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Biomedical subjects

J Gilmore

Publications and source records attributed to J Gilmore.

At least 19 recordsLinked to original sources
PubMed2001

The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches.

Schizophrenia is commonly considered a neurodevelopmental disorder that is associated with significant morbidity; however, unlike other neurodevelopmental disorders, the symptoms of schizophrenia often do not manifest for decades. In most patients, the formal onset of schizophrenia is preceded by prodromal symptoms, including positive symptoms, mood symptoms, cognitive symptoms, and social withdrawal. The proximal events that trigger the formal onset of schizophrenia are not clear but may include developmental biological events and environmental interactions or stressors. Treatment with antipsychotic drugs clearly ameliorates psychotic symptoms, and maintenance therapy may prevent the occurrence of relapse. The use of atypical antipsychotic agents may additionally ameliorate the pathophysiology of schizophrenia and prevent disease progression. Moreover, if treated properly early in the course of illness, many patients can experience a significant remission of their symptoms and are capable of a high level of recovery following the initial episode. Because the clinical deterioration that occurs in schizophrenia may actually begin in the prepsychotic phase, early identification and intervention may favorably alter the course and outcome of schizophrenia.

Acute Disease↗
PubMed2001

Identification of a 43-kDa protein in human liver cytosol that binds to the 3'-untranslated region of CYP2A6 mRNA.

Hepatic expression of cytochrome P450 2A6 (CYP2A6) varies widely in humans and is induced during hepatitis; however, the mechanism regulating CYP2A6 has not been established. The murine orthologue Cyp2a5 is regulated post-transcriptionally by mRNA stabilization. A 43-kDa protein that binds to the 3'-untranslated region (3'-UTR) of Cyp2a5 mRNA has been identified, but its role in mRNA stabilization is unclear. We hypothesized that similar interactions occur between cytosolic proteins in human liver and CYP2A6 3'-UTR mRNA. We identified, by RNA electrophoretic mobility shift assay, an hepatic cytosolic protein that binds specifically to sequences in the 3'-UTR of CYP2A6. Complexes did not form with denatured proteins and were eliminated with proteinase K digestion. Complex formation was inhibited with a molar excess of unlabeled CYP2A6 RNA but not by non-specific competitor RNA. Protein-mRNA interactions were not affected by probe denaturation, suggesting that RNA secondary structure is not essential for binding. UV cross-linking of complexes revealed RNA-binding proteins in both human and mouse liver cytosols with molecular masses of approximately 43 kDa. Using truncated RNA probes corresponding to various lengths of CYP2A6 mRNA, the protein-binding site was localized to a 50-nucleotide region between bases 1478 and 1527 of the 3'-UTR. Complex formation with hepatic cytosolic protein from four human subjects correlated with levels of hepatic CYP2A6 microsomal protein, suggesting a possible regulatory role. Further characterization of the RNA-binding protein, the primary binding site, and the influence of this interaction on CYP2A6 mRNA stability will help to elucidate the relevance of these findings to the post-transcriptional control of CYP2A6.

3' Untranslated Regions↗
PubMed2001

LY393615, a novel neuronal Ca(2+) and Na(+) channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia.

In the present studies we have examined the effects of a new calcium channel blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl]methylamine hydrochloride, NCC1048) in a model of hypoxia-hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia-hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615 dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume following Endothelin-1 (Et-1) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or 1 h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model of focal ischaemia. The animals had the middle cerebral artery occluded for 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction in infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, with good bioavailability protects against neuronal damage caused by hypoxia-hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo. The compound is neuroprotective when administered post-occlusion and may therefore be a useful anti-ischaemic agent.

Animals↗
PubMed2001

Lack of association between an interleukin 1 beta (IL-1beta) gene variation and refractory temporal lobe epilepsy.

PURPOSE: We attempted to confirm recent findings of Kanemoto et al. that demonstrated a positive association (p < 0.017) between a polymorphism in the promoter region of the interleukin 1-beta (IL-1beta) gene and the clinical phenotype of temporal lobe epilepsy with hippocampal sclerosis (TLE+HS). METHODS: We determined the frequency of this polymorphism in a group of 61 TLE+HS patients of European ancestry and compared it with that found in 119 ethnically matched control subjects. RESULTS: Analysis of genotype and allele frequencies showed no statistically significant difference in the distribution of the polymorphism between the two groups (p = 0.10). CONCLUSIONS: These data suggest that this IL-1beta promoter polymorphism does not act as a strong susceptibility factor for TLE+HS in a population of individuals of European ancestry.

Epilepsy, Temporal Lobe↗
PubMed2001

High-throughput genomic and proteomic analysis using microarray technology.

