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Biomedical subjects

R Day

Publications and source records attributed to R Day.

At least 73 records · Page 4Linked to original sources
PubMed1999

Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2.

The International Consensus Meeting on the Mode of Action of COX-2 Inhibition (ICMMAC) brought together 17 international experts in arthritis, gastroenterology and pharmacology on 5 6 December 1997. The meeting was convened to provide a definition of COX-2 specificity and to consider the clinical relevance of COX-2-specific agents. These compounds are a new class of drugs that specifically inhibit the enzyme COX-2 while having no effect on COX-1 across the whole therapeutic dose range. The objectives of the meeting were to review the currently available data regarding the roles and biology of COX-1 and COX-2, and to foster a consensus definition on COX-2 specificity. At the present time, no guidelines exist for the in vitro and in vivo assessment of COX specificity, and it was felt that consensus discussion might clarify some of these issues. The meeting also reviewed recent clinical data on COX-2-specific inhibitors. The following article reflects discussion at this meeting and provides a consensus definition of COX-2-specific inhibitors.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Fever and acute brief psychosis in urban and rural settings in north India.

BACKGROUND: This case-control study used data from Chandigarh, North India to investigate the association between antecedent fever and acute brief psychosis. AIMS: To assess whether antecedent fever may be a biological correlate of acute brief psychosis, and contribute to the nosology of acute brief psychosis. METHOD: The study was based in an incidence cohort from two catchment areas, an urban and a rural site, that were part of the World Health Organization Determinants of Outcome study. The cases (n = 17) met criteria for acute brief psychosis; controls (n = 40) were patients with other acute and subacute psychoses. The Life Events Schedule was used to determine the presence of antecedent fever. RESULTS: The crude odds ratio for fever as a risk factor for acute brief psychosis was 6.2 (P = 0.004). The odds ratio in a logistic regression analysis--adjusted for site, gender and CATEGO classification--was 11.2 (P = 0.003). CONCLUSIONS: Antecedent fever may be a biological correlate of acute brief psychosis. This finding supports the validity of this entity, and has implications for its aetiology and diagnosis.

Acute Disease↗
PubMed1999

Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study.

PURPOSE: This is the initial report from the health-related quality of life (HRQL) component of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. This report provides an overview of HRQL findings, comparing tamoxifen and placebo groups, and advice to clinicians counseling women about the use of tamoxifen in a prevention setting. PATIENTS AND METHODS: This report covers the baseline and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months of the study. Findings are presented from the Center for Epidemiological Studies-Depression Scale (CES-D), the Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF-36) and sexual functioning scale, and a symptom checklist. RESULTS: No differences were found between placebo and tamoxifen groups for the proportion of participants scoring above a clinically significant level on the CES-D. No differences were found between groups for the MOS SF-36 summary physical and mental scores. The mean number of symptoms reported was consistently higher in the tamoxifen group and was associated with vasomotor and gynecologic symptoms. Significant increases were found in the proportion of women on tamoxifen reporting problems of sexual functioning at a definite or serious level, although overall rates of sexual activity remained similar. CONCLUSION: Women need to be informed of the increased frequency of vasomotor and gynecologic symptoms and problems of sexual functioning associated with tamoxifen use. Weight gain and depression, two clinical problems anecdotally associated with tamoxifen treatment, were not increased in frequency in this trial in healthy women, which is good news that also needs to be communicated.

Adult↗
PubMed1999

Narcolepsy and other causes of excessive daytime sleepiness.

Narcolepsy is a chronic disorder characterized by excessive daytime sleepiness, cataplexy, and other auxiliary symptoms. An interview can ascertain specific symptomatology, whereas a polysomnogram can reveal distinct clinical features. The clinical and laboratory evaluation together enable an accurate diagnosis of narcolepsy. This diagnosis includes a wide spectrum of symptom combinations. Treatment of narcolepsy should include the empathic guidance of a sleep clinician, an emphasis on sleep hygiene, and in many cases pharmacotherapy.

Circadian Rhythm↗
PubMed1999

Development of the Royal Marsden Hospital paediatric oncology quality of life questionnaire.

