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C Roberts

Publications and source records attributed to C Roberts.

At least 73 records · Page 4Linked to original sources
PubMed2001

Clustering of hepatotoxins based on mechanism of toxicity using gene expression profiles.

Microarray technology, which allows one to quantitate the expression of thousands of genes simultaneously, has begun to have a major impact on many different areas of drug discovery and development. The question remains of whether microarray analysis and gene expression signature profiles can be applied to the field of toxicology. To date, there are very few published studies showing the use of microarrays in toxicology and important questions remain regarding the predictability and accuracy of applying gene expression profiles to toxicology. To begin to address these questions, we have treated rats with 15 different known hepatotoxins, including allyl alcohol, amiodarone, Aroclor 1254, arsenic, carbamazepine, carbon tetrachloride, diethylnitrosamine, dimethylformamide, diquat, etoposide, indomethacin, methapyrilene, methotrexate, monocrotaline, and 3-methylcholanthrene. These agents cause a variety of hepatocellular injuries including necrosis, DNA damage, cirrhosis, hypertrophy, and hepatic carcinoma. Gene expression analysis was done on RNA from the livers of treated rats and was compared against vehicle-treated controls. The gene expression results were clustered and compared to the histopathology findings and clinical chemistry values. Our results show strong correlation between the histopathology, clinical chemistry, and gene expression profiles induced by the agents. In addition, genes were identified whose regulation correlated strongly with effects on clinical chemistry parameters. Overall, the results suggest that microarray assays may prove to be a highly sensitive technique for safety screening of drug candidates and for the classification of environmental toxins.

Amiodarone↗
PubMed2001

Fatal disseminated adenoviral infection in a renal transplant patient.

Immunosuppressed patients are more susceptible to adenoviral infection and carry a significantly higher mortality than immunocompetent patients. Renal transplant patients with adenoviral infection most often present with infection of the kidney and urinary tract within weeks to months of transplant surgery, suggesting reactivation of the latent adenovirus in the immunosuppressed host as the source of infection. We describe the first case of a fatal adenovirus infection after several years of immunosuppression in a kidney transplant patient. Postmortem examination of several tissues, using standard viral culture and polymerase chain reaction, was positive for adenovirus serotype 21. This case is unusual in that the fatal disseminated viral infection occurred after 6 years of immunosuppression, suggesting that the source of adenovirus was a novel infection rather than reactivation of latent infection, or infection from the transplanted tissue. Furthermore, this is the first report of adenovirus type 21 in an immunosuppressed patient.

Adenoviridae Infections↗
PubMed2001

Interaction of serotonin autoreceptor antagonists in the rat dorsal raphe nucleus: an in vitro fast cyclic voltammetry study.

5-HT1A, 5-HT1B and 5-HT1D receptors are known to function as 5-HT autoreceptors in the rat dorsal raphe nucleus (DRN), modulating local 5-HT efflux. However, there are no studies on the simultaneous blockade of these receptors in the DRN. We investigated the effect of 5-HT1B and 5-HT1D receptor antagonists on 5-HT efflux in rat DRN, alone and in the presence of 5-HT1A receptor antagonists, using the technique of fast cyclic voltammetry. The 5-HT1A receptor antagonist, WAY 100635, and the 5-HT1B receptor antagonist, SB-224289, had no effect on 5-HT efflux while the 5-HT1B/1D receptor antagonist, GR 127935, produced a small decrease in 5-HT efflux. In contrast, the 5-HT1D receptor antagonist, BRL 15572, produced a significant increase in 5-HT efflux. Co-perfusion of WAY 100635 and SB-224289 significantly increased 5-HT efflux. In addition, WAY 100635 reversed the small inhibition of 5-HT efflux observed with GR 127935 but had no effect on the BRL 15572-induced increase. Antagonism of all three 5-HT autoreceptors with SB-224289, BRL 15572 and WAY 100635 significantly increased 5-HT efflux. These data confirm that 5-HT efflux within the DRN is under the control of 5-HT1A, 5-HT1B and 5-HT1D autoreceptors and elevation of 5-HT efflux was greatest following antagonism of 5-HT1A and 5-HT1B receptors.

Animals↗
PubMed2001

Disparities in cancer diagnosis and survival.

