Biomedical subjects

John Brown

Publications and source records attributed to John Brown.

At least 37 records · Page 2Linked to original sources

PubMed2004

Prevalence of HLA-DRB1 genotype and altered Fas/Fas ligand expression in adrenocortical carcinoma.

A distinctive feature of malignant adrenocortical neoplasms is decreased major histocompatibility complex (MHC) class II molecule expression. However, it is unknown whether there exists a restriction to certain MHC genotypes and whether this involves alterations of the Fas/Fas ligand system and thereby affects tissue homeostasis. Therefore, MHC class II phenotype and genotype and expression patterns of the Fas/Fas ligand system were investigated in 24 adrenocortical tumors (n(Adenomas) = 14, n(Carcinomas) = 10) and an adrenal cancer cell line (NCI-H295). No MHC class II antigen expression was detected in carcinomas. The DRB1*01 genotype was found in 54.5% of patients with carcinoma (P = 0.046). No prevalence of any genotype could be detected in patients with adenomas, which exhibited varying levels of antigen expression. Fas receptor expression was 75.0% in adenomas compared with 20.0% in carcinomas (P = 0.0196), whereas ligand expression was 37.7% in adenomas and reached almost 100% in the carcinomas investigated in this study (P = 0.0033). In summary, the DRB1*01 genotype may be correlated to a higher risk for malignancy. Additional studies on MHC class II genotype and phenotype and the altered Fas/Fas ligand system in adrenal neoplasms may help to identify mechanisms of immune escape and suggest new diagnostic approaches.

Adolescent↗

PubMed2004

Patterning of renal cGMP production by the natriuretic peptide receptor type A and blood pressure in spontaneously hypertensive rats.

Although important advances have been made over past decades in studying the mechanisms of hypertension, the nature of cellular signaling patterns involved and their relationship remain unclear. High cGMP production rates in isolated renal glomeruli have been presented as a characteristic of spontaneously hypertensive rat (SHR) even before the development of hypertension, which suggests that this event might be a cause of the increase in blood pressure. Using cross-breeding between SHR and WKY parental strains to obtain F1 and F2 hybrids, we have investigated the patterning of high blood pressure and cGMP production rates. We have found that, in the F2 population, the mean blood pressure and both basal and ANP(1-28)-stimulated cGMP production are similar to the parental SHR. In addition, we have found a positive correlation between blood pressure and high cGMP production rates in the F2 population. The higher cGMP production was not a consequence of hypertension, since in DOCA-salt hypertensive rats cGMP production was similar to that observed in normotensive WKY rats. These observations suggest that high cGMP production is a characteristic linked to hypertension. Finally, reciprocal crosses between the SHR and WKY parental strains showed that in the F1 population blood pressure but not cGMP production are associated with the Y chromosome.

Animals↗

PubMed2004

In vivo detection of macrophages in human carotid atheroma: temporal dependence of ultrasmall superparamagnetic particles of iron oxide-enhanced MRI.

UNLABELLED: Background- It has been suggested that inflammatory cells within vulnerable plaques may be visualized by superparamagnetic iron oxide particle-enhanced MRI. The purpose of this study was to determine the time course for macrophage visualization with in vivo contrast-enhanced MRI using an ultrasmall superparamagnetic iron oxide (USPIO) agent in symptomatic human carotid disease. METHODS: Eight patients scheduled for carotid endarterectomy underwent multisequence MRI of the carotid bifurcation before and 24, 36, 48, and 72 hours after Sinerem (2.6 mg/kg) infusion. RESULTS: USPIO particles accumulated in macrophages in 7 of 8 patients given Sinerem. Areas of signal intensity reduction, corresponding to USPIO/macrophage-positive histological sections, were visualized in all 7 of these patients, optimally between 24 and 36 hours, decreasing after 48 hours, but still evident up to 96 hours after infusion. CONCLUSIONS: USPIO-enhanced MRI of carotid atheroma can be used to identify macrophages in vivo. The temporal change in the resultant signal intensity reduction on MRI suggests an optimal time window for the detection of macrophages on postinfusion imaging.

