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Biomedical subjects

R J Brown

Publications and source records attributed to R J Brown.

At least 19 recordsLinked to original sources
PubMed2006

New insights into growth hormone action.

It has been 75 years since Evans and Long identified a somatic growth-promoting substance in pituitary extracts, yet it is only in the last 20 years that the molecular basis for this action has been established. Three key elements in this elucidation were the cloning of the GH receptor, the identification of Janus kinase (JAK) 2 as the receptor-associated tyrosine kinase, and the delineation of signal transduction and activators of transcription (STAT) 5a/b as the key transcription factor(s) activated by JAK2. The interaction between these three elements results in enhanced postnatal growth and is the subject of this review. We describe a new model for GH receptor activation based on subunit rotation within a constitutive dimer, together with the phenotype and hepatic transcript profile of mice with targeted knockins to the receptor cytoplasmic domain. These support a central role for STAT5a/b in postnatal growth.

Amino Acid Sequence↗
PubMed2004

Differential sensitivity of three marine invertebrates to copper assessed using multiple biomarkers.

Understanding how biomarkers relate to each other on exposure to particular contaminants in different species is key to their widespread application in environmental management. However, few studies have systematically used multiple biomarkers in more than a single species to determine the variability of sublethal effects of a particular contaminant. In this study, three marine invertebrates, the shore crab Carcinus maenas, the common limpet Patella vulgata and the blue mussel Mytilus edulis, were exposed over 7 days in the laboratory to environmentally realistic concentrations of the priority pollutant copper. A combination of molecular, cellular and physiological biomarkers was measured in each organism to detect the toxic effects of copper. Biomarkers included lysosomal stability (neutral red retention), neurotoxicity (acetylcholinesterase activity), metabolic impairment (total haemolymph protein), physiological status (heart rate) and induction of protective metallothionein proteins. P. vulgata was the most sensitive to copper with significant effects measured in all biomarkers at concentrations of 6.1 microg Cu l(-1). In C. maenas, cellular and neurotoxic endpoints were affected significantly only at 68.1 microg Cu l(-1). Exposure to copper also induced metallothionein production in crabs. Over a 7-day exposure period, M. edulis was the most tolerant species to copper with significant effects being observed at the cellular level only at 68.1 microg Cu l(-1) . In all three species, cellular and neurotoxic pathways were more sensitive to disruption than physiological processes (protein and heart rate). Results illustrate how a suite of biomarkers applied to different sentinel species can provide a 'diagnosis of stress', whereby, effects at the molecular level can be used to interpret the level of physiological impairment of the organism.

Acetylcholinesterase↗
PubMed2004

Reliability of self-reported diagnoses in patients with neurologically unexplained symptoms.

BACKGROUND: Patients with neurologically unexplained symptoms (NUS) often have a previous history of other medically unexplained symptoms. A past history of such symptoms can help make a positive diagnosis of a somatoform or affective disorder, and enable appropriate management strategies. However, information on past medical diagnoses is primarily obtained from patient interviews and may be inaccurate, particularly in patients with NUS. OBJECTIVE: To assess the reliability of past medical diagnoses reported by patients with NUS compared with patients with confirmed neurological disease (ND) without suspicion of somatoform illness. METHODS: 21 patients with NUS and 16 patients with ND were interviewed about their current and past medical problems and diagnoses. The accuracy of the reported diagnoses was assessed through examination of their complete general practice notes. RESULTS: The median number of previous diagnoses reported by patients with NUS was significantly higher than in controls (7 v 3, p = 0.001). There was no difference in the median number of confirmed diagnoses between the two groups (2 v 2.5); however, the median percentage of reported diagnoses confirmed by investigations was significantly smaller in the NUS group (22% v 80%, p = 0.001). The additional diagnoses reported by patients with NUS not only comprised functional syndromes such as irritable bowel syndrome or non-cardiac chest pain (6% v 0%, p = 0.01), but also organic diagnoses which had either been unequivocally excluded (5% v 0%, p = 0.006), were based on equivocal findings often found after multiple investigations (9% v 0%, p = 0.01), or had not been investigated before a clinical diagnosis was made (50% v 18%, p = 0.04). CONCLUSION: Reported previous diagnoses should not be taken at face value when the current differential diagnosis includes a functional/somatoform neurological syndrome, particularly if the list of past medical diagnoses is long. Confirmation of previous diagnoses from alternative sources may contribute to a diagnosis of somatoform disorder, allowing appropriate management strategies for the current (and past) complaints to be initiated.