BACKGROUND: High-density microarrays are ideally suited for analyzing thousands of genes against a small number of samples. The next step in the discovery process is to take the resulting genes of interest and rapidly screen them against thousands of patient samples, tissues, or cell lines to further investigate their involvement in disease risk or the response to medication. METHODS: We used a microarray technology platform for both single-nucleotide polymorphisms (SNPs) and protein expression. Each microarray contains up to 250 elements that can be customized for each application. Slides contained either a 16- or 96-microarray format (4000-24,000 elements per slide), allowing the corresponding number of samples to be rapidly processed in parallel. RESULTS: Results for SNP genotyping and protein profiling agreed with results of restriction fragment length polymorphism (RFLP) analysis or ELISA, respectively. Genotyping analyses, using the microarray technology, on large sample sets over multiple polymorphisms in the NAT2 gene were in full agreement with traditional methodologies, such as sequencing and RFLP analysis. The multiplexed protein microarray had correlation coefficients of 0.82-0.99 (depending on analyte) compared with ELISAs. CONCLUSIONS: The integrated microarray technology platform is adaptable and versatile, while offering the high-throughput capabilities needed for drug development and discovery applications.

Arylamine N-Acetyltransferase↗
PubMed2000

An evaluation of hospital cleaning regimes and standards.

A four-part study assessing cleanliness in up to 113 environmental surfaces in an operating theatre and a hospital ward is reported. Surfaces were assessed visually, using microbiological methods and ATP bioluminescence. Results from a preliminary random survey indicated variability in cleanliness. These results were then used to select sites for monitoring before and after routine cleaning, over a 14-day period. Using published microbiological and ATP specifications 70 and 76% of these sites were unacceptable after cleaning. Visual assessment was a poor indicator of cleaning efficacy with only 18% considered unacceptable. Sites most likely to fail in the ward were in the toilet and kitchen, areas which are frequently implicated in the spread of infectious intestinal disease. Operating theatre sites had lower ATP results but 61% of sites would be considered unacceptable. There was no significant difference in general microbiological or ATP results overall before and after routine cleaning. Although some important hand contact sites showed no significant difference, overall there was a significant decrease in staphylococcal and enterobacteria counts in the ward but not in the operating theatre after cleaning. The routine cleaning programmes used did not include a biocide and cleaning using a hypochlorite based sanitizer gave much lower values. The results are discussed in relation to infection control, cleaning audits and cleaning schedules: an integrated cleaning monitoring programme using ATP bioluminescence in conjunction with visual and microbiological assessments is recommended.

Adenosine Triphosphate↗
PubMed1999

Detection and treatment of depression in a VA primary care clinic.

The Veterans Health Administration clinical guideline for major depressive disorder was used in screening 574 male veterans treated in primary care settings in the Department of Veterans Affairs health care system. Thirteen percent (N=73) screened positive for depression, and 33 percent of those patients showed evidence of a major depressive episode. Pre- and posttreatment assessment of a sample of 16 patients treated for depression in a primary care setting revealed statistically significant improvement with treatment.

Adult↗
PubMed1999

Body mass index and health.

OBJECTIVES: This article describes the prevalence of the four international body mass index (BMI) categories--underweight (18.5 or less), acceptable weight (18.6 to 24.9), overweight (25 to 29.9) and obese (30 or more)--by selected socio-demographic and lifestyle characteristics. It also examines the association between BMI and selected health problems. DATA SOURCE: The data are from the household component of the 1996/97 National Population Health Survey, conducted by Statistics Canada. Results are based on a sample of 50,347 respondents aged 20 to 64. ANALYTICAL TECHNIQUES: Prevalence estimates of BMI categories were calculated. Multivariate analyses were used to examine associations between BMI and various health conditions by smoking status, while controlling for age and sex. MAIN RESULTS: In 1996/97, about half of Canadian adults were in the acceptable weight range; 34% were overweight; 12%, obese; and 2%, underweight. Being overweight or obese was associated with asthma, arthritis, back problems, high blood pressure, diabetes and thyroid disorders, although this varied with smoking status. Underweight smokers had high odds of reporting cancer, bowel disorders, ulcers, and migraine.

Adult↗
PubMed1998

Groin pain in the soccer athlete: fact, fiction, and treatment.

Groin pain in the soccer athlete is a common problem accounting for 5% of soccer injuries. Groin distribution has proved to be the most common cause of groin pain. Other causes are direct trauma, ostetis pubis, muscle injuries, fractures, bursitis, hip problems, and hernia and referred pain. Soccer players with groin pain present a complex management problem that is discussed.

Athletic Injuries↗
PubMed1998

Medication use during pregnancy for neurologic conditions.

Care of the pregnant patient is challenging because of the multiple physiologic changes associated with pregnancy and the need to consider the impact of any intervention on the fetus. This article addresses management issues that arise while caring for patients with epilepsy, eclampsia, stroke, multiple sclerosis, and headache. An emphasis is placed on considerations involving medication use and approaches to patient care are suggested.