Aged↗

PubMed2004

Correlation of quantitative EEG in acute ischemic stroke with 30-day NIHSS score: comparison with diffusion and perfusion MRI.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) methods such as diffusion- (DWI) and perfusion-weighted (PWI) imaging have been widely studied as surrogate markers to monitor stroke evolution and predict clinical outcome. The utility of quantitative electroencephalography (qEEG) as such a marker in acute stroke has not been intensively studied. The aim of the present study was to correlate ischemic cortical stroke patients' clinical outcomes with acute qEEG, DWI, and PWI data. MATERIALS AND METHODS: DWI and PWI data were acquired from 11 patients within 7 and 16 hours after onset of symptoms. Sixty-four channel EEG data were obtained within 2 hours after the initial MRI scan and 1 hour before the second MRI scan. The acute delta change index (aDCI), a measure of the rate of change of average scalp delta power, was compared with the National Institutes of Health Stroke Scale scores (NIHSSS) at 30 days, as were MRI lesion volumes. RESULTS: The aDCI was significantly correlated with the 30-day NIHSSS, as was the initial mean transit time (MTT) abnormality volume (rho=0.80, P<0.01 and rho=0.79, P<0.01, respectively). Modest correlations were obtained between the 15-hour DWI lesion volume and both the aDCI and 30-day NIHSSS (rho=0.62, P<0.05 and rho=0.73, P<0.05, respectively). CONCLUSIONS: In this small sample the significant correlation between 30-day NIHSSS and acute qEEG data (aDCI) was equivalent to that between the former and MTT abnormality volume. Both were greater than the modest correlation between acute DWI lesion volume and 30-day NIHSSS. These preliminary results indicate that acute qEEG data might be used to monitor and predict stroke evolution.

Acute Disease↗

PubMed2004

Two macroscopic and microscopic brain imaging studies of human hippocampus in early Alzheimer's disease and schizophrenia research.

Among the many diseases that affect the hippocampus, a small yet highly important brain region responsible for memory and identity, Alzheimer's disease and schizophrenia are among the most devastating. We describe a two-stage, region-of-interest based linear mixed model approach to the analysis of a longitudinal functional magnetic resonance (FMRI) study of human memory function under several drug challenges. We then describe a Monte Carlo approach to testing members of nested hierarchies of linear models in a stereological study of different types and locations of human hippocampal neurons. Last, we attempt to draw the attention of the biostatistical community interested in imaging neuroscience to the intriguing complexities of human hippocampal research in early Alzheimer's disease, schizophrenia and other brain diseases via brain imaging methods.

Alzheimer Disease↗

PubMed2004

A common N400 EEG component reflecting contextual integration irrespective of symbolic form.

OBJECTIVE: Electroencephalographic (EEG) waves modulated by context have been identified about 400 ms after presentation of a new semantic stimulus, such as a word or a number, within a prior context. However, it is not known if any component of these waves arises from a common brain system activated by different symbolic forms. METHODS: Multichannel EEG recordings were performed in 10 healthy subjects during the presentation of lexical and numerical series with congruent and incongruent endings. EEG was analysed using a combination of independent component and cluster analysis. RESULTS: Contextual integration of semantic stimuli elicited a negative independent component at around 400 ms that shared the same pattern of spatio-temporal covariation across numerical series and sentences within single subjects. This independent component was bigger following incongruent endings. CONCLUSIONS: These data provide evidence that one element of the activity contributing to the N400 is common to different symbolic forms. SIGNIFICANCE: One component of the brain systems evaluating the semantic inter-relationship of new stimuli with prior context may be common to different symbolic forms.

Acoustic Stimulation↗

PubMed2004

Chronic oral gabapentin reduces elements of central sensitization in human experimental hyperalgesia.

