Images of interest. Gastrointestinal: white small bowel, macroglobulinemia and splenic marginal-zone lymphoma.
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Aged, 80 and over↗
Biomedical subjects
C Brennan
Publications and source records attributed to C Brennan.
EphA/ephrin-A interactions during optic nerve regeneration: restoration of topography and regulation of ephrin-A2 expression.
During visual system development, interactions between Eph tyrosine kinase receptors and their ligands, the ephrins, guide retinal ganglion cell (RGC) axons to their topographic targets in the optic tectum. Here we show that Eph/ephrin interactions are also involved in restoring topography during RGC axon regeneration in goldfish. Following optic nerve crush, EphA/ephrin-A interactions were blocked by intracranial injections of recombinant Eph receptor (EphA3-AP) or phospho-inositol phospholipase-C. Topographic errors with multiple inputs to some tectal loci were detected electrophysiologically and increased projections to caudal tectum demonstrated by RT-97 immunohistochemistry. In EphA3-AP-injected fish, ephrin-A2-expressing cells in the retino-recipient tectal layers were reduced in number compared to controls and their distribution was no longer graded. The findings, supported by in vitro studies, implicate EphA/ephrin-A interactions in restoring precise topography and in regulating ephrin-A2 expression during regeneration.
Animals↗
Production of pro-inflammatory cytokines correlates with the symptoms of acute sickness behaviour in humans.
BACKGROUND: Elaboration of the concept of cytokine-induced sickness behaviour in recent years has opened new avenues for understanding brain involvement in sickness and recovery processes. Additionally, this has led to much speculation about the role of the immune system in neuropsychiatric syndromes, including depression and chronic fatigue. However, few studies have examined this phenomenon as it naturally occurs in sick humans, and none has attempted to document the quantitative relationships between cytokine levels and non-specific symptoms. The aim of this research was to examine human sickness behaviour and its immunological correlates in documented Epstein-Barr virus (EBV), Q fever or Ross River virus (RRV) infections. METHOD: We studied two separate samples. The first consisted of 21 patients with acute Q fever. The second included 48 patients with acute RRV or EBV infection. Psychological and somatic symptom profiles were derived from self-report measures completed at enrolment. Quantification of proinflammatory cytokines [interleukin (IL)-1beta and IL-6] in sera and supernatants of peripheral blood mononuclear cell (PBMC) cultures was undertaken by specific ELISAs. RESULTS: Levels of IL-1beta and IL-6 spontaneously released from PBMC cultures were consistently correlated with reported manifestations of acute sickness behaviour including fever, malaise, pain, fatigue, mood and poor concentration. CONCLUSIONS: IL-1beta and IL-6 produced as part of the host response represent sensitive markers of sickness behaviour in humans with acute infection. Further work is needed to systematically characterize the spectrum and natural history of sickness behaviour in humans and to elucidate its biological basis.
Acute Disease↗
Immunodetection of UCP1 in rat thymocytes.
Thymi were dissected from rats and connective tissue was removed. Mitochondria were purified from isolated thymocytes and immunoblot analysis was performed using an antibody specific for uncoupling protein 1, which detected a 32.5 kDa protein associated with mitochondria from the thymocytes. This implies that rat thymocytes contain uncoupling protein 1.
Animals↗
Electroporation of single cells and tissues with an electrolyte-filled capillary.
We show how an electrolyte-filled capillary (EFC) coupled to a high-voltage power supply can be used as a versatile electroporation tool for the delivery of dyes, drugs, and biomolecules to the cytoplasm of single cells and cells in tissues. A large-voltage pulse applied across the EFC (fused silica, 30 cm long, 375-microm o.d., 30-microm i.d.) gives rise to a small electric field outside the terminus of the EFC, which causes pore formation in cell membranes and induces an electroosmotic flow of electrolyte. When the EFC contains cell-loading agents, then the electroosmotic flow delivers the agents at the site of pore formation. The combination of pore formation and delivery enables loading of materials into the cytoplasm. By patch-clamp and fluorescence microscopy, formation of pores was observed at estimated transmembrane voltages of <85 mV with half-maximum values around 206 mV. The electroporation protocol was demonstrated by introduction of fluorogenic dyes into single NG108-15 cells, cellular processes, and small populations of cells in organotypic hippocampal cultures. Preliminary results are shown in which this protocol was employed for in vivo electroporation of ventral mesencephalon in rat brains. The technique was also used to access organelle-based detection systems inside cells. As a demonstration, 1,4,5-inositoltriphosphate was added to the electrolyte and detected by intracellular organelles in electroporated cells.