Brain Diseases↗
PubMed1998

Towards Arabidopsis genome analysis: monitoring expression profiles of 1400 genes using cDNA microarrays.

cDNA microarrays containing 1443 Arabidopsis thaliana genes were analyzed for expression profiles in major organs of Arabidopsis plants. Novel expression profiles were identified for many coding sequences with putative gene identifications. Expression patterns of novel sequences provided clues to their possible functions. The results demonstrate how microarrays containing a large number of Arabidopsis genes can provide a powerful tool for plant gene discovery, functional analysis and elucidation of genetic regulatory networks.

Arabidopsis↗
PubMed1997

Clomipramine challenge responses covary with Tridimensional Personality Questionnaire scores in healthy subjects.

Cloninger's Unified Biosocial Theory of Personality postulates a relationship between the relative functional activity of central serotonergic, dopaminergic, and noradrenergic neurotransmitter systems, and the strength of three elemental dimensions of personality. These dimensions are Harm Avoidance, Novelty Seeking, and Reward Dependence, respectively. Accordingly, we predicted that neuroendocrine responses to serotonergic challenge would correlate with Harm Avoidance scores, but not with Novelty Seeking or Reward Dependence scores. We examined the relationship between the prolactin and cortisol responses to a 12.5-mg intravenous clomipramine challenge and these personality dimensions as measured by Cloninger's Tridimensional Personality Questionnaire in 32 healthy subjects. The cortisol response correlated only with Harm Avoidance scores, as predicted; however, prolactin response did not correlate with Harm Avoidance scores. Instead, it demonstrated an inverse relationship with Novelty Seeking scores. There was a positive relationship of baseline prolactin with Harm Avoidance in a post hoc analysis. Cortisol response to serotonergic challenge may be a better indicator for responsivity of serotonergic systems as they relate to the personality dimension of Harm Avoidance than is prolactin. Prolactin responses may be overly affected by dopaminergic influences; however, baseline prolactin may still be a valid indicator of serotonergic tone.

Adolescent↗
PubMed1997

Effects of Ca2+ and Na+ channel inhibitors in vitro and in global cerebral ischaemia in vivo.

In the present study we have examined the effects of the small organic molecules: NNC 09-0026 ((-)-trans-1-butyl-4-(4-dimethylaminophenyl)-3-[(4-trifluoromethyl-ph eno xy) methyl] piperidine dihydrochloride); SB 201823-A (4-[2-(3,4-dichlorophenoxy)ethyl]-1-pentyl piperidine hydrochloride); NS 649 (2-amino-1-(2,5-dimethoxyphenyl)-5-trifluoromethyl benzimidazole); CNS 1237 (N-acenaphthyl-N'-4-methoxynaphth-1-yl guanidine) and riluzole on human omega-conotoxin sensitive N-type voltage-dependent Ca2+ channel currents (ICa) expressed in HEK293 cells, on Na+ channel currents (INa) in acutely isolated cerebellar Purkinje neurones in vitro and in the gerbil model of global cerebral ischaemia in vivo. Estimated IC50 values for steady-state inhibition of ICa were as follows; NNC 09-0026, 1.1 microM; CNS 1237, 4.2 microM; SB 201823-A, 11.2 microM; NS 649, 45.7 microM and riluzole, 233 microM. Estimated IC50 values for steady-state inhibition of Na+ channel currents were as follows: NNC 09-0026, 9.8 microM; CNS 1237, 2.5 microM; SB 201823-A, 4.6 microM; NS 649, 36.7 microM and riluzole, 9.4 microM. In the gerbil model of global cerebral ischaemia the number of viable cells (mean +/- S.E.M.) per 1 mm of the CA1 was 215 +/- 7 (sham operated), 10 +/- 2 (ischaemic control), 44 +/- 15 (NNC 09-0026 30 mg/kg i.p.), 49 +/- 19 (CNS 1237 30 mg/kg i.p.), 11 +/- 2 (SB 201823-A 10 mg/kg i.p.), 17 +/- 4 (NS 649 50 mg/kg i.p.) and 48 +/- 18 (riluzole 10 mg/kg i.p.). Thus NNC 09-0026, CNS 1237 and riluzole provided significant neuroprotection when administered prior to occlusion while SB 201823-A and NS 649 failed to protect. These results indicate that the Ca2+ channel antagonists studied not only inhibited human N-type voltage-dependent Ca2+ channels but were also effective blockers of rat Na+ channels. Both NNC 09-0026 and CNS 1237 showed good activity at both Ca2+ and Na+ channels and this may contribute to the observed neuroprotection.

Animals↗
PubMed1997

Serotonin transporter binding sites and mRNA levels in depressed persons committing suicide.