Our objective was to develop a health-related quality of life measure for use in pediatric oncology. The development process followed the EORTC Quality of Life Study Group (QLSG) guidelines but utilized a parental proxy rating methodology developed within the framework of the EORTC QLSG. Data are reported on the preliminary stages of development, which include interviews in the target population, specialist review of questionnaire content and initial results on the psychometric structure of the measure. The questionnaire has been translated from English to Swedish and Dutch and is available for international field testing. Suggestions for further development of the new measure are described, including the need for parallel forms for use with children and adolescents as well as the parental proxy rating form described here.

Child↗
PubMed1999

Patient based methods for assessing adverse events in clinical trials in rheumatology. Progress report for the OMERACT Drug Toxicity Working Party. Outcome Measures in Rheumatology.

There has been increasing recognition in recent years that the measurement of drug related toxicities in rheumatology clinical trials has been sub-optimal. The OMERACT Drug Toxicity Working Party was established to address this issue. The first task of the working party was to identify a minimum set of attributes of drug related toxicity that would be important to patients, clinicians, investigators, and policymakers. The working party then developed consensus on a standard set of properties for instruments to measure these attributes. Existing instruments in the field of rheumatology were ascertained by literature review and by contact with experts in the field. Four instruments were ascertained and evaluated using the guidelines developed by the working party. This report outlines the progress and preliminary results of these activities.

Antirheumatic Agents↗
PubMed1998

Absent or low expression of the zeta chain in T cells at the tumor site correlates with poor survival in patients with oral carcinoma.

Immunohistology for expression of the CD3zeta and CD3epsilon chains in TIL was performed in 138 paraffin-embedded primary oral squamous cell carcinoma tissues and 10 nontumor, inflammatory lesions. Semiquantitative analysis of the staining intensity for zeta chain expression and number of zeta chain expression-positive cells distinguished tumors with absent or low zeta expression (42 of 132) from those with normal zeta expression (90 of 132). Zeta chain expression was inversely correlated with the tumor stage. Survival was significantly lower in patients whose TIL had absent or low zeta expression, controlling for stage (P = 0.003) and lymph node status (P = 0.0005). The prognostic value of zeta chain was restricted to patients with stage III or IV tumors (P = 0.003). The data indicate that absent or decreased zeta expression in TIL combined with tumor stage or nodal status defines a group of patients with oral squamous cell carcinoma who have an extremely poor prognosis.

Adult↗
PubMed1998

Molecular cloning and tissue distribution of rat sarcosine dehydrogenase.

Sarcosine dehydrogenase (SarDH) is a mitochondrial flavoenzyme involved in the oxidative degradation of choline to glycine. The absence of SarDH activity in humans is genetically transmitted and is the cause of an amino acid metabolism disorder called sarcosinemia. Tryptic fragments of the purified enzyme from rat liver were subjected to Edman degradation and the sequences obtained were used to clone the cDNA encoding the full length protein. The deduced amino acid sequence of SarDH shares an overall similarity of 47% with dimethylglycine dehydrogenase (Me2GlyDH), another flavoenzyme involved in the mitochondrial choline catabolism with a similar FAD-binding domain. Covalent binding of FAD to SarDH was demonstrated by the observation of strong fluorescence at 530 nm under excitation at 450 nm of the enzyme immunoprecipitated under denaturing conditions from liver extracts. The localization of SarDH immunoreactivity in the mitochondrial matrix was confirmed by Western-blot analysis of purified mitochondrial fractions. Finally, the tissue distribution of SarDH was investigated by Northern-blot analysis of total RNA and Western-blot analysis of total protein from several rat tissues. A strong expression in the liver, but also in the lung, pancreas, kidney, thymus, and oviduct was observed. We therefore suggest that the enzymes of the choline catabolism pathway are important also for metabolism in nonhepatic tissues.