Animals↗
The effect of 1,3-diaryl-[1H]-pyrazole-4-acetamides on glucose utilization in ob/ob mice.
This article provides evidence of a new class of compounds, 1,3-diaryl-[1H]-pyrazole-4-acetamides, initially identified from their ability to increase glucose transport in an adipocyte and muscle cell line and ultimately demonstrating dramatic glucose lowering in ob/ob mice, a diabetic animal model. The lead compound, 1, possessed some behavioral-like effects which were removed by structural variation during the course of this investigation. Specifically, 11g (R1 = meta-CF(3), Ar2 = 4'biphenyl, R3 = diethylamide) illustrated the potency of this series with ED(50) values for glucose lowering in ob/ob mice of 3.0 mg/kg/day. Concomitant with its effect on glucose lowering, 11g also caused a 50% reduction in insulin levels consistent with an agent that increases whole body insulin sensitivity. 11g showed favorable pharmacokinetic data with acceptable absorption, negligible metabolism, and good duration of action. 11g demonstrated no appreciable adipogenic effect through PPAR gamma agonism, a characteristic of the thiazolidinediones (TZD), and so represents a potentially new class of agents for the treatment of diabetes.
Acetamides↗
Morphogenesis of prechordal plate and notochord requires intact Eph/ephrin B signaling.
Eph receptors and their ligands, the ephrins, mediate cell-to-cell signals implicated in the regulation of cell migration processes during development. We report the molecular cloning and tissue distribution of zebrafish transmembrane ephrins that represent all known members of the mammalian class B ephrin family. The degree of homology among predicted ephrin B sequences suggests that, similar to their mammalian counterparts, zebrafish B-ephrins can also bind promiscuously to several Eph receptors. The dynamic expression patterns for each zebrafish B-ephrin support the idea that these ligands are confined to interact with their receptors at the borders of their complementary expression domains. Zebrafish B-ephrins are expressed as early as 30% epiboly and during gastrula stages: in the germ ring, shield, prechordal plate, and notochord. Ectopic overexpression of dominant-negative soluble ephrin B constructs yields reproducible defects in the morphology of the notochord and prechordal plate by the end of gastrulation. Notably disruption of Eph/ephrin B signaling does not completely destroy structures examined, suggesting that cell fate specification is not altered. Thus abnormal morphogenesis of the prechordal plate and the notochord is likely a consequence of a cell movement defect. Our observations suggest Eph/ephrin B signaling plays an essential role in regulating cell movements during gastrulation.
Amino Acid Sequence↗
Human chorionic gonadotrophin inhibition of pregnant human myometrial contractility.
OBJECTIVE: To evaluate the effect of human chorionic gonadotrophin (hCG) on pregnant human myometrial contractility in vitro and to determine whether the hCG-elicited effect was oestrogen dependant. METHODS: Isometric tension recording was performed under physiological conditions in isolated myometrial strips from biopsies obtained at elective caesarean section. The effect of cumulative additions of hCG (0.001, 0.01, 0.1, 1.0 and 10 iu/mL) on myometrial contractility was evaluated. Secondarily, the contractile activity of pregnant myometrium following hCG exposure was investigated in tissue pre-treated with beta-oestradiol. RESULTS: hCG exerted a statistically significant relaxant effect on pregnant human myometrial tissue. The relaxant effect increased with increasing concentrations of hCG from 8.96% (SEM 2.06) (0.001 iu/mL hCG: P < 0.01 ) to a net cumulative total of 58.50% (SEM 3.74) (10 iu/mL hCG; P < 0.01). The relaxant effect was also time-dependant, increasing in magnitude throughout the duration of experiments. Beta-oestradiol did not significantly affect the response of myometrial tissue to hCG. CONCLUSIONS: These results clearly demonstrate that hCG exerts a significant concentration-dependant relaxant effect on human myometrial tissue obtained rate in pregnancy. These findings outline an inhibitory physiological role of hCG on human myometrial contractility and raise the possibility of its potential use as a tocolytic.
Adult↗
Clinical computing: electronic sign-out using a personal digital assistant.
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California↗
Eph signalling functions downstream of Val to regulate cell sorting and boundary formation in the caudal hindbrain.