Adult↗
PubMed2004

Religiosity is associated with hippocampal but not amygdala volumes in patients with refractory epilepsy.

OBJECTIVE: To assess the relationship between the behavioural triad of hyper-religiosity, hypergraphia and hyposexuality in epilepsy, and volumes of the mesial temporal structures. METHOD: Magnetic resonance images were obtained from 33 patients with refractory epilepsy and mesial temporal structure volumes assessed. Amygdala and hippocampal volumes were then compared in high and low scorers on the religiosity, writing, and sexuality sub-scales of the Neurobehavioural Inventory. RESULTS: Patients with high ratings on the religiosity scale had significantly smaller right hippocampi. Religiosity scores rated by both patient and carer showed a significant negative correlation with right hippocampal volumes in this group. There were no other differences in amygdala or hippocampal volumes between these groups, or between high and low scorers on the writing and sexuality sub-scales. CONCLUSIONS: These findings suggest that right hippocampal volumes are negatively correlated with religiosity in patients with refractory epilepsy.

Adult↗
PubMed2003

Suppressor of cytokine signalling gene expression is elevated in breast carcinoma.

Cytokines are important for breast cell function, both as trophic hormones and as mediators of host defense mechanisms against breast cancer. Recently, inducible feedback suppressors of cytokine signalling (SOCS/JAB/SSI) have been identified, which decrease cell sensitivity to cytokines. We examined the expression of SOCS genes in 17 breast carcinomas and 10 breast cancer lines, in comparison with normal tissue and breast lines. We report elevated expression of SOCS-1-3 and CIS immunoreactive proteins within in situ ductal carcinomas and infiltrating ductal carcinomas relative to normal breast tissue. Significantly increased expression of SOCS-1-3 and CIS transcripts was also shown by quantitative in situ hybridisation within both tumour tissue and reactive stroma. CIS transcript expression was elevated in all 10 cancer lines, but not in control lines. However, there was no consistent elevation of other SOCS transcripts. CIS protein was shown by immunoblot to be present in all cancer lines at increased levels, mainly as the 47 kDa ubiquitinylated form. A potential proliferative role for CIS overexpression is supported by reports that CIS activates ERK kinases, and by strong induction in transient reporter assays with an ERK-responsive promoter. The in vivo elevation of SOCS gene expression may be part of the host/tumour response or a response to autocrine/paracrine GH and prolactin. However, increased CIS expression in breast cancer lines appears to be a specific lesion, and could simultaneously shut down STAT 5 signalling by trophic hormones, confer resistance to host cytokines and increase proliferation through ERK kinases.

Breast Neoplasms↗
PubMed2003

A copepod life-cycle test and growth model for interpreting the effects of lindane.

A full life-cycle test was performed to measure the effects of lindane (3.2-3,200 microg l(-1)) on the survival, development and reproduction of the freshwater copepod Bryocamptus zschokkei. This copepod survived at relatively high concentrations of lindane compared with other freshwater crustaceans with a 10 day LC50 of 241 microg l(-1) (95% CL of 141-440). 'Equiproportional development', which assumes that each moult stage represents a specific proportion of the total development time, and is not affected by processes that influence metabolism such as temperature and food quality, was used to determine the mode of action of lindane on development in B. zschokkei. Development to adult was significantly longer at 100 microg l(-1) lindane compared with the controls, however, development remained equiproportional regardless of lindane exposure. Increased development times, therefore, are not due to a direct effect of lindane on the moulting process but are due probably to reduced food intake or increased metabolism through the stress imposed by toxicant exposure. Although the survival data suggest that B. zschokkei is relatively tolerant of lindane exposure, reproduction was affected at low lindane concentrations. At 32 microg l(-1) lindane, significantly fewer eggs and viable offspring were produced per female compared with the solvent control. At very low lindane concentrations (3.2 and 10 microg l(-1)), there was a significant increase in the numbers of offspring produced per female compared with the controls and this is interpreted as a hormesis effect. In conclusion, a full life-cycle test demonstrated B. zschokkei is relatively sensitive to lindane compared with other freshwater crustaceans. Incorporating a copepod growth model (equiproportional development) into the life-cycle test design, provided information on the dominant mode of action of the toxicant.