BACKGROUND: Concern has been raised over the disproportionate cancer mortality among minority and low-income persons. The current study examined differences in disease stage at the time of diagnosis and subsequent survival for patients who are medically indigent compared with the rest of the population of cancer patients in Michigan. METHODS: The authors linked three Michigan statewide data bases: the Cancer Registry, Medicaid enrollment files, and death certificates. The analysis focused on female breast, cervix, lung, prostate, and colon carcinoma, and differences were analyzed in the incidence, disease stage at the time of diagnosis, and survival between younger women and older women who were either insured or not insured by Medicaid. To estimate the risk of late stage diagnosis and death, the authors used logistic regression, controlling for age, race, and Medicaid enrollment. Ordered logit models also were used as a refinement of disease stage prediction. RESULTS: Medically indigent persons had a disproportionately larger share of cancer. Persons age < 65 years who were insured by Medicaid had the greatest risk of late stage diagnosis and death across all five disease sites analyzed. African-American women had a greater risk of death from breast carcinoma compared with other women independent of Medicaid status. No interaction effects were found between age, race, and/or gender and Medicaid enrollment. CONCLUSIONS: The results of this study showed that the disparities in cancer outcomes may be greater than previously thought and are consistent across disease sites. If advancements made in cancer control are to be shared by the low-income population, then improvements clearly are needed in cancer prevention, early detection, and treatment for the poor.

Adult↗
PubMed2001

Closed suction surgical wound drainage after orthopaedic surgery.

BACKGROUND: Closed suction drainage systems are frequently used to drain fluids, particularly blood, from surgical wounds. The aim of these systems is to reduce the occurrence of wound haematomas and infection. OBJECTIVES: To evaluate the effectiveness of closed suction drainage systems for orthopaedic surgery. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Injuries Group specialised register (May 2001), MEDLINE (1996-May 2001) and references from articles. SELECTION CRITERIA: All randomised or quasi-randomised trials comparing the use of closed suction drainage systems with no drainage systems for all types of elective and emergency orthopaedic surgery. DATA COLLECTION AND ANALYSIS: Both reviewers independently assessed trial quality, using a nine item scale, and extracted data. Wherever appropriate and possible, the data are presented graphically. MAIN RESULTS: Twenty-one studies involving 2772 patients with 2971 wounds were included in the analysis. The types of surgery involved were hip and knee replacement, shoulder surgery, hip fracture surgery, spinal surgery, cruciate ligament reconstruction, open meniscectomy and fracture fixation surgery. Many of the studies had poor methodology and reporting of outcomes. Pooling of results indicated no difference in the incidence of wound infection, haematoma or dehiscence between those allocated to drains and the un-drained wounds. There was a tendency to an increased risk of re-operation for wound complications in the group with drains (relative risk (RR) 2.25, 95% confidence intervals (CI) 0.95 to 5.33), but due to the small numbers of cases involved definite conclusions cannot be made for this outcome. Blood transfusion was required more frequently in those who received drains (RR 1.41, 95% CI 1.10 to 1.80). The need for reinforcement of wound dressings (RR 0.22, 95% CI 0.13 to 0.40) and bruising around the operation site was more common in the group without drains. REVIEWER'S CONCLUSIONS: There is insufficient evidence from randomised trials to support or refute the routine use of closed suction drainage in orthopaedic surgery. Further randomised trials are required before definite conclusions can be made.

Hematoma↗
PubMed2001

The effect of SB-269970, a 5-HT(7) receptor antagonist, on 5-HT release from serotonergic terminals and cell bodies.