Rhombomeres are segmental units of the developing vertebrate hindbrain that underlie the reiterated organisation of cranial neural crest migration and neuronal differentiation. valentino (val), a zebrafish homologue of the mouse bzip transcription factor-encoding gene, kreisler, is required for segment boundary formation caudal to rhombomere 4 (r4). val is normally expressed in r5/6 and is required for cells to contribute to this region. In val(-) mutants, rX, a region one rhombomere in length and of mixed identity, lies between r4 and r7. While a number of genes involved in establishing rhombomeric identity are known, it is still largely unclear how segmental integrity is established and boundaries are formed. Members of the Eph family of receptor tyrosine kinases and their ligands, the ephrins, are candidates for functioning in rhombomere boundary formation. Indeed, expression of the receptor ephB4a coincides with val in r5/6, whilst ephrin-B2a, which encodes a ligand for EphB4a, is expressed in r4 and r7, complementary to the domain of val expression. Here we show that in val(-) embryos, ephB4a expression is downregulated and ephrin-B2a expression is upregulated between r4 and r7, indicating that Val is normally required to establish the mutually exclusive expression domains of these two genes. We show that juxtaposition of ephB4a-expressing cells and ephrin-B2a-expressing cells in the hindbrain leads to boundary formation. Loss of the normal spatial regulation of eph/ephrin expression in val mutants correlates not only with absence of boundaries but also with the inability of mutant cells to contribute to wild-type r5/6. Using a genetic mosaic approach, we show that spatially inappropriate Eph signalling underlies the repulsion of val(-) cells from r5/6. We propose that Val controls eph expression and that interactions between EphB4a and Ephrin-B2a mediate cell sorting and boundary formation in the segmenting caudal hindbrain.
Animals↗
1-Phenyl-5-pyrazolyl ureas: potent and selective p38 kinase inhibitors.
Inhibitors of the MAP kinase p38 are potentially useful for the treatment of arthritis and osteoporosis. Several 2,3-dichlorophenyl ureas were identified as small-molecule inhibitors of p38 by a combinatorial chemistry effort. Optimization for cellular potency led to the discovery of a new class of potent and selective p38 kinase inhibitors, exemplified by the 1-phenyl-5-pyrazolyl urea 7 (IC50 = 13 nM).
Antirheumatic Agents↗
A principal components-based method for the detection of neuronal activity maps: application to optical imaging.
We present a novel analysis technique for the extraction of neuronal activity patterns from functional imaging data. We illustrate this technique on data from optical imaging. Optical imaging of the mammalian visual cortex probe the patterns in which the neuronal responses to various aspects of the visual world, such as orientation and color, are spatially organized within the cortex. Recovering these patterns from the image data is a challenging problem as the neuronal response signal is extremely weak in comparison to the background vegetative processes (e.g., circulation and respiration). The proposed technique obtains the neuronal activity pattern using a combination of principal component analysis and statistical significance testing. The performance of this method is compared with the results of existing analysis techniques. The comparison shows the new method to be more sensitive than previous methods.
Animals↗
Characterization of single-cell electroporation by using patch-clamp and fluorescence microscopy.
Electroporation of single NG108-15 cells with carbon-fiber microelectrodes was characterized by patch-clamp recordings and fluorescence microscopy. To minimize adverse capacitive charging effects, the patch-clamp pipette was sealed on the cell at a 90(o) angle with respect to the microelectrodes where the applied potential reaches a minimum. From transmembrane current responses, we determined the electric field strengths necessary for ion-permeable pore formation and investigated the kinetics of pore opening and closing as well as pore open times. From both patch-clamp and fluorescence microscopy experiments, the threshold transmembrane potentials for dielectric breakdown of NG108-15 cells, using 1-ms rectangular waveform pulses, was approximately 250 mV. The electroporation pulse preceded pore formation, and analyte entry into the cells was dictated by concentration, and membrane resting potential driving forces. By stepwise moving a cell out of the focused field while measuring the transmembrane current response during a supramaximal pulse, we show that cells at a distance of approximately 30 microm from the focused field were not permeabilized.
Animals↗
Ephrin-B regulates the Ipsilateral routing of retinal axons at the optic chiasm.
In Xenopus tadpoles, all retinal ganglion cells (RGCs) send axons contralaterally across the optic chiasm. At metamorphosis, a subpopulation of EphB-expressing RGCs in the ventrotemporal retina begin to project ipsilaterally. However, when these metamorphic RGCs are grafted into embryos, they project contralaterally, suggesting that the embryonic chiasm lacks signals that guide axons ipsilaterally. Ephrin-B is expressed discretely at the chiasm of metamorphic but not premetamorphic Xenopus. When expressed prematurely in the embryonic chiasm, ephrin-B causes precocious ipsilateral projections from the EphB-expressing RGCs. Ephrin-B is also found in the chiasm of mammals, which have ipsilateral projections, but not in the chiasm of fish and birds, which do not. These results suggest that ephrin-B/EphB interactions play a key role in the sorting of axons at the vertebrate chiasm.
