Zoster gangrenosum: necrotizing fasciitis as a complication of herpes zoster.
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Adult↗
Biomedical subjects
S R Jones
Publications and source records attributed to S R Jones.
Molecular mechanisms involved in the estrogen-dependent regulation of calcineurin in systemic lupus erythematosus T cells.
Previous experiments in our laboratory indicated that calcineurin expression and PP2B phosphatase activity increased when estrogen was cultured with SLE T cells but not with T cells from normal women. In this report we extended our findings to show that estrogen receptor (ER) antagonism by ICI 182,780 inhibited the estrogen-dependent increase in calcineurin mRNA and phosphatase PP2B activity indicating that estrogen action was mediated through the ER. Inhibition of de novo protein synthesis with cycloheximide suggested that the estrogen-dependent increase in T cell calcineurin mRNA was a direct effect of the ER and new protein synthesis was not required. Estrogen increased calcineurin mRNA in systemic lupus erythematosus (SLE) T cells at 6 h after the start of culture correlating with increased phosphatase activity at this same time. Phosphatase activity increased significantly (P < 0.02) in lupus T cells cultured for 8 h in estradiol-containing medium. Reverse transcription and polymerase chain amplification revealed that ER-beta and ER-alpha were expressed in female and male T cells from SLE patients and normal controls. However, calcineurin steady-state mRNA levels were unaffected by estradiol in cultured T cells from male SLE patients and normal male and female controls. These data indicate that estrogen, bound to the ER, evokes a direct increase in calcineurin expression in T cells from female lupus patients. This gender-specific response suggests that ER function is altered in women with the female predominant autoimmune disease, SLE.
Adolescent↗
Bone histomorphometric and biomechanical abnormalities in mice homozygous for deletion of the dopamine transporter gene.
Dopamine (DA) has been reported to have effects on calcium and phosphorus metabolism. The dopamine transporter (DAT) is believed to control the temporal and spatial activity of released DA by rapid uptake of the neurotransmitter into presynaptic terminals. We have evaluated the histologic and biomechanical properties of the skeleton in mice homozygous for deletion of the DA transporter gene (DAT) to help delineate the role of DA in bone biology. We have demonstrated that DAT-/-mice have reduced bone mass and strength. DAT-/- animals had shorter femur length and dry weight. Ash calcium content of the femur was 32% lower in the DAT-/- mice than in the wild-type animals. Cancellous bone volume in the proximal tibial metaphysis was significantly lower in the DAT-/- animals (p < 0.04). There was a 32% reduction in trabecular thickness (p = NS). For the vertebrae, cancellous bone volume was again lower in the DAT-/- animals compared with wild-type as a consequence of increased trabecular spacing (p < 0.05) and reduced trabecular number (p < 0.05). Cortical thickness and bone area in the femoral diaphysis were reduced in the DAT-/-animals. The ultimate bending load (femoral strength) for the DAT-/- mice was 30% lower than the wild-type mice (p = 0.004). Thus, deletion of the DAT gene results in deficiencies in skeletal structure and integrity.
Animals↗
Aminosterols from the dogfish shark Squalus acanthias.
Seven new aminosterols related to squalamine (8) were isolated from the liver of the dogfish shark Squalus acanthias. Their structures (1-7) were determined using spectroscopic methods, including 2D NMR and HRFABMS. These aminosterols possess a relatively invariant cholestane skeleton with a trans AB ring junction, a spermidine or spermine attached equatorially at C3, and a steroidal side-chain that may be sulfated. The structure of the lone spermine conjugate, 7 (MSI-1436), was confirmed by its synthesis from (5alpha,7alpha, 24R)-7-hydroxy-3-ketocholestan-24-yl sulfate. Some members of this family of aminosterols exhibit a broad spectrum of antimicrobial activity comparable to squalamine.
Animals↗
Mice lacking the norepinephrine transporter are supersensitive to psychostimulants.
The action of norepinephrine (NE) is terminated, in part, by its uptake into presynaptic noradrenergic neurons by the plasma-membrane NE transporter (NET), which is a target for antidepressants and psychostimulants. Disruption of the NET gene in mice prolonged the clearance of NE and elevated extracellular levels of this catecholamine. In a classical test for antidepressant drugs, the NET-deficient (NET-/-) animals behaved like antidepressant-treated wild-type mice. Mutants were hyper-responsive to locomotor stimulation by cocaine or amphetamine. These responses were accompanied by dopamine D2/D3 receptor supersensitivity. Thus altering NET expression significantly modulates midbrain dopaminergic function, an effect that may be an important component of the actions of antidepressants and psychostimulants.
Amphetamine↗
Environmental effects of radionuclides--observations on natural ecosystems.