The serotonin transporter (5-HTT) has been found altered in postmortem brain samples from persons committing suicide, but the results of radioligand binding studies have been inconsistent. In the present series of experiments, autoradiographic radioligand binding and in situ hybridization techniques were utilized to examine 5-HTT function in the brains of 8 depressed subjects who had committed suicide, and matched controls. It was hypothesized that depressed subjects would demonstrate decreased numbers of 5-HTT binding sites and mRNA; however, [125I]RTI-55 binding to the 5-HTT was not different in the midbrain, hippocampus, or frontal cortex of depressed subjects. Also, 5-HTT mRNA levels in dorsal and median raphe nuclei were not different between controls and depressed subjects. The current results, although limited in scope because of the small number of subjects included, offer no evidence that alterations in the 5-HTT occur in pertinent brain regions of depressed individuals.

Adult↗
PubMed1997

Discovery and analysis of inflammatory disease-related genes using cDNA microarrays.

cDNA microarray technology is used to profile complex diseases and discover novel disease-related genes. In inflammatory disease such as rheumatoid arthritis, expression patterns of diverse cell types contribute to the pathology. We have monitored gene expression in this disease state with a microarray of selected human genes of probable significance in inflammation as well as with genes expressed in peripheral human blood cells. Messenger RNA from cultured macrophages, chondrocyte cell lines, primary chondrocytes, and synoviocytes provided expression profiles for the selected cytokines, chemokines, DNA binding proteins, and matrix-degrading metalloproteinases. Comparisons between tissue samples of rheumatoid arthritis and inflammatory bowel disease verified the involvement of many genes and revealed novel participation of the cytokine interleukin 3, chemokine Gro alpha and the metalloproteinase matrix metallo-elastase in both diseases. From the peripheral blood library, tissue inhibitor of metalloproteinase 1, ferritin light chain, and manganese superoxide dismutase genes were identified as expressed differentially in rheumatoid arthritis compared with inflammatory bowel disease. These results successfully demonstrate the use of the cDNA microarray system as a general approach for dissecting human diseases.

Arthritis, Rheumatoid↗
PubMed1997

Lack of pineal beta-adrenergic receptor alterations in suicide victims with major depression.

Noradrenergic function may be altered in depressive illness and thereby contribute to decreased pineal production of melatonin levels, as previously described in some depressed subjects. In the present study, the hypothesis was tested that pineal beta-adrenergic binding would be increased in persons committing suicide with evidence of depressive disorders, reflecting diminished noradrenergic input. Initially, post-mortem human pineal glands were obtained at autopsy. Diagnostic and symptomatic information was then systematically collected from family members using standardized interview techniques. Seven subjects who committed suicide and suffered from major depression, and without exposure to treatment for depressive symptoms were age- and sex-matched with control subjects. Pineal beta-adrenergic binding was assessed by quantitative autoradiography employing four concentrations of [125I]pindolol. Because of possibly complex adrenergic regulation of the pineal, beta-adrenergic receptor binding were subtyped using the selective blocker ICI 89406. No differences in beta-adrenergic receptors were detected between subjects with major depression compared to the matched controls.

Adult↗
PubMed1996

The effects of ifenprodil and eliprodil on voltage-dependent Ca2+ channels and in gerbil global cerebral ischaemia.

Ifenprodil and eliprodil are both non-competitive NMDA receptor antagonists which have been shown to inhibit neuronal Ca2+ channel currents. We have examined the effects of these agents on two defined subtypes of voltage-dependent Ca2+ channels and in the gerbil model of global cerebral ischaemia. Recombinantly expressed human alpha 1B-1 alpha 2b beta 1-3 Ca2+ subunits in HEK293 cells, which results in an omega-conotoxin-sensitive neuronal N-type voltage-dependent Ca2+ channel and omega-Aga IVA sensitive Ca2+ channels (P-type) in acutely isolated cerebellar Purkinje neurones were reversibly inhibited by ifenprodil and eliprodil. Human N-type Ca2+ channel currents were inhibited by ifenprodil and eliprodil with IC50 values of 50 microM and 10 microM respectively whereas P-type Ca2+ channel currents were inhibited reversibly by ifenprodil and eliprodil with approximate IC50 values of 60 microM and 9 microM respectively. Maximum current block observed for both channel subtypes was approximately 80% for both ifenprodil and eliprodil. For neuroprotection studies, animals were subjected to 5 min bilateral carotid artery occlusion with or without administration of either ifenprodil or eliprodil (5, 10 or 20 mg/kg i.p.) immediately after surgery followed by two further doses (2.5, 5 or 10 mg/kg, respectively) at 3 and 6 h post-occlusion. Both compounds provided significant protective effects against ischaemia-induced neurodegeneration in the CA1 region of the hippocampus. These results indicate that both ifenprodil and eliprodil protect against ischaemia-induced neurodegeneration when administered post-occlusion and that they also block N and P-type voltage-dependent Ca2+ channels.

Animals↗