Animals↗
Group therapy program development: clinician-administrator collaboration in new practice settings.
Despite being practiced widely and applied to many conditions, group therapy is underutilized in some segments of the market. One important reason for its underuse is the lack of a model for group program development. Program development requires an integrated effort involving many disciplines. Effective collaboration between clinicians and administrators is an essential but underappreciated component in the development of group programs in independent practice associations.
Health Facility Administrators↗
Anteroposterior patterning is required within segments for somite boundary formation in developing zebrafish.
Somite formation involves the establishment of a segmental prepattern in the presomitic mesoderm, anteroposterior patterning of each segmental primordium and formation of boundaries between adjacent segments. How these events are co-ordinated remains uncertain. In this study, analysis of expression of zebrafish mesp-a reveals that each segment acquires anteroposterior regionalisation when located in the anterior presomitic mesoderm. Thus anteroposterior patterning is occurring after the establishment of a segmental prepattern in the paraxial mesoderm and prior to somite boundary formation. Zebrafish fss(-), bea(-), des(-) and aei(-) embryos all fail to form somites, yet we demonstrate that a segmental prepattern is established in the presomitic mesoderm of all these mutants and hox gene expression shows that overall anteroposterior patterning of the mesoderm is also normal. However, analysis of various molecular markers reveals that anteroposterior regionalisation within each segment is disturbed in the mutants. In fss(-), there is a loss of anterior segment markers, such that all segments appear posteriorized, whereas in bea(-), des(-) and aei(-), anterior and posterior markers are expressed throughout each segment. Since somite formation is disrupted in these mutants, correct anteroposterior patterning within segments may be a prerequisite for somite boundary formation. In support of this hypothesis, we show that it is possible to rescue boundary formation in fss(-) through the ectopic expression of EphA4, an anterior segment marker, in the paraxial mesoderm. These observations indicate that a key consequence of the anteroposterior regionalisation of segments may be the induction of Eph and ephrin expression at segment interfaces and that Eph/ephrin signalling subsequently contributes to the formation of somite boundaries.
Amino Acid Sequence↗
European cerebrospinal fluid consensus group--a TeamRoom (Lotus Notes)-based communication network.
A group of clinical neurochemists from all over Europe used TeamRoom to share information and to trace their discussions in a computer network. TeamRoom is a Lotus Notes based groupware tool enabling collaboration amongst geographically dispersed teams. As a result of this work a picture is emerging in the virtual TeamRoom space that represents a new kind of consensus in the use of cerebrospinal fluid analysis for diagnosis of neurological diseases. This kind of consensus differs from the conventional written report in giving a more complex and potentially richer representation of the field, in which both common views and minority perspectives are revealed. If direct access to this work is made available to other clinical neurochemists for consultation via a website, they may see their own practice in a wider context. This approach to improving different evolving traditions is more suitable for a global multicultural environment than a singular view of best practice produced by a more traditional process of group discussion. We refer to the benefits of a mixture of face to face meetings, collaboration in TeamRoom and teleconferencing for work in a non-hierarchical, multicultural and multilingual group. We suggest that the TeamRoom concept is a valuable model for enhancing self-organized harmonization across the developing European Union.
Computer Communication Networks↗
Affective startle modulation in clinical depression: preliminary findings.
BACKGROUND: Modulation of the startle reflex by affective foreground stimuli was investigated in a group receiving inpatient treatment for major depressive episodes (n = 14) and an age and gender matched nondepressed group (n = 14). METHODS: Participants viewed 27 pleasant, neutral, and unpleasant pictures chosen from the International Affective Picture System. Acoustic startle probes were presented during picture viewing, and participants also rated the affective qualities of the pictures. RESULTS: While ratings of the pictures were largely similar between the depressed and nondepressed groups, they displayed dissimilar patterns of startle modulation. In the nondepressed group, blinks elicited during unpleasant pictures were significantly larger than during pleasant pictures, whereas the depressed group failed to show this effect. Analyses, which separated the depressed participants into moderate and severe groups based on Beck Depression Inventory scores, revealed that while the moderately depressed group also showed a normal pattern of startle modulation, the severely depressed showed potentiated startles during the pleasant pictures. CONCLUSIONS: These preliminary results suggest that severely depressed patients may respond to some pleasant stimuli as if they are aversive, possibly because such stimuli are seen as signals of frustrative nonreward.
Acoustic Stimulation↗