Animals↗
PubMed2002

Investigation of the possible spread of foot-and-mouth disease virus by the burning of animal carcases on open pyres.

An atmospheric dispersion model was used to predict the airborne spread and concentrations of foot-and-mouth disease virus within the plumes generated by 11 pyres built to burn infected carcases during the epidemic of 2001 in the UK. On the basis of assumptions about the quantity of virus emitted during the three hours after the pyres were built and the threshold concentration of virus required to cause an infection in cattle, it was concluded that none of the disease breakdowns which occurred under the plumes was due to the spread of virus from the pyres.

Air Microbiology↗
PubMed2002

Surgeon workload and motion efficiency with robot and human laparoscopic camera control.

BACKGROUND: Surgeons are now being assisted by robotic systems in a wide range of laparoscopic procedures. Some reports have suggested that robot-assisted camera control (RACC) may be superior to a human driver in terms of quality of view and directional precision, as well as long-term cost savings. Therefore, we setout to investigate the impact of RACC of surgeon motion efficiency. METHODS: Twenty pigs were randomized to undergo a standardized laparoscopic Nissen fundoplication with either a human or RACC system, the AESOP 2000. All procedures were performed by the same surgical fellow. Time was recorded for dissection and suture phases. Inertial motion sensors were used to monitor both the surgeon's hands and the camera. Digitized data were analyzed to produce summary measures related to overall motion. RESULTS: The operative times were slightly longer with RACC (mean 80.2 +/- 20.6 vs 73.1 +/- 15.4 min, not significant). With regard to operative times and surgeon motion measures, the only statistically significant differences were for setup and breakdown times, which contributed <15% to the total time for the procedure. CONCLUSION: In terms of impact on surgeon motion efficiency and operative time under normal surgical conditions, RACC is essentially the same as an expert human driver. However, careful planning and structuring of the surgical suite may yield some small gains in operative time.

Animals↗
PubMed2001

Feline leukemia virus in a captive bobcat.

An 11-mo-old captive-bred male neutered bobcat (Felis rufus) presented with lethargy, anorexia, leukopenia, neutropenia, lymphopenia, and nonregenerative anemia. The animal was diagnosed as feline leukemia virus (FeLV) positive by immunofluorescent antibody and enzyme-linked immunosorbant assay (ELISA) testing. It died despite supportive care. Pathologic examination revealed multifocal non-suppurative encephalitis, diffuse interstitial pneumonia, multifocal hepatocellular necrosis, non-suppurative peritonitis, and lymphoid depletion. FeLV was isolated from peripheral blood mononuclear cells, bone marrow, spleen, and lymph node. FeLV-specific gag sequences were amplified by DNA polymerase chain reaction (PCR) and aligned with known domestic cat FeLV's. The source of the virus was speculated to be a domestic cat that was a surrogate nurse. Case reports of FeLV in nondomestic felids are few, and FeLV does not appear to be enzootic in wild felids, except European wildcats (Felis silvestris) in France and Scotland. Introduction of FeLV into free-living and captive nondomestic felid populations could have serious consequences for their health and survival. Measures to prevent the introduction of this virus to nondomestic felids are warranted.

Animals↗
PubMed2000

Use of amino acid analysis for estimating the individual concentrations of proteins in mixtures.

The concentrations of five individual proteins in a mixture were determined from one amino acid analysis of the mixture by solving for each protein using simultaneous equations. Dried casein and whey were separated into five individual protein components using reversed-phase HPLC. Individual proteins were collected and analyzed for amino acid composition. These data were used as standards. Mixtures of purified proteins were analyzed for total amino acid composition and the concentrations of individual proteins in the mixtures were determined by solving simultaneous equations based on the amino acid analysis composition of the standards.

Amino Acids↗
PubMed2000

Regulation of collagenase-3 gene expression in osteoblastic and non-osteoblastic cell lines.