1. The presence of 5-HT(7) receptor mRNA and protein in 5-HT neurons suggests that this receptor may act as a 5-HT autoreceptor. In this study, the effect of the 5-HT(7) receptor antagonist, SB-269970 ((R)-1-[3-hydroxy phenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine), was investigated on 5-HT release in the guinea-pig and rat cortex and the rat dorsal raphe nucleus (DRN), using the techniques of in vitro [(3)H]-5-HT release or fast cyclic voltammetry, respectively. 2. Cortical slices were loaded with [(3)H]-5-HT and release was evoked by electrical stimulation. 5-CT inhibited the evoked release of [(3)H]-5-HT in a concentration-dependent manner. SB-269970 had no significant effect on [(3)H]-5-HT release while the 5-HT(1B) receptor antagonist, SB-224289 significantly potentiated [(3)H]-5-HT release. In addition, SB-269970 was unable to attenuate the 5-CT-induced inhibition of release while SB-224289 produced a rightward shift of the 5-CT response, generating estimated pK(B) values of 7.8 and 7.6 at the guinea-pig and rat terminal 5-HT autoreceptors respectively. 3. Rat DRN slices were electrically stimulated and the evoked 5-HT efflux detected by voltammetric analysis. 8-OH-DPAT inhibited evoked 5-HT efflux and was fully reversed by WAY 100635. SB-269970 had no effect on either 5-HT efflux per se or 8-OH-DPAT-induced inhibition of 5-HT efflux. In addition, 5-CT inhibited 5-HT efflux in a concentration-dependent manner. SB-269970 was unable to attenuate the 5-CT-induced inhibition of 5-HT efflux. 4. In conclusion, we were unable to provide evidence to suggest a 5-HT autoreceptor role for 5-HT(7) receptors. However, investigations with more selective 5-HT(7) receptor agonists are needed to confirm the data reported here.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

SB-272183, a selective 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptor antagonist in native tissue.

A novel compound, SB-272183 (5-Chloro-2, 3-dihydro-6-[4-methylpiperazin-1-yl]-1[4-pyridin-4-yl]napth-1-ylaminocarbonyl]-1H-indole), has been shown to have high affinity for human 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with pK(i) values of 8.0, 8.1 and 8.7 respectively and is at least 30 fold selective over a range of other receptors. [(35)S]-GTPgammaS binding studies showed that SB-272183 acts as a partial agonist at human recombinant 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors with intrinsic activities of 0.4, 0.4 and 0.8 respectively, compared to 5-HT. SB-272183 inhibited 5-HT-induced stimulation of [(35)S]-GTPgammaS binding at human 5-HT(1A) and 5-HT(1B) receptors to give pA(2) values of 8.2 and 8.5 respectively. However, from [(35)S]-GTPgammaS autoradiographic studies in rat and human dorsal raphe nucleus, SB-272183 did not display intrinsic activity up to 10 microM but did block 5-HT-induced stimulation of [(35)S]-GTPgammaS binding. From electrophysiological studies in rat raphe slices in vitro, SB-272183 did not effect cell firing rate up to 1 microM but was able to attenuate (+)8-OH-DPAT-induced inhibition of cell firing to give an apparent pK(b) of 7.1. SB-272183 potentiated electrically-stimulated [(3)H]-5-HT release from rat and guinea-pig cortical slices at 100 and 1000 nM, similar to results previously obtained with the 5-HT(1B) and 5-HT(1D) receptor antagonist, GR127935. Fast cyclic voltammetry studies in rat dorsal raphe nucleus showed that SB-272183 could block sumatriptan-induced inhibition of 5-HT efflux, with an apparent pK(b) of 7.2, but did not effect basal efflux up to 1 microM. These studies show that, in vitro, SB-272183 acts as an antagonist at native tissue 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

Are serum anticonvulsant levels in people with epilepsy appropriately monitored?

The medical care of people with epilepsy has often been described as being poor, although objective markers for the quality of epilepsy care are lacking. This paper describes the results of using a simple quality marker, appropriate measuring of serum anticonvulsant levels, in assessing the quality of epilepsy care. The checking of serum phenytoin levels in certain clinical circumstances is advocated, whereas the checking of serum sodium valproate levels is not generally supported. A total of 1254 people with epilepsy in the community had their medical records examined for evidence of checking of anticonvulsant levels and 1204 of these individuals completed questionnaires about their epilepsy and its treatment. Of those on phenytoin, only 26% to 47% had phenytoin levels checked appropriately; 23% of patients on sodium valproate were inappropriately having their serum levels checked. The only clinical or organizational factor that predicted whether checking of serum phenytoin levels was performed was whether or not patients reported three common phenytoin side-effects but this still showed a small effect size (odds ratio 2.4).

Anticonvulsants↗
PubMed2001

Effects of 8-epi-PGF2alpha on isolated bronchial smooth muscle of healthy and heaves-affected horses.