Amino Acid Sequence↗
PubMed1998

Colocalization of heparin and receptor binding sites on keratinocyte growth factor.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. FGFs are also known as heparin-binding growth factors because they bind to heparin and their physical and biological properties are modulated by heparin. Consistent with a role as a paracrine effector, KGF is produced by cells of mesenchymal origin but is active primarily, if not exclusively, on epithelial cells. KGF is involved in a variety of physiological processes, including proliferation, differentiation, wound healing, and cytoprotection. To identify regions in KGF that contribute to heparin and tyrosine kinase receptor interactions, nine peptides spanning defined motifs in the predicted structure of KGF were synthesized, and their heparin and receptor binding properties were analyzed. Peptides at the amino and carboxyl termini bound heparin, and one peptide showed relative binding comparable to that of KGF. Competitive binding studies showed that this peptide along with two other overlapping peptides specifically displaced KGF bound to the KGF receptor. These three peptides were also selectively recognized by a neutralizing monoclonal antibody against KGF, though only in the presence of heparin. Together, these data suggest that the sites for heparin and receptor binding both reside in the amino and carboxyl termini of KGF, which are spatially juxtaposed in the predicted three-dimensional structure of this molecule.

Amino Acid Sequence↗
PubMed1998

Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival.

BACKGROUND: The most accurate predictor of disease recurrence in patients treated for head and neck squamous cell carcinoma is, at present, the extent of regional lymph node metastasis. Since elevated levels of epidermal growth factor receptor (EGFR) and of its ligand, transforming growth factor-alpha (TGF-alpha), have been detected in primary tumors of patients with head and neck squamous cell carcinoma, we determined whether tumor levels of these proteins were of prognostic importance. METHODS: Monoclonal antibodies specific for EGFR and TGF-alpha were used for immunohistochemical detection of each protein in tissue sections of primary tumors from 91 patients who were treated by surgical resection. Levels of immunoreactive EGFR and TGF-alpha were quantified by use of a computerized image analysis system and were normalized to appropriate standards. The logrank test and proportional hazards regression analysis were used to calculate the probability that EGFR and TGF-alpha levels were associated with disease-free survival (i.e., no recurrence of cancer) and cause-specific survival (i.e., patients do not die of their disease). All P values were two-sided. RESULTS: When tumor levels of EGFR or TGF-alpha were analyzed as continuous variables, disease-free survival and cause-specific survival were reduced among patients with higher levels of EGFR (both P = .0001) or TGF-alpha (both P = .0001). In a multivariate analysis, tumor site, tumor level of EGFR, and tumor level of TGF-alpha were statistically significant predictors of disease-free survival; in a similar analysis, regional lymph node stage and tumor levels of EGFR and of TGF-alpha were significant predictors of cause-specific survival. CONCLUSION: Quantitation of EGFR and TGF-alpha protein levels in primary head and neck squamous cell carcinomas may be useful in identifying subgroups of patients at high risk of tumor recurrence and in guiding therapy.

Adult↗
PubMed1998

Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity.

Endoproteolytic processing of the 26-kDa protein precursor prodynorphin (proDyn) at paired and single basic residues is most likely carried out by the proprotein convertases (PCs); however, the role of PCs at single basic residues is unclear. In previous studies we showed that limited proDyn processing by PC1/PC3 at both paired and single basic residues resulted in the formation of 8- and 10-kDa intermediates. Because PC2 is colocalized with proDyn, we examined the potential role of this convertase in cleaving proDyn. PC2 cleaved proDyn to produce dynorphin (Dyn) A 1-17, Dyn B 1-13, and alpha-neo-endorphin, without a previous requirement for PC1/PC3. PC2 also cleaved at single basic residues, resulting in the formation of the C-peptide and Dyn A 1-8. Only PC2, but not furin or PC1/PC3, could cleave the Arg-Pro bond to yield Dyn 1-8. Structure-activity studies with Dyn A 1-17 showed that a P4 Arg residue is important for single basic cleavage by PC2 and that the P1' Pro residue impedes processing. Conversion of Dyn A 1-17 or Dyn B 1-13 into leucine-enkephalin (Leu-Enk) by PC2 was never observed; however, Dyn AB 1-32 cleavage yielded small amounts of Leu-Enk, suggesting that Leu-Enk can be generated from the proDyn precursor only through a specific pathway. Finally, PC2 cleavages at single and paired basic residues were enhanced when carried out in the presence of carboxypeptidase (CP) E. Enhancement was blocked by GEMSA, a specific inhibitor of CPE activity, and could be duplicated by other carboxypeptidases, including CPD, CPB, or CPM. Our data suggest that carboxypeptidase activity enhances PC2 processing by the elimination of product inhibition caused by basic residue-extended peptides.

