Life and death decisions. Cell and molecular biology of apoptosis, BSCB Autumn meeting, The Edinburgh Conference Centre, Heriot Watt University, Edinburg, 10-13 September 2000.
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Animals↗
Biomedical subjects
C Watson
Publications and source records attributed to C Watson.
An examination of the sensitivity of reported trends in childhood leukemia incidence rates to geographic location and diagnostic coding (United States).
BACKGROUND: There have been conflicting reports of increased incidence of childhood leukemia in the United States with some, but not other, registries reporting increasing rates over the past two decades. Because of the reported discrepancy in childhood leukemia incidence rates an analysis of the SEER database was undertaken. METHODS: The latest SEER data (1973-1995) were analyzed for trends in childhood (age 0-14) leukemia incidence rates by histologic group (all leukemia combined, acute lymphocytic leukemia (ALL), acute mylogenous leukemia (AML), and other acute leukemia) for each SEER reporting region. RESULTS: A significant increase in ALL during 1973-1995 was observed in the combined SEER data, but the increase was a function of whether the first 3 years, data from the SEER Detroit reporting region are included. For the years 1973-1975 the Detroit region reported to much lower rates for ALL and much higher rates for "other acute leukemias" relative to the other SEER regions, resulting in an exaggerated temporal increase in ALL. CONCLUSION: Excluding both the temporal variability, and coding differences for Detroit in the 1973-1975 time frame, there has been no significant increase in childhood leukemia of any histologic group or age category in the United States from the 1970s to 1990s.
Adolescent↗
NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway.
Using a mouse model in which tumors show a growth-regression-recurrence pattern, we investigated the mechanisms for down-regulation of cytotoxic T lymphocyte-mediated tumor immunosurveillance. We found that interleukin 4 receptor (IL-4R) knockout and downstream signal transducer and activator of transcription 6 (STAT6) knockout, but not IL-4 knockout, mice resisted tumor recurrence, which implicated IL-13, the only other cytokine that uses the IL-4R-STAT6 pathway. We confirmed this by IL-13 inhibitor (sIL-13R alpha 2-Fc) treatment. Loss of natural killer T cells (NKT cells) in CD1 knockout mice resulted in decreased IL-13 production and resistance to recurrence. Thus, NKT cells and IL-13, possibly produced by NKT cells and signaling through the IL-4R-STAT6 pathway, are necessary for down-regulation of tumor immunosurveillance. IL-13 inhibitors may prove to be a useful tool in cancer immunotherapy.
Animals↗
Low migraine headache recurrence with naratriptan: clinical parameters related to recurrence.
OBJECTIVE: To evaluate clinical parameters that may affect the incidence of headache recurrence or the time to headache recurrence, or both, in migraineurs treated with naratriptan, 2.5-mg tablets. BACKGROUND: The incidence of headache recurrence within 24 hours of treatment with naratriptan, 2.5-mg tablets (17%-28%), is lower than that reported for other currently available selective serotonin agonists. Identifying clinical parameters that influence headache recurrence may further reduce the incidence of headache recurrence or prolong the time to recurrence, or both, for naratriptan-treated patients. METHODS: We examined the effects of three clinical parameters (predose pain severity, headache duration prior to treatment, and relief status 4 hours post dose) on the incidence of and time to headache recurrence across four placebo-controlled naratriptan clinical trials. The impact of these parameters on headache recurrence was examined individually and in combination. RESULTS: Predose pain severity had no effect on the incidence of headache recurrence (overall 23%; moderate 22%, severe 23%). The median time to recurrence was longer for patients with moderate pain before treatment compared with patients with severe pain before treatment (14.5 hours versus 9.3 hours, respectively). Overall time to headache recurrence was 11.8 hours. Patients with headache recurrence reported a longer time until they treated the headache compared with patients without headache recurrence (median, 145 minutes versus 97.5 minutes). Patients who treated headache pain within 3 hours of onset had a lower incidence of headache recurrence (20%) than patients who treated their headache more than 3 hours after onset (28%). Patients with no pain 4 hours post dose had a lower incidence of and a longer time to headache recurrence compared with patients with mild pain 4 hours post dose (17% versus 32%; median, 17.8 hours versus 8.1 hours, respectively). The interaction of all three clinical parameters was significant in predicting headache recurrence. CONCLUSIONS: The overall incidence of headache recurrence is low after naratriptan, 2.5 mg, compared with other currently available selective serotonin agonists. Predose pain severity, time to treatment, and 4-hour relief status appear related to the incidence of or time to headache recurrence, or both. Treating less severe migraine attacks, treating earlier within an attack, and obtaining complete relief post dose may enhance the low incidence of headache recurrence and achieve longer times to recurrence with naratriptan, 2.5 mg.