Collagenase-3 expression in osteoblastic (UMR 106-01, ROS 17/2.8) and non-osteoblastic cell lines (BC1, NIH3T3) was examined. We observed that parathyroid hormone (PTH) induces collagenase-3 expression only in UMR cells but not in BC1 (which express collagenase-3 constitutively) or ROS and NIH3T3 cells. Since we know from UMR cells that the AP-1 factors and Cbfa1 are required for collagenase-3 expression, we analyzed the expression and PTH regulation of these factors by gel shift and Northern blot analysis in all cell lines. Gel mobility shift with a [(32)P]-labeled collagenase-3 AP-1 site probe indicated the induction of c-Fos in osteoblastic cells upon PTH treatment. While c-fos was induced in UMR cells, both c-fos and jun B were induced in ROS cells. Since Jun B is inhibitory of Fos and Jun in the regulation of the rat collagenase-3 gene in UMR cells, it is likely that high levels of Jun B prevent PTH stimulation of collagenase-3 in ROS cells. When we carried out gel shift analysis with a [(32)P]-labeled collagenase-3 RD (runt domain) site probe and Northern blot analysis with a Cbfa1 specific probe, we have observed the presence of Cbfa1 in both osteoblastic and non-osteoblastic cell lines, but there was no change in the levels of Cbfa1 RNA or protein in these cells under either control conditions or PTH treatment. From our studies above, it is evident that the expression of collagenase-3 and its regulation by PTH in osteoblastic and non-osteoblastic cells may be influenced by differential temporal stimulation of the AP-1 family members, especially c-Fos and Jun B along with the potential for posttranslational modification(s) of Cbfa1.

Animals↗
PubMed2000

Changes in cortical activity during suppression in stereoblindness.

Patients with strabismus or anisometropic amblyopia fixate and attend with one eye and suppress the image from the other eye. Here we use a visual evoked potential technique to show that patients who lack normal stereopsis retain suppressive binocular interactions but lack a characteristic form of non-linear binocular interaction that is present in normal observers. Oscillating grating targets presented at different temporal frequencies in the two eyes evoke a strong response in normal observers at a frequency equal to the sum of the two input frequencies for fusable targets but not for rivalrous ones. However increasing contrast in one eye reduces the response amplitude from the other eye under either fusable (dichoptic masking) or rivalrous conditions. Stereo-deficient observers lack the sum-frequency response, but retain dichoptic masking interactions. Dichoptic masking is stronger when the masker is presented to the patients' dominant rather than non-dominant eyes, suggesting that a subset of preserved binocular inhibitory interactions form the basis of clinical suppression.

Blindness↗
PubMed2000

Distribution of the HLA-DQA1 and polymarker alleles in the Basque population of Spain.

HLA-DQA1 and polymarker (LDLR, GYPA, HBGG, D7S8, and GC) genotypic and allelic frequencies are determined for a population sample of 102 unrelated Basque individuals using PCR-based methodology. All six loci met Hardy-Weinberg expectations in at least two of the three analyses performed (HLA-DQA1 failed to meet Hardy-Weinberg requirements in the heterozygote deficiency test). Three linkage analysis programs (GDA, GENEPOP and LINKDOS) detected possible linkage disequilibrium between LDLR and HBGG and results from one (GDA) indicated a possible non-random association between HBGG and HLA-DQA1 as well. Allelic data for the six loci are compared to that previously established for other populations (18 for polymarker alone, 16 for polymarker plus HLA-DQA1) to determine homogeneity between the Basque sample and these groups. According to the results of G-tests based on these loci, the Tadjik, a nomadic Caucasian group from western Asia, and the Basque residents are the only sample populations surveyed that are homogenous with the Basque sample. Phylogenetic analysis places the Basque sample correctly within the Caucasian cluster.

Alleles↗
PubMed2000

Relationships between (1)H NMR relaxation data and some technological parameters of meat: a chemometric approach.