Amino Acid Sequence↗
PubMed1998

Lymphatic mapping with isosulfan blue dye in squamous cell carcinoma of the head and neck.

OBJECTIVE: To determine whether intraoperative lymphatic mapping with isosulfan blue dye and sentinel lymph node biopsy accurately demonstrates the pathway of regional metastases from mucosal sites in squamous cell carcinoma of the head and neck. DESIGN: A prospective clinical study of intraoperative lymphatic mapping. SETTING: An academic tertiary referral center. PATIENTS: Patients with previously untreated squamous cell carcinoma of the head and neck whose surgical treatment included neck dissection. INTERVENTION: Injection of isosulfan blue dye into the mucosa surrounding squamous cell carcinomas of the upper aerodigestive tract during cervical lymphadenectomy. OUTCOME MEASURES: Correlation of the pathologic findings in the blue sentinel lymph node with those in the remaining cervical lymphatics. RESULTS: No blue-stained cervical lymphatics were identified after injection of the mucosa surrounding the primary squamous cell carcinoma with isosulfan dye. CONCLUSION: The technique of intraoperative lymphatic mapping with isosulfan blue dye requires further study before it can be used for the detection of occult cervical metastases in squamous cell carcinoma of the head and neck.

Adolescent↗
PubMed1998

All-trans-retinoic acid modulation of drug-metabolizing enzyme activities: investigation with selective metabolic drug probes.

PURPOSE: All-trans-retinoic acid (ATRA) is a retinoid analogue that has been shown to be effective in acute promyelocytic leukemia. It is currently being investigated for efficacy in the treatment and prevention of various types of cancer. One of the factors limiting its use is the observed increase in ATRA clearance and elimination which occurs shortly after treatment is started, leading to reduced levels of drug in the body and loss of effectiveness. ATRA efficacy may be enhanced if this autoinduction of metabolism can be overcome, for example through the inhibition of the activity of the induced specific metabolizing enzyme(s). This requires the identification of this induced enzyme(s) and development of approaches to selectively inhibit its activity. METHODS: In the course of a phase II evaluation of ATRA in prostate cancer, we investigated the activities of five specific cytochrome P450 (CYP) (CYPs 1A2, 2C19, 2D6, 2E1 and 3A4) and N-acetyltransferase enzymes using a newly developed five-drug cocktail involving caffeine, mephenytoin, debrisoquine, chlorzoxazone and dapsone respectively. Enzyme activities were assessed in 17 patients with hormone-refractory prostate cancer before the initiation of ATRA therapy, after 14 days of continuous ATRA administration and 7 days after cessation of drug therapy. RESULTS: After 14 days of ATRA therapy, the activities of CYP2E1 (chlorzoxazone hydroxylase) and N-acetyltransferase (in fast acetylators only) were increased by 83% and 29% (P < 0.05), respectively. Both activities returned to baseline by 7 days after cessation of therapy and the profiles were similar to the changes seen in the clearance of ATRA itself. There were no changes in the activities of any of the other enzymes investigated. CONCLUSION: This study shows that ATRA selectively modulates the activities of specific metabolizing enzymes and that this approach may be useful in identifying enzymes that can be explored in an attempt to mitigate ATRA autoinduction through selective modulation of enzyme activities. Further investigations are required to determine whether the elevated enzymes are also responsible for the increased clearance and elimination of ATRA.

Adenocarcinoma↗
PubMed1998

Long-term tamoxifen citrate use and potential ocular toxicity.

PURPOSE: To estimate the prevalence of abnormalities in visual function and ocular structures associated with the long-term use of tamoxifen citrate. METHODS: A single-masked, cross-sectional study involving multiple community and institutional ophthalmologic departments was conducted with a volunteer sample of 303 women with breast cancer currently taking part in a randomized clinical trial to determine the efficacy of tamoxifen (20 mg/day) in preventing recurrences. Participants included women who had never been on drug (n=85); women who had taken tamoxifen for an average of 4.8 years, then been off the drug for an average of 2.7 years (n=140); and women who had been on tamoxifen continuously for an average of 7.8 years (n=78). Women were evaluated by questionnaire, psychophysical testing, and clinical examination to determine any abnormalities in visual function and the comparative prevalences of corneal, lens, retinal, and optic nerve pathology. RESULTS: There were no cases of vision-threatening ocular toxicity among the tamoxifen-treated participants. Compared with nontreated participants, the tamoxifen-treated women had no differences in the activities of daily vision, visual acuity measurements, or other tests of visual function except for color screening. Intraretinal crystals (odds ratio [OR]=3.58, P=.178) and posterior subcapsular opacities (OR=4.03, P=.034) were more frequent in the tamoxifen-treated group. CONCLUSIONS: Women should have a thorough baseline ophthalmic evaluation within the first year of initiating tamoxifen therapy and receive appropriate follow-up evaluations.