Acute Disease↗
Identification of genes regulated by UV/salicylic acid.
PURPOSE: Previous work from the authors' group and others has demonstrated that some of the effects of UV irradiation on gene expression are modulated in response to the addition of salicylic acid to irradiated cells. The presumed effector molecule responsible for this modulation is NF-kappaB. In the experiments described here, differential-display RT-PCR was used to identify those cDNAs that are differentially modulated by UV radiation with and without the addition of salicylic acid. MATERIALS AND METHODS: Differential-display RT-PCR was used to identify differentially expressed genes. RESULTS: Eight such cDNAs are presented: lactate dehydrogenase (LDH-beta), nuclear encoded mitochondrial NADH ubiquinone reductase 24 kDa (NDUFV2), elongation initiation factor 4B (eIF4B), nuclear dots protein SP100, nuclear encoded mitochondrial ATPase inhibitor (IF1), a cDNA similar to a subunit of yeast CCAAT transcription factor HAP5, and two expressed sequence tags (AA187906 and AA513156). CONCLUSIONS: Sequences of four of these genes contained NF-kappaB DNA binding sites of the type that may attract transrepressor p55/p55 NF-kappaB homodimers. Down-regulation of these genes upon UV irradiation may contribute to increased cell survival via suppression of p53 independent apoptosis.
Adenosine Triphosphatases↗
Relationship between EEG and positron emission tomography abnormalities in clinical epilepsy.
Positron emission tomography (PET) is a relatively noninvasive neuroimaging method by means of which a large variety of human brain functions can be assessed. Localized neurochemical abnormalities detected by PET were found in patients with partial epilepsy and suggested the use of this modality for localizing epileptogenic regions of the brain. The clinical usefulness of PET is determined by its sensitivity and specificity for identifying epileptogenic areas as defined by ictal surface and intracranial EEG recordings. The findings obtained from comparative EEG and glucose PET data are reviewed with special emphasis on patients undergoing presurgical evaluation because of medically intractable temporal and extratemporal lobe epilepsy. The utility of glucose PET studies for identifying regions of seizure onset is presented, and the limited specificity of glucose metabolic abnormalities for the detection of various EEG patterns in clinical epilepsy is discussed. The authors review the available intracranial EEG and PET comparisons using [11C]flumazenil (FMZ) PET, a tracer for the assessment of tau-amino-butyric acid/benzodiazepine receptor function. They also summarize their experience with [11C]flumazenil PET in identifying cortical regions that show various ictal and interictal cortical EEG abnormalities in patients with extratemporal seizure origin. Finally, the authors demonstrate that further development of new PET tracers, such as alpha-[11C]methyl-L-tryptophan, is feasible and clinically useful and may increase the number of patients in whom PET studies can replace invasive EEG monitoring.
Biomarkers↗
Evaluating nursing administration instruments.