To better quantify risk to non-human species from exposure to environmental radioactivity, understanding of the behaviour of radionuclides in the biosphere needs to be increased. This study outlines current thinking on ecological risk assessment (ERA) methodology and applies the indicator species or critical groups approach to biota inhabiting a semi-natural coniferous woodland contaminated with the radionuclides 137Cs, 238Pu, 239+240Pu and 241Am. The majority of these radionuclides originate from routine aerial emissions from the nuclear fuel reprocessing plant at BNFL, Sellafield, Cumbria, UK. Radionuclide activity concentrations have been determined in biota from the woodland and estimates of absorbed dose rates (mGy d(-1)) have been calculated using the dosimetric models outlined. Dose rates to the key indicator species, Oniscus asellus, Carabus violaceous and Apodemus sylvaticus (detritivorous invertebrate, predatory invertebrate and the granivorous wood mouse) have been determined at 3.0 x 10(-3) mGy d(-1), 2.2 x 10(-3) mGy d(-1) and 1.0 x 10(-3) mGy d(-1) respectively. The values are at least three orders of magnitude lower than the 1 mGy d(-1) level below which no observable effects on populations in a terrestrial ecosystem are thought to occur. Limitations of this approach are discussed.
Animals↗
Changes in the temporal and spatial expression of H beta 58 during formation and maturation of the chorioallantoic placenta in the Rat.
Cloning and sequencing of a cDNA amplified by RNA fingerprinting at the implantation site of pregnant rats revealed 80% similarity with H beta 58, previously shown to be essential for formation of the chorioallantoic placenta in the mouse. H beta 58 mRNA was detected in the endometrium of hormonally sensitized rats stimulated to undergo decidualization and in the contralateral uterine horns lacking a decidual stimulus, indicating that uterine expression of H beta 58 mRNA did not require decidualization or the presence of a blastocyst. Immunodetection in the early postimplantation uterus (Days 6-8 of pregnancy) showed H beta 58 localized in the luminal and glandular epithelia and some stromal cells. Decidual cells at Day 6 of pregnancy expressed H beta 58, and by Day 9 of pregnancy, the protein localized throughout the maternal decidua. The temporal and spatial distribution of H beta 58 in the developing chorioallantoic placenta was assessed at Days 10, 12, and 14 of pregnancy. Immunoreactive H beta 58 localized to erythroid cells within the developing fetal vasculature of the chorioallantoic primordia at Day 10 of pregnancy. By Day 12, the fetal vasculature extended into the placental labyrinth, and the erythroid stem cells continued to strongly express H beta 58. At Day 14 of pregnancy, immunoreactivity became evident in the trophoblast giant cells and syncytiotrophoblast of the fetal placenta. As the chorioallantoic placenta matured (Day 18), H beta 58 mRNA was 3.6-fold higher in the labyrinth compared with the junctional region. Stable cell lines (HRP/LRP) isolated from the rat labyrinthine placenta expressed H beta 58 mRNA and protein. The expression pattern of H beta maternal and fetal placental tissues and its early expression in fetal erythroid stem cells during formation and maturation of the chorioallantoic placenta suggest that H beta 58 plays key roles in the regulatory networks that control hematopoietic development and placentation.
Allantoin↗
Transit of normal rat uterine stromal cells through G1 phase of the cell cycle requires progesterone-growth factor interactions.
Understanding of cell cycle regulation in hormonally responsive cells lags behind studies in other systems because few models have been available to identify the role of steroid hormones and their receptors in this process. This study investigates progesterone-dependent effects on the progression of normal uterine stromal cells through early G1 phase of the cell cycle. Quiescent rat uterine stromal cells were stimulated to reenter the cell cycle by adding serum-free medium containing medroxyprogesterone acetate (MPA) and basic fibroblast growth factor (FGF). [3H]thymidine incorporation increased significantly (P = 0.025) in cells stimulated with both FGF alone and MPA plus FGF compared with the control cells. Moreover, cells stimulated with MPA plus FGF incorporated significantly more (P = 0.01) [3H]thymidine than cells treated with FGF alone, suggesting requisite interactions between progesterone and FGF for stromal cell entry into S phase. Flow cytometric analysis of stimulated stromal cells showed FGF alone and MPA plus FGF increased significantly (P = 0.002) the percentage of cells in S phase at 12 h. Incorporation of bromodeoxyuridine into stromal cell nuclei indicated that FGF alone and MPA plus FGF increased the percentage of cells entering S phase at 18 and 24 h compared with the control cells. In addition, MPA plus FGF increased significantly (P = 0.001) the number of cells entering S phase at 24 h compared with FGF alone and sustained S phase entry compared with FGF alone, MPA alone, or the control cells. Stromal cells inhibited from G1 reentry by inhibition of mitosis showed accelerated entry into S phase in response to MPA plus FGF compared with FGF alone. Cyclin D1 messenger RNA increased in stromal cells treated with MPA plus FGF at 9, 12, and 15 h. Addition of RU 486 to cells stimulated with MPA plus FGF for 9 h reduced cyclin D1 messenger RNA accumulation by 40%. Western blot analysis of cyclin D1 immunoprecipitates indicated complex formation with both cyclin-dependent kinase 4 (Cdk4) and cyclin dependent kinase 6 (Cdk6). Cyclin D1-Cdk complexes and kinase activity correlated temporally with increased cyclin D1 expression in cells cultured with MPA plus FGF. Taken together, these results show that progesterone-FGF interactions increase cyclin D1 expression, correlating with accelerated stromal cell entry into S phase compared with cells treated with FGF alone. Moreover, progesterone plus FGF sustains the timing of stimulation for transit of uterine stromal cells through G1 into S phase compared with FGF alone.