BACKGROUND: In chronic pain, increased activity from intact or damaged peripheral nerve endings results in an enhanced response in central pain transmission systems, a mechanism known as central sensitization. Central sensitization can also be invoked in human experimental models. Therefore, these models may be useful to characterize novel analgesics in humans. The anticonvulsant gabapentin has demonstrated efficacy in patients with neuropathic pain, but its mode of action remains unclear. This study examined the effects of gabapentin on signs of central sensitization (brush and pinprick hyperalgesia) in a human model of capsaicin-evoked pain, using a gabapentin dosing regimen similar to that used in the clinic. The aims were to determine whether gabapentin, dosed in a manner similar to that used in the clinic, affected the various components of central sensitization and to assess the utility of this model for characterizing novel analgesics. METHODS: Intradermal capsaicin (100 microg/20 microl) was administered in the volar forearm of 41 male human volunteers to induce pain and clinical signs of central sensitization. Gabapentin (titrated to 2,400 mg daily) or placebo was given orally for 15 days in a randomized, double-blind, parallel-group design. The capsaicin test was conducted at baseline and after gabapentin or placebo. Endpoints were the size of areas of brush-evoked allodynia (with cotton gauze) and pinprick hyperalgesia (with von Frey filament), and the intensity of ongoing brush- and pinprick-evoked pain. RESULTS: Gabapentin significantly reduced the area of brush allodynia compared with placebo (P </= 0.05) and insignificantly attenuated the area of pinprick hyperalgesia. Gabapentin had no significant effect on spontaneous and evoked pain intensity. CONCLUSION: Oral gabapentin, administered to healthy volunteers in a regimen similar to that used in treating chronic neuropathic pain, reduces measures of central sensitization evoked by intradermal capsaicin. This suggests that the pain-relieving effect in chronic neuropathic pain condition is linked to the effect of gabapentin on central sensitization. The ability of the capsaicin model to detect the efficacy of this standard treatment of neuropathic pain suggests that it may have a predictive value for detection of efficacy in human subjects.

Adult↗

PubMed2004

Molecular signatures of self-renewal, differentiation, and lineage choice in multipotential hemopoietic progenitor cells in vitro.

The molecular mechanisms governing self-renewal, differentiation, and lineage specification remain unknown. Transcriptional profiling is likely to provide insight into these processes but, as yet, has been confined to "static" molecular profiles of stem and progenitors cells. We now provide a comprehensive, statistically robust, and "dynamic" analysis of multipotent hemopoietic progenitor cells undergoing self-renewal in response to interleukin-3 (IL-3) and multilineage differentiation in response to lineage-affiliated cytokines. Cells undergoing IL-3-dependent proliferative self-renewal displayed striking complexity, including expression of genes associated with different lineage programs, suggesting a highly responsive compartment poised to rapidly execute intrinsically or extrinsically initiated cell fate decisions. A remarkable general feature of early differentiation was a resolution of complexity through the downregulation of gene expression. Although effector genes characteristic of mature cells were upregulated late, coincident with morphological changes, lineage-specific changes in gene expression were observed prior to this, identifying genes which may provide early harbingers of unilineage commitment. Of particular interest were genes that displayed differential behavior irrespective of the lineage elaborated, many of which were rapidly downregulated within 4 to 8 h after exposure to a differentiation cue. These are likely to include genes important in self-renewal, the maintenance of multipotentiality, or the negative regulation of differentiation per se.

Animals↗

PubMed2004

The effect of intravenous infusion of adenosine on electrically evoked hyperalgesia in a healthy volunteer model of central sensitization.