OBJECTIVE: To identify and evaluate available measures that can be used to examine the effects of management innovations in five important areas: autonomy, conflict, job satisfaction, leadership, and organizational climate. BACKGROUND: Management interventions target the context in which care is delivered and through which evidence for practice diffuses. These innovations need to be evaluated for their effects on desired outcomes. However, busy nurses may not have the time to locate, evaluate, and select instruments to measure expected nursing administration outcomes without research-based guidance. Multiple and complex important contextual variables need psychometrically sound and easy-to-use measurement instruments identified for use in both practice and research. METHOD: An expert focus group consensus methodology was used in this evaluation research to review available instruments in the five areas and evaluate which of these instruments are psychometrically sound and easy to use in the practice setting. RESULTS: The result is a portfolio of measures, clustered by concept and displayed on a spreadsheet. Retrieval information is provided. The portfolio includes the expert consensus judgment as well as useful descriptive information. CONCLUSIONS: The research reported here identifies psychometrically sound and easy-to-use instruments for measuring five key variables to be included in a portfolio. The results of this study can be used as a beginning for saving time in instrument selection and as an aid for determining the best instrument for measuring outcomes from a clinical or management intervention.
Conflict, Psychological↗
The use of stimulus-biased assay systems to detect agonist-specific receptor active states: implications for the trafficking of receptor stimulus by agonists.
The quantitative comparison of the relative potency of agonists is a standard method of receptor and agonist classification. If agonist potency ratios do not correspond in two given tissues, this is used as presumptive data to conclude that the receptors in those two tissues are different. This article presents data to show that a single receptor can demonstrate varying agonist potency ratios in different host cells. These data are described in terms of the production of more than one agonist-selective receptor active state and the interaction of these different active states with multiple G proteins in the membrane to produce cellular response. Stable host human embryonic kidney 293 cells with enhanced quantities of the respective Galpha-protein were created. Wild-type and Galpha-subunit enriched cells were then transiently transfected with human calcitonin receptor type 2 (hCTR2). Binding did not detect differences in the G protein-enriched cells versus wild-type cells. In contrast, functional studies did show differences between the host cell lines and Galpha-subunit enriched cell lines. The relative potency of eight calcitonin agonists was measured in studies of calcium fluorescence in transfected cells containing human calcitonin receptor type 2 by comparing pEC(50) (-log molar concentration producing half-maximal response) values. In Galphas-enriched cells, the relative order of potency of the agonists changed. The host-cell dependent differences in potency ratios ranged from 2-fold to more than 46-fold. This finding is not consistent with the idea that all of the agonists produce response in the same manner (i.e., through a common active state of the receptor). These data are consistent with the idea that these different agonists produce arrays of active states that differentially use G proteins. This idea is discussed in terms of the design of stimulus-bias assay systems to detect agonist-selective receptor active states with resulting potential for increased selectivity of agonists.
Binding, Competitive↗
Use of constitutive G protein-coupled receptor activity for drug discovery.
This article describes the behavior of transiently transfected human receptors into melanophores and the potential use of constitutive receptor activity to screen for new drug entities. Specifically, transient transfection of melanophores with different concentrations of receptor cDNA presumably leads to increased levels of receptor expression. This leads to an increased response to agonists (both maxima and potency) and, in some cases, an agonist-independent constitutive receptor activity. Transfections with increasing concentrations of the G(s) protein-coupled human calcitonin receptor type 2 (hCTR2) cDNA produced sufficient levels of constitutively activated receptor to cause elevated basal cellular responses. This was observed as a decrease in the transmittance of light through melanophores (consistent with G(s) protein activation) and increased response to human calcitonin. The receptor-mediated nature of this response was confirmed by its reversal with the hCTR2 peptide inverse agonist AC512. A collection of ligands for hCTR2 either increased or decreased constitutive hCTR2 activity, suggesting that the constitutive system was a sensitive discriminator of positive and negative ligand efficacy. Similar results were obtained with G(i)-protein-coupled receptors. Transient transfection of NPY1, NPY2, NPY4, CXCR4, and CCR5 cDNA produced increased light transmittance through melanophores (consistent with G(i)-protein activation). NPY1 cDNA produced little constitutive response on transfection, whereas maximal levels of constitutive activity ranging from 30 to 45% were observed for the other G(i)-protein-coupled receptors. Responses to agonists for these receptors increased (both maxima and potency) with increasing cDNA transfection. The receptor/G(i)-protein nature of both the constitutive and agonist-mediated responses was confirmed by elimination with pertussis toxin pretreatment. These data are discussed in terms of the theoretical aspects of constitutive receptor activity and the applicability of this approach for the general screening of G protein-coupled orphan receptors.