In this paper chemometrics (ANOVA and PCR) is used to measure unbiased correlations between NMR spin-echo decays of pork M. Longissimus dorsi obtained through Carr-Purcell-Meiboom-Gill (CPMG) experiments at low frequency (20 MHz) and the values of 14 technological parameters commonly used to assess pork meat quality. On the basis of the ANOVA results, it is also found that the CPMG decays of meat cannot be best interpreted with a "discrete" model (i.e., by expanding the decays in a series of a discrete number of exponential components, each with a different transverse relaxation time), but rather with a "continuous" model, by which a continuous distribution of T(2)'s is allowed. The latter model also agrees with literature histological results.

Algorithms↗
PubMed2000

Uniform-penalty inversion of multiexponential decay data. II. Data spacing, T(2) data, systemic data errors, and diagnostics.

The basic method of UPEN (uniform penalty inversion of multiexponential decay data) is given in an earlier publication (Borgia et al., J. Magn. Reson. 132, 65-77 (1998)), which also discusses the effects of noise, constraints, and smoothing on the resolution or apparent resolution of features of a computed distribution of relaxation times. UPEN applies negative feedback to a regularization penalty, allowing stronger smoothing for a broad feature than for a sharp line. This avoids unnecessarily broadening the sharp line and/or breaking the wide peak or tail into several peaks that the relaxation data do not demand to be separate. The experimental and artificial data presented earlier were T(1) data, and all had fixed data spacings, uniform in log-time. However, for T(2) data, usually spaced uniformly in linear time, or for data spaced in any manner, we have found that the data spacing does not enter explicitly into the computation. The present work shows the extension of UPEN to T(2) data, including the averaging of data in windows and the use of the corresponding weighting factors in the computation. Measures are implemented to control portions of computed distributions extending beyond the data range. The input smoothing parameters in UPEN are normally fixed, rather than data dependent. A major problem arises, especially at high signal-to-noise ratios, when UPEN is applied to data sets with systematic errors due to instrumental nonidealities or adjustment problems. For instance, a relaxation curve for a wide line can be narrowed by an artificial downward bending of the relaxation curve. Diagnostic parameters are generated to help identify data problems, and the diagnostics are applied in several examples, with particular attention to the meaningful resolution of two closely spaced peaks in a distribution of relaxation times. Where feasible, processing with UPEN in nearly real time should help identify data problems while further instrument adjustments can still be made. The need for the nonnegative constraint is greatly reduced in UPEN, and preliminary processing without this constraint helps identify data sets for which application of the nonnegative constraint is too expensive in terms of error of fit for the data set to represent sums of decaying positive exponentials plus random noise.

Geologic Sediments↗
PubMed2000

Cardiogenic shock due to cardiac free-wall rupture or tamponade after acute myocardial infarction: a report from the SHOCK Trial Registry. Should we emergently revascularize occluded coronaries for cardiogenic shock?

OBJECTIVES: We sought to compare the characteristics and outcomes of patients with acute myocardial infarction (MI) and cardiogenic shock (CS) caused by rupture of the ventricular free wall or tamponade versus shock from other causes. BACKGROUND: Free-wall rupture is a recognized cause of mortality in patients with acute MI. Some of these patients present subacutely, which provides an opportunity for intervention. Recognition of factors that distinguish them from the overall shock cohort would be beneficial. METHODS: The international SHOCK Trial Registry enrolled patients concurrently with the randomized SHOCK Trial. Thirty-six centers consecutively enrolled all patients with suspected CS after MI, regardless of trial eligibility. RESULTS: Of the 1,048 patients studied, 28 (2.7%) had free-wall rupture or tamponade. These patients had less pulmonary edema, less diabetes, less prior MI, and less prior congestive heart failure (all p < 0.05). They more often had new Q waves in two or more leads (51.9% vs. 31.5%, p < 0.04), but MI location and time to shock onset after MI did not differ. Of patients with rupture or tamponade, 75% had pericardial effusions. No hemodynamic characteristics identified patients with rupture/tamponade. Most patients with rupture/tamponade had surgery and/or pericardiocentesis (27/28); their in-hospital survival rate was identical to that of the group overall (39.3%). Women and older patients with rupture/tamponade tended to survive intervention less often. CONCLUSIONS: Free-wall rupture and tamponade may present as CS after MI, and survival after intervention is similar to that of the overall shock cohort. All patients with CS after MI should have echocardiography in order to detect subacute rupture or tamponade and initiate appropriate interventions.

Aged↗