Aged↗
PubMed1998

Neuroendocrine protein 7B2 is essential for proteolytic conversion and activation of proprotein convertase 2 in vivo.

The 7B2 protein is widely distributed in neural and endocrine tissues. Its biological function was found to be related to the processing enzyme proprotein convertase 2 (PC2), a mammalian subtilisin/kexin-like endoproteinase that cleaves at specific single or multiple basic amino-acid residues. In order to examine the proposed function of 7B2 on PC2 in in vivo models, we first compared the distribution of 7B2 and PC2 mRNAs in the rat brain. Expression of 7B2 mRNA was found to be pan-neuronal, but additionally, we observed 7B2 mRNA in ependymal cells and in the subcommissural organ. Although the expression of PC2 mRNA was exclusively neuronal, it was more restricted, sparing some regions expressing high levels of 7B2. This finding suggests that 7B2 has an additional function in non-PC2-expressing cells. No evidence of PC2-positive/7B2-negative cells could be obtained in the adult rat brain. However, in the developing rat brain (E17), such regions were easily observed, showing higher levels of pro-PC2 (75 kD). Similarly, in the animal model of insulin-induced hypoglycemic shock, where adrenomedullary 7B2 expression is decreased, the ratio of pro-PC2 to mature PC2 (75 kD:68 kD) was observed to be increased. Finally, the human neuroepithelioma SK-N-MCIXC expresses PC2 but not 7B2. Accordingly, only inactive pro-PC2 forms were observed: 75-kD intracellular and 71-kD extracellular. After stable transfection of SK-N-MCIXC cells with 27-kD pro-7B2, mature and active (68-kD) PC2 was secreted into the medium. Our data demonstrate a critical role of 7B2 in the proteolytic conversion and activation of PC2 in vivo.

Adrenal Glands↗
PubMed1998

Cloning, sequence analysis, and distribution of rat metallocarboxypeptidase Z.

A cDNA encoding human carboxypeptidase Z (CPZ), a novel metallocarboxypeptidase, was recently cloned (Song and Fricker, J. Biol. Chem., 272, 1054, 1997). In the present study, a cDNA encoding the rat homolog of CPZ was identified. As with the human form, rat CPZ contains an N-terminal domain of 120 amino acids that has 20% to 30% amino acid identity with the "frizzled" domain found on proteins that interact with Wnt, a protein involved in tissue polarity in early embryogenesis. Sequence analysis showed rat and human CPZ to be highly conserved within the frizzled domain (77% amino acid identity), the carboxypeptidase domain (91%), and the C-terminal 28 residues (78%). The entire rat CPZ protein has high sequence similarity with human CPZ (81% amino acid identity), moderate sequence similarity to human carboxypeptidase N (45%), human carboxypeptidase E (41%), and human carboxypeptidase M (33%), and less sequence similarity with other metallocarboxypeptidases. Northern blot analysis showed rat CPZ mRNA to be abundant in the placenta, with low to moderate levels in the brain, lung, thymus, and kidney. The BRL3A rat liver cell line and the PC12 rat adrenal cell line express high levels of CPZ mRNA. In situ hybridization analysis indicated that CPZ is expressed only in specific cell types. For example, in the brain, CPZ mRNA is present in leptomeningeal cells, but not in the majority of other cell types. This distribution in leptomeningeal cells is shared by AEBP1, a recently reported member of the metallocarboxypeptidase gene family. However, the distribution of CPZ and AEBP1 differ in pituitary and thyroid. Taken together, these studies suggest that CPZ functions in a range of cell types.

Amino Acid Sequence↗