8-Epi-PGF2alpha, a prostaglandin-like compound generated by oxidative stress, has been shown to be an in vitro bronchoconstrictor in airways from healthy laboratory animals and healthy humans, but it has never been studied in diseased airways. Here, the bronchoconstrictive capacity of 8-epi-PGF2alpha on isolated bronchial rings (BR) of healthy and heaves-affected horses was evaluated by comparing the maximal effect and the potency of 8-epi-PGF2alpha to those of (1) acetylcholine (ACh), (2) its stereoisomer PGF2alpha and (3) its synthetic receptor agonist, U46619. Furthermore, the potential capacity of 8-epi-PGF2alpha to enhance the cholinergic (ACh) responsiveness of bronchial smooth muscle was investigated. 8-Epi-PGF2alpha contracted BR with a rank order of efficacy of Ach > U44619 > PGF2alpha > 8-epi-PGF2alpha in both healthy and heaves-affected horses. The contractile maximal response elicited by 8-epi-PGF2alpha was significantly smaller than that elicited by the other drugs, but was significantly higher in BR from heaves-affected horses than in those sampled in healthy horses, whilst pD2 values were similar. A subthreshold concentration of 8-epi-PGF2alpha (10-7 M) did not induce in vitro cholinergic hyper-responsiveness in BR of either healthy or heaves-affected horses. In conclusion, it has been demonstrated that 8-epi-PGF2alpha is an in vitro bronchoconstrictor of minor importance in healthy horses, but whose efficacy is significantly increased in heaves-affected horses.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Change management in primary care: design and evaluation of an internet-delivered course.

OBJECTIVES: To deliver and evaluate an internet course in change management for primary care professionals. DESIGN: A 12-week course delivered over the internet. Respondents were allocated into two groups: one had access to the course tutor individually, while the other could also communicate with the rest of the learner group. Learning outcomes were assessed by means of pre- and post-intervention questionnaires and by interviews with some participants. SUBJECTS: 111 primary care professionals. RESULTS: Subjects showed significant improvements on all learning outcomes. The group with access to the course tutor alone completed more units and had greater improvements in their learning outcomes. More of this group completed the course and completed a portfolio. Respondents who could communicate with other members of the group did not find this a positive experience. CONCLUSION: The internet can be used to deliver learning in change management to primary care professionals. Access to a discussion forum did not improve, and possibly impaired learning. More work is needed on the mentoring of internet learning.

Computer-Assisted Instruction↗
PubMed2001

A clinical validation of the Dysmorphic Concern Questionnaire.

OBJECTIVE: The current study addressed the concept of dysmorphic concern as a symptom that may exist in a number of disorders. The aims of the study were to: (i) validate a recently developed questionnaire that measures dysmorphic concern, the Dysmorphic Concern Questionnaire (DCQ); and (ii) evaluate the relationship of dysmorphic concern to depressed mood, social phobia, and obsessive-compulsive symptomatology. METHOD: Sixty-five psychiatric inpatients were diagnosed using the computerized version of the Composite International Diagnostic Interview (CIDI-A). They then completed the DCQ, and questionnaires measuring body dysmorphic disorder (the Body Dysmorphic Disorder Examination, or BDDE), depression, social phobia, and obsessive-compulsive disorder (OCD). The factor structure and convergent validity of the DCQ were determined, and associations with mood and anxiety symptoms explored. RESULTS: The DCQ was found to be a reliable and valid instrument that is sensitive to dysmorphic concern. Furthermore, although dysmorphic concern was associated with body dysmorphic disorder (BDD), depression, social phobia and OCD, only the score from the BDDE predicted DCQ score in a multiple regression analysis. Finally, BDD symptomatology was best defined by the presence of negative body beliefs as measured by the DCQ. CONCLUSIONS: Negative body beliefs are the hallmark of BDD. However, the existence of dysmorphic concern does not necessarily imply a diagnosis of BDD. The DCQ is a quick and efficient means of identifying dysmorphic concern in those who present with depression, OCD, social phobia or BDD.

Adolescent↗
PubMed2001

Diploma in Hospital Infection Control: a progress report.

The Diploma in Hospital Infection Control (DipHIC) was established by the Hospital Infection Society (HIS), the London School of Hygiene and Tropical Medicine (LSHTM) and the Public Health Laboratory Service (PHLS) in 1997 and has now completed two examinations. We outline progress since the announcement of the diploma and changes to the written examination and reflective portfolio. The reflective process is described and guidance provided to active infection control practitioners wishing to consider application for the diploma by accreditation of prior learning.

