Haenszel, chi 2 = 7.213, p = 0.007). The mephenytoin S/R ratios were 0.39 +/- 0.23 in patients with EMS versus 0.18 +/- 0.13 in control subjects (p < or = 0.005). There was no difference in dapsone acetylation between the two groups. A pattern of xenobiotic metabolism may play a role in the pathogenesis of EMS, but the precise role that it plays remains unclear.

Alleles↗

PubMed1994

Assessing anger expression in children and adolescents.

Anger expression styles are associated with psychological and physical well-being among adults. Little is known about the role of anger expression in children's functioning. This lack of knowledge has resulted, in part, from a lack of validated tools for anger expression measurement. The Pediatric Anger Expression Scale-3rd edition (PAES-III; Jacobs, Phelps, & Rohrs, 1989; Jacobs & Kronaizl, 1991) has been proposed as a reliable and valid assessment instrument of anger expression styles. The PAES-III includes three scales that measure anger turned inward, anger expressed outwardly, and anger controlled cognitively or behaviorally. We evaluated the psychometric properties of this instrument when it is administered verbally to children with juvenile rheumatoid arthritis, children with juvenile diabetes mellitus, and healthy children. Internal consistency was adequate for anger-in and anger-out, but marginal for anger-control. Concurrent validity was supported for the total sample. A principal components analysis suggested a four-factor model of anger expression. Overall, the PAES-III was found to have psychometric limitations. Use of a modified PAES-III may facilitate pediatric behavioral medicine research addressing risk factors for maladjustment among children with chronic illnesses.

Adaptation, Psychological↗