Amino Acid Sequence↗
Adherence to antiviral drug regimens in HIV-infected adolescent patients engaged in care in a comprehensive adolescent and young adult clinic.
Inconsistent use of antiviral medications for the treatment of HIV may lead to the emergence of resistant strains in HIV-infected adults. Patterns of adherence with these drug regimens in adolescents remains unknown. Identifying nonadherence in HIV-infected patients to antiviral regimens and developing corrective measures could improve patient outcomes. This study was undertaken to understand adherence in HIV-infected youths engaged in care and to reduce patterns of nonadherence. A retrospective analysis of 25 charts (78%) of HIV-infected youths (n = 32, age 13 to 21 years) were consecutively reviewed from January 1993 to May 1998. Charts were reviewed for documentation of factors previously documented to be associated with adherence: housing stability, social support, prior sexually transmitted diseases (STDs) and/or pregnancy, HIV exposure category, number of clinic visits, number of pills per day, number of medications per day, knowledge of medication schedule, age, gender, race/ethnicity, health status as revealed by CD4 count and viral load, and recorded patterns of adherence to medications and clinic appointments. Thirteen of the 18 (72%) patients who were receiving antiretroviral medication were nonadherent. Sixty-seven percent of the females and 80% of the males reported missing doses. Housing instability (p = 0.031) and/or length of treatment with antiviral medications (months of treatment) (p = 0.043) were significantly correlated with nonadherence. The stability of the adolescents' living situations was the most significant correlate of medication adherence for this population of HIV-infected youth.
Adolescent↗
Is epileptogenic cortex truly hypometabolic on interictal positron emission tomography?
Positron emission tomography (PET) of glucose metabolism is often applied for the localization of epileptogenic brain regions, but hypometabolic areas are often larger than or can miss epileptogenic cortex in nonlesional neocortical epilepsy. The present study is a three-dimensional brain surface analysis designed to demonstrate the functional relation between glucose PET abnormalities and epileptogenic cortical regions. Twelve young patients (mean age, 10.8 years) with intractable epilepsy of neocortical origin underwent chronic intracranial electroencephalographic monitoring. The exact location of the subdural electrodes was determined on high-resolution three-dimensional reconstructed magnetic resonance imaging scan volumes. The electrodes were classified according to their locations over cortical areas, which were defined as hypometabolic, normometabolic, or at the border between hypometabolic and normal cortex (metabolic "border zones") based on interictal glucose PET. Electrodes with seizure onset were located over metabolic border zones significantly more frequently than over hypometabolic or normometabolic regions. Seizure spread electrodes also more frequently overlay metabolic border zones than hypometabolic regions. These findings suggest that cortical areas with hypometabolism should be interpreted as regions mostly not involved in seizure activity, although epileptic activity commonly occurs in the surrounding cortex. This feature of hypometabolic cortex is remarkably similar to that of structural brain lesions surrounded by epileptogenic cortex. Cortical areas bordering hypometabolic regions can be highly epileptogenic and should be carefully assessed in presurgical evaluations.
Brain Diseases, Metabolic↗
Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters.