Certification↗
PubMed2001

Generation of a high-density rat EST map.

We have developed a high-density EST map of the rat, consisting of >11,000 ESTs. These ESTs were placed on a radiation hybrid framework map of genetic markers spanning all 20 rat autosomes, plus the X chromosome. The framework maps have a total size of approximately 12,400 cR, giving an average correspondence of 240 kb/cR. The frameworks are all LOD 3 chromosomal maps consisting of 775 radiation-hybrid-mapped genetic markers and ESTs. To date, we have generated radiation-hybrid-mapping data for >14,000 novel ESTs identified by our Rat Gene Discovery and Mapping Project (http://ratEST.uiowa.edu), from which we have placed >11,000 on our framework maps. To minimize mapping errors, ESTs were mapped in duplicate and consensus RH vectors produced for use in the placement procedure. This EST map was then used to construct high-density comparative maps between rat and human and rat and mouse. These maps will be a useful resource for positional cloning of genes for rat models of human diseases and in the creation and verification of a tiling set of map order for the upcoming rat-genome sequencing.

Animals↗
PubMed2001

Retinal thickness measurements from optical coherence tomography using a Markov boundary model.

We present a system for detecting retinal boundaries in optical coherence tomography (OCT) B-scans. OCT is a relatively new imaging modality giving cross-sectional images that are qualitatively similar to ultrasound. However, the axial resolution with OCT is much higher, on the order of 10 microm. Objective, quantitative measures of retinal thickness may be made from OCT images. Knowledge of retinal thickness is important in the evaluation and treatment of many ocular diseases. The boundary-detection system presented here uses a one-dimensional edge-detection kernel to yield edge primitives. These edge primitives are rated, selected, and organized to form a coherent boundary structure by use of a Markov model of retinal boundaries as detected by OCT. Qualitatively, the boundaries detected by the automated system generally agreed extremely well with the true retinal structure for the vast majority of OCT images. Only one of the 1450 evaluation images caused the algorithm to fail. A quantitative evaluation of the retinal boundaries was performed as well, using the clinical application of automatic retinal thickness determination. Retinal thickness measurements derived from the algorithm's results were compared with thickness measurements from manually corrected boundaries for 1450 test images. The algorithm's thickness measurements over a 1-mm region near the fovea differed from the corrected thickness measurements by less than 10 microm for 74% of the images and by less than 25 microm (10% of normal retinal thickness) for 98.4% of the images. These errors are near the machine's resolution limit and still well below clinical significance. Current, standard clinical practice involves a qualitative, visual assessment of retinal thickness. A robust, quantitatively accurate system such as ours can be expected to improve patient care.

Algorithms↗
PubMed2001

SB-236057-A: a selective 5-HT1B receptor inverse agonist.

5-HT1B autoreceptors are involved in the control of extracellular 5-HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5-HT1B receptor inverse agonist, SB-236057-A (1'-ethyl-5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazolyl-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro (furo[2,3-f]indole-3,4'-piperidine) hydrochloride). SB 236057-A has been shown to have high affinity for human 5-HT1B receptors (pK(i) = 8.2) and displays 80 or more fold selectivity for the human 5-HT1B receptor over other 5-HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5-HT1B receptors SB-236057-A displayed inverse agonism (pA(2) = 8.9) using [(35)S]GTPgammaS binding, and silent antagonism (pA(2) = 9.2) using cAMP accumulation. SB-236057-A also acted as an antagonist at the 5-HT terminal autoreceptor as measured by [3H]5-HT release from electrically stimulated guinea pig and human cortical slices. In the guinea pig, pharmacokinetic analysis demonstrated that SB-236057-A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints. In vivo microdialysis studies demonstrated that SB-236057-A is an antagonist in the guinea pig cortex but has no effect on extracellular 5-HT levels per se. In contrast, SB-236057-A increased extracellular 5-HT levels in the guinea pig dentate gyrus. This increase in 5-HT release was comparable to that observed after 14 days of paroxetine administration. SB-236057-A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5-HT autoreceptor is of the 5-HT1B subtype. It appears that acute 5-HT1B receptor blockade, by virtue of increased 5-HT release in the dentate gyrus, may provide a rapidly acting antidepressant.

Animals↗