Human pain models invoking central sensitization, one of the key mechanisms of chronic pain, may be useful for characterizing new analgesics. A new model of electrical hyperalgesia can detect the efficacy of several analgesic mechanisms. Because IV adenosine can alleviate neuropathic pain, we investigated its effect on experimental sensitization. This was a double-blinded, randomized, two-period crossover study in 20 healthy volunteers. Current pulses (0.5 ms; 1 Hz) were applied intracutaneously to achieve pain rating of approximately 5 on a 0-10 numeric rating scale. Pain, areas of pinprick hyperalgesia, and tactile allodynia were assessed during the 2.5-h stimulation period. Adenosine (50 microg. kg(-1). min(-1)) and placebo were infused IV over 60 min. Additional testing was performed 24 h after each treatment. Adenosine reduced the area of pinprick hyperalgesia during the infusion compared with placebo; there was no significant effect on tactile allodynia or pain rating. The effect on hyperalgesia developed over 15 min and was significant (P < or = 0.05) for the rest of the infusion period. There was no difference between treatments at 24 h. Thus, in accordance with reports on neuropathic pain, adenosine reduced central sensitization in the human model of electrical hyperalgesia. However, adenosine did not have the long-term effects seen in patients. The model can investigate mechanisms of drugs for the treatment of chronic pain.

Adenosine↗

PubMed2004

Barriers to the treatment of childhood caries perceived by dentists working in different countries.

OBJECTIVE: To explore whether dentists' beliefs and attitudes to providing preventive and restorative dental care for young children can form a barrier to the provision of care. BASIC RESEARCH DESIGN: The Barriers to Childhood Caries Treatment (BaCCT) Questionnaire, a standardised international measure was developed and applied. PARTICIPANTS: Through a research consortium, each site was asked to recruit 100 dentists. The sample participating was not intended to be nationally representative. Dentists were mainly randomly selected and contacted by mail with one or more mailings depending on site. RESULTS: 2,333 dentists in 14 countries and 17 sites participated. Factor analysis identified four factors as potential barriers. Two factors were found to be barriers in many sites. First, in most countries, dentists agreed that young children's coping skills limit their ability to accept dental care. Secondly, dentists with negative personal feelings, for example, that providing care can be stressful and troublesome and that they feel time constrained. Differences in dentists' beliefs can be partly explained by their work profile, with those treating children often, and those working under systems where they feel they can provide quality care being least likely to identify barriers to providing care for children. CONCLUSIONS: The BaCCT Questionnaire was determined to be a valid psychometric measure. Separately, it was found that health systems do impact on dentists' ability to deliver preventive and restorative care for children but that these effects vary across countries and further work is needed to determine how best these should be examined.

Attitude of Health Personnel↗

PubMed2003

PPARgamma activation enhances cell surface ENaCalpha via up-regulation of SGK1 in human collecting duct cells.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that belongs to the nuclear receptor family that plays a critical role in adipocyte differentiation and lipid metabolism. Here we report for the first time that PPARgamma is expressed in human renal cortical collecting ducts (CCD), segments of the nephor involved in regulation of sodium and water homeostasis via action of the epithelial sodium channel (ENaC). ENaC activity is regulated by the hormones aldosterone and insulin, primarily through co-ordinate actions on serum and glucocorticoid regulated kinase 1 (SGK1). We show that SGK1 activity is stimulated by treatment of a human CCD cell line with PPARgamma agonists, paralleled by an increase in SGK1 mRNA that is abolished by pretreatment with a specific PPARgamma antagonist, and that this leads to increased levels of cell surface ENaCalpha. Electrophoretic mobility shift assays suggest that these effects are caused by binding of PPARgamma to a specific response element in the SGK1 promoter. Our results identify SGK1 as a target for PPARgamma and suggest a novel role for PPARgamma in regulation of sodium re-absorption in the CCD via stimulation of ENaC activity. This pathway may play a role in sodium retention caused by activation of PPARgamma in man.

Cell Line↗

PubMed2003

PPAR gamma-dependent anti-inflammatory action of rosiglitazone in human monocytes: suppression of TNF alpha secretion is not mediated by PTEN regulation.