It is well established that human serum paraoxonase (PON1) catalyzes the hydrolysis of organophosphate insecticides and nerve agents, as well as that of a number of aromatic carboxylic acid esters. Our laboratory has recently found a new class of PON1 substrates that includes at least 30 lactones and cyclic carbonate esters. The lactone substrates vary in their ring size from 4 to 7 atoms. Substituents on the ring carbons may enhance or reduce the rate of lactone hydrolysis. An appreciable degree of stereospecificity exists with some activities differing up to 9-fold between enantiomers (i.e., S-alpha-hydroxy-gamma-butyrolactone is hydrolyzed 5 to 9 times faster than the R form). Thiolactones are hydrolyzed less efficiently, and some lactams are potent inhibitors. Four lactone-containing drugs-spironolactone, mevastatin, simvastatin, and lovastatin-have been identified as substrates for PON1. All lactone substrates are hydrolyzed by both the Q and R isozymes of human serum PON1. However, some lactone substrates are hydrolyzed faster by the Q than R isozyme, whereas others show a reverse preference. Moreover, these new substrates include homogentisic acid lactone, mevalonic acid lactone, homocysteine thiolactone, and gamma-hydroxybutyric acid lactone-all lactone forms of endogenous compounds. It is reasonable to expect that further investigations may uncover PON1 lactone substrates that are, themselves, endogenous compounds. In this article we characterize the basic enzymatic properties of PON1's newly identified hydrolytic activities with lactone and cyclic carbonate ester substrates and compare these properties with those of representative arylesters and organophosphates.
Aryldialkylphosphatase↗
Glucose and [11C]flumazenil positron emission tomography abnormalities of thalamic nuclei in temporal lobe epilepsy.
OBJECTIVES: To analyze interictal patterns of thalamic nuclei glucose metabolism and benzodiazepine receptor binding in patients with medically intractable temporal lobe epilepsy (TLE) using high-resolution 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and [11C]flumazenil (FMZ) PET. BACKGROUND: Structural and glucose metabolic abnormalities of the thalamus are considered important in the pathophysiology of TLE. The differential involvement of various thalamic nuclei in humans is not known. METHODS: Twelve patients with TLE underwent volumetric MRI, FDG and FMZ PET, and prolonged video-EEG monitoring. Normalized values and asymmetries of glucose metabolism and FMZ binding were obtained in three thalamic regions (dorsomedial nucleus [DMN], pulvinar, and lateral thalamus [LAT]) defined on MRI and copied to coregistered, partial-volume-corrected FDG and FMZ PET images. Hippocampal and amygdaloid FMZ binding asymmetries and thalamic volumes also were measured. RESULTS: The DMN showed significantly lower glucose metabolism and FMZ binding on the side of the epileptic focus. The LAT showed bilateral hypermetabolism and increased FMZ binding. There was a significant correlation between the FMZ binding asymmetries of the DMN and amygdala. The PET abnormalities were associated with a significant volume loss of the thalamus ipsilateral to the seizure focus. CONCLUSIONS: Decreased [11C]flumazenil (FMZ) binding and glucose metabolism of the dorsomedial nucleus (DMN) are common and have strong lateralization value for the seizure focus in human temporal lobe epilepsy. Decreased benzodiazepine receptor binding can be due to neuronal loss, as suggested by volume loss, but also may indicate impaired gamma-aminobutyric acid (GABA)ergic transmission in the DMN, which has strong reciprocal connections with other parts of the limbic system. Increased glucose metabolism and FMZ binding in the lateral thalamus could represent an upregulation of GABA-mediated inhibitory circuits.
Adolescent↗
Lead mineral transformation by fungi.
Pyromorphite (Pb5(PO4)3Cl), the most stable lead mineral under a wide range of geochemical conditions [1], can form in urban and industrially contaminated soils [2] [3] [4] [5]. It has been suggested that the low solubility of this mineral could reduce the bioavailability of lead, and several studies have advocated pyromorphite formation as a remediation technique for lead-contaminated land [3] [5] [6], if necessary using addition of phosphate [6]. Many microorganisms can, however, make insoluble soil phosphate bioavailable [7] [8] [9] [10], and the solubilisation of insoluble metal phosphates by free-living and symbiotic fungi has been reported [11] [12] [13] [14] [15]. If pyromorphite can be solubilised by microbial phosphate-solubilising mechanisms, the question arises of what would happen to the released lead. We have now clearly demonstrated that pyromorphite can be solubilised by organic-acid-producing fungi, for example Aspergillus niger, and that plants grown with pyromorphite as sole phosphorus source take up both phosphorus and lead. We have also discovered the production of lead oxalate dihydrate by A. niger during pyromorphite transformation, which is the first recorded biogenic formation of this mineral. These mechanisms of lead solubilisation, or its immobilisation as a novel lead oxalate, have significant implications for metal mobility and transfer to other environmental compartments and organisms. The importance of considering microbial processes when developing remediation techniques for toxic metals in soils is therefore emphasised.