Thiazolidinediones (TZDs) are insulin-sensitising drugs that are ligands for the nuclear receptor PPAR gamma. They have been shown to inhibit PMA-stimulated secretion of TNFalpha from human monocytes, although only at concentrations well in excess of circulating levels observed during TZD therapy, suggesting a mechanism of action independent of PPAR gamma activation. Here we show that insulin-sensitising concentrations of the TZD rosiglitazone partially inhibit serum- or LPS- (but not PMA-) stimulated TNF alpha secretion from primary human monocytes, with an IC(50) of around 50nM. We also show that the observed effects are independent of PPAR gamma-mediated regulation of the lipid phosphatase PTEN. Reversed stimulus specificity, IC(50) in the insulin-sensitising range, and the fact that partial inhibition of TNF alpha secretion is also observed with a structurally unrelated PPAR gamma agonist, GW7845, demonstrate a mechanism of action distinct from that observed with higher TZD concentrations. These findings thus represent the first report of a PPAR gamma-dependent and therapeutically relevant anti-inflammatory action of TZDs in isolated human monocytes.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2003

Differences between natriuretic peptide receptors in the olfactory bulb and hypothalamus from spontaneously hypertensive and normotensive rat brain.

Natriuretic peptide receptor-A (NPR-A) functional characteristics in the hypothalamus and olfactory bulb (OB) have been investigated in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Autoradiographic studies demonstrate a decreased number of atrial natriuretic peptide (ANP) binding sites in the olfactory bulb and hypothalamus in SHR compared to WKY rats. We found that NPR-A showed a lower maximal binding capacity (B(max)) and higher affinity in SHR than in WKY rats both in the olfactory bulb and hypothalamus. However, despite the lower B(max) in SHR, both ANP(1-28) and ANP(5-25) stimulated similar or greater cGMP production than in WKY rats. These differences were found even before the development of hypertension. NPR-A in the olfactory bulb and hypothalamus from 3-week-old SHR showed a lower B(max) and K(d) and a higher cGMP production rate than in WKY rats, suggesting that these characteristics are intrinsic of NPR-A in SHR, instead of being a result of hypertension itself. The present study provides evidences for altered NPR-A receptor properties and function in the olfactory bulb and hypothalamus from SHR, which might be involved in the pathogenesis of hypertension.

Animals↗

PubMed2003

The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant alpha1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker.

The peripheral benzodiazepine receptor ligand PK11195 has been used as an in vivo marker of neuroinflammation in positron emission tomography studies in man. One of the methodological issues surrounding the use of the ligand in these studies is the highly variable kinetic behavior of [(11)C]PK11195 in plasma. We therefore undertook a study to measure the binding of [(3)H]PK11195 to whole human blood and found a low level of binding to blood cells but extensive binding to plasma proteins. Binding assays using [(3)H]PK11195 and purified human plasma proteins demonstrated a strong binding to alpha1-acid glycoprotein (AGP) and a much weaker interaction with albumin. Immunodepletion of AGP from plasma resulted in the loss of plasma [(3)H]PK11195 binding demonstrating: (i) the specificity of the interaction and (ii) that AGP is the major plasma protein to which PK11195 binds with high affinity. PK11195 was able to displace fluorescein-dexamethasone from AGP with IC(50) of <1.2 microM, consistent with a high affinity interaction. These findings are important for understanding the behavior of the ligand in positron emission tomography studies for three reasons. Firstly, AGP is an acute phase protein and its levels will vary during infection and pathological inflammatory diseases such as multiple sclerosis. This could significantly alter the free plasma concentrations of the ligand and contribute to its variable kinetic behavior. Secondly, AGP and AGP-bound ligand may contribute to the access of [(11)C]PK11195 to the brain parenchyma in diseases with blood brain barrier breakdown. Finally, local synthesis of AGP at the site of brain injury may contribute the pattern of [(11)C]PK11195 binding observed in neuroinflammatory diseases.

Acute-Phase Proteins↗

PubMed2003

Practice and difficulty evoke anatomically and pharmacologically dissociable brain activation dynamics.

Brain activation is adaptive to task difficulty and practice. We used functional MRI to map brain systems activated by an object-location learning task in 24 healthy elderly volunteers each scanned following placebo and two of four active drugs studied. We distinguished a fronto-striatal system adaptive to difficulty from a posterior system adaptive to practice. Fronto-striatal response to increased cognitive load was significantly attenuated by scopolamine, sulpiride and methylphenidate; practice effects were not modulated by these drugs but were enhanced by diazepam. We also found enhancement by methylphenidate, and attenuation by sulpiride, of load response in premotor, cingulate and parietal regions comprising a spatial attention network. Difficulty and practice evoke anatomically and pharmacologically dissociable brain activation dynamics, which are probably mediated by different neurotransmitter systems in humans.

Adrenergic Uptake Inhibitors↗

PubMed2003

Surface expression of minichromosome maintenance proteins provides a novel method for detecting patients at risk for developing adenocarcinoma in Barrett's esophagus.

PURPOSE: The purpose is to determine whether a novel cell cycle marker, minichromosome maintenance protein 2 (Mcm2), predicted esophageal adenocarcinoma (AC) risk in Barrett's esophagus (BE) and whether this could be used in combination with a surface sampling method. EXPERIMENTAL DESIGN: Archival specimens [30 normal squamous esophagus (NE), 20 gastric antrum (GA), 13 duodenum (D2), 62 BE +/- dysplasia, and 16 (AC)] were stained for Mcm2. Sequential biopsies from nine patients who developed AC during surveillance were compared with 18 matched controls who did not progress. Prospective endoscopic cytological brushings (61 NE, 90 BE +/- dysplasia, and 11 AC) were scored as Mcm2 positive or negative. RESULTS: Mcm2 was not expressed on the luminal surface of NE, GA, and D2. In BE, the percentage of surface cells expressing Mcm2 correlated highly with the degree of dysplasia (P < 0.0001). In patients who developed AC, biopsies before dysplasia had higher Mcm2 expression than the matched control patients (mean, 28.4 and 3.4% positive cells, respectively, P < 0.0001). In the prospective cohort, the histopathological diagnosis of dysplasia or AC and the Mcm2-positive brushings were concordant in 91% of the patients (P < 0.005), and the results correlated with the frequency of cases with surface expression of Mcm2 in the retrospective study (P < 0.0001). CONCLUSIONS: Surface expression of Mcm2 can be used to detect dysplasia and AC, as well as patients with BE at risk for subsequent development of dysplasia and AC. A brushing technique combined with Mcm2 staining has the potential to be exploited in surveillance and screening protocols.

Adenocarcinoma↗

PubMed2002

Tar ball frequency data and analytical results from a long-term beach monitoring program.

Following the spill of fuel oils from the New Carissa in February 1999, approximately 300 km of beaches on the Pacific coast of North America were surveyed. A long-term observation program focused on the documentation of stranded tar balls in the vicinity of the spill site. Systematic beach surveys which were conducted over the period March 1999 to April 2001 and semi-logarithmic scale, time-series plots proved the most useful format for identifying trends. Beach monitoring continued through to August 2001. by which time 212 tar balls had been analyzed by GC/MS for their chemical characteristics. The samples of tar balls collected between February 1999 and August 2001 were qualitatively compared with New Carissa source oils (NCSO) and 101 (48%) were not consistent with NSCO. The presence of tar balls that are not related to an incident can confound attempts to define cleanup or endpoint criteria and to assess possible injury to natural resources.

Accidents↗

PubMed2002

Dendroaspis natriuretic peptide-like immunoreactivity and its regulation in rat aortic vascular smooth muscle.

Dendroaspis natriuretic peptide (DNP) is a recently isolated 38 amino acid peptide that shares structural and functional properties with the other members of the natriuretic peptide family. The present study demonstrates the presence of DNP-like immunoreactivity in sections of rat aorta, carotid artery and renal vasculature and tubules. DNP-like immunoreactivity was detected in culture aortic vascular smooth muscle cells and medium and is regulated by endothelin-1, angiotensin II and sodium nitroprusside but not by transforming growth factor-beta. Our observations indicate that DNP elicits a marked inhibitory effect on DNA synthesis in culture rat aortic vascular smooth muscle cells.

Amino Acid Sequence↗