Aspergillus niger↗
Hepatotrophic effect of cyclosporine and FK 506 is not mimicked by rapamycin.
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Animals↗
Constitutive receptor systems for drug discovery.
This paper discusses the use of constitutively active G-protein-coupled receptor systems for drug discovery. Specifically, the ternary complex model is used to define the two major theoretical advantages of constitutive receptor screening-namely, the ability to detect antagonists as well as agonists directly and the fact that constitutive systems are more sensitive to agonists. In experimental studies, transient transfection of Chinese hamster ovary cyclic AMP response element (CRE) luciferase reporter cells with cDNA for human parathyroid hormone receptor, glucagon receptor, and glucagon-like peptide (GLP-1) receptor showed cDNA concentration-dependent constitutive activity with parathyroid hormone (PTH-1) and glucagon. In contrast, no constitutive activity was observed for GLP-1 receptor, yet responses to GLP-1 indicated that receptor expression had taken place. In another functional system, Xenopus laevi melanophores transfected with cDNA for human calcitonin receptor showed constitutive activity. Nine ligands for the calcitonin receptor either increased or decreased constitutive activity in this assay. The sensitivity of the system to human calcitonin increased with increasing constitutive activity. These data indicate that, for those receptors which naturally produce constitutive activity, screening in this mode could be advantageous over other methods.
Animals↗
Surgical outcome in patients with epilepsy and dual pathology.
High-resolution MRI can detect dual pathology (an extrahippocampal lesion plus hippocampal atrophy) in about 5-20% of patients with refractory partial epilepsy referred for surgical evaluation. We report the results of 41 surgical interventions in 38 adults (mean age 31 years, range 14-63 years) with dual pathology. Three patients had two operations. The mean postoperative follow-up was 37 months (range 12-180 months). The extrahippocampal lesions were cortical dysgenesis in 15, tumour in 10, contusion/infarct in eight and vascular malformation in five patients. The surgical approach aimed to remove what was considered to be the most epileptogenic lesion, and the 41 operations were classified into lesionectomy (removal of an extrahippocampal lesion); mesial temporal resection (removal of an atrophic hippocampus); and lesionectomy plus mesial temporal resection (removal of both the lesion and the atrophic hippocampus). Lesionectomy plus mesial temporal resection resulted in complete freedom from seizures in 11/15 (73%) patients, while only 2/10 (20%) patients who had mesial temporal resection alone and 2/16 (12.5%) who had a lesionectomy alone were seizure-free (P < 0.001). When classes I and II were considered together results improved to 86, 30 and 31%, respectively. Our findings indicate that in patients with dual pathology removal of both the lesion and the atrophic hippocampus is the best surgical approach and should be considered whenever possible.
Adolescent↗
Investigation of a unique male and female sibship with Kallmann's syndrome and 46,XX gonadal dysgenesis with short stature.
A sibship is described where the brother and a sister both have Kallmann's syndrome (anosmia and deficiency of gonadotrophin releasing hormone) and the woman also has streak ovaries. Although there are several conditions that may occur with Kallmann's syndrome, there are no known reports of ovarian dysgenesis being associated with this disorder. Cytogenetic analysis showed no rearrangement or major deletions of the chromosomes. Linkage analysis using informative microsatellite markers predicts that a gene other than KAL1 (at Xp22.3) is implicated in the Kallmann's syndrome manifesting concurrently with ovarian dysgenesis found in this family.
Adult↗