Animals↗
Radionuclide behaviour and transport in a coniferous woodland ecosystem: vegetation, invertebrates and wood mice, Apodemus sylvaticus.
Activity concentrations of radionuclides (134Cs, 137Cs, 238Pu, 239 + 240Pu and 241Am) were measured in vegetation, invertebrates and wood mice, Apodemus sylvaticus, collected in Lady Wood, a coniferous woodland in the vicinity of the British Nuclear Fuels reprocessing plant at Sellafield, Cumbria, UK. Vegetation was of low diversity and biomass with activity concentrations ranging from 1 to 5 Bq kg-1 (134Cs), 0.3-0.5 Bq kg-1 (238Pu), 0.8-8 Bq kg-1 (239 + 240Pu), and 0.6-16 Bq kg-1 (241Am), dry wt. Caesium-137 activity concentrations were high compared to the reference site in Cheshire, varying between 65 and 280 Bq kg-1. Marked inter-specific and temporal differences in radionuclide activity concentrations were recorded for invertebrate populations. Caesium-137, 238Pu, 239 + 240Pu and 241Am activity concentrations in detritivorous invertebrates were consistently higher than in all other invertebrate groups reflecting contamination of the leaf litter. The activity concentrations in detritivores increased during the autumn and winter, reflecting changes in diet as food sources varied throughout the year. Activity concentrations in invertebrates caught in Lady Wood were generally an order of magnitude higher than for the reference site. Activity concentrations in wood mice varied between 7 and 150 Bq kg-1 (137Cs), 0.1-0.3 Bq kg-1 (238Pu), 0.1-0.6 Bq kg-1 (239 + 240Pu) and 0.2-0.4 Bq kg-1 (241Am). There were clear differences in the activity concentration of 137Cs (P < 0.01), 239 + 240Pu (P < 0.05) and 241Am (P < 0.05) in animals caught in Lady Wood compared to the reference site. However, the activity concentrations for 238Pu were similar at both sites, reflecting a low gastrointestinal transfer. Seasonal variation in activity concentrations was observed for 137Cs, 238Pu and 241Am. This variation is attributed to changes in the age structure of the population and diet throughout the year.
Americium↗
Functional hyperdopaminergia in dopamine transporter knock-out mice.
Dopamine is an important regulator of many central nervous system functions. Hyperfunction of the dopaminergic system is believed to be related to several pathological conditions. Genetic deletion of the dopamine transporter gene in mice results in a persistent extracellular hyperdopaminergic tone, that is functionally revealed as hyperactivity. The lack of a reuptake mechanism produces a marked increase in functional extracellular dopamine which results in profound plasticity of pre- and postsynaptic parameters of dopamine homeostasis. The mice lacking the dopamine transporter gene may represent an appropriate model to elucidate the molecular adaptive changes accompanying pathological states associated with hyperdopaminergic function.
Animals↗
Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity.
The mechanism by which psychostimulants act as calming agents in humans with attention-deficit hyperactivity disorder (ADHD) or hyperkinetic disorder is currently unknown. Mice lacking the gene encoding the plasma membrane dopamine transporter (DAT) have elevated dopaminergic tone and are hyperactive. This activity was exacerbated by exposure to a novel environment. Additionally, these mice were impaired in spatial cognitive function, and they showed a decrease in locomotion in response to psychostimulants. This paradoxical calming effect of psychostimulants depended on serotonergic neurotransmission. The parallels between the DAT knockout mice and individuals with ADHD suggest that common mechanisms may underlie some of their behaviors and responses to psychostimulants.
Animals↗
Application of microdialysis and voltammetry to assess dopamine functions in genetically altered mice: correlation with locomotor activity.
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Animals↗
Loss of autoreceptor functions in mice lacking the dopamine transporter.
Autoreceptors provide an important inhibitory feedback mechanism for dopamine neurons by altering neuronal functions in response to changes in extracellular levels of dopamine. Elevated dopamine may be a component of several neuropsychiatric disorders. However, evidence concerning the state of autoreceptors in such conditions has remained elusive. The function of dopamine autoreceptors was assessed in mice lacking the dopamine transporter (DAT). Genetic deletion of the DAT gene in mice results in a persistent elevation in levels of extracellular dopamine. Direct assessment of impulse-, synthesis- and release-regulating autoreceptors in these mice reveals a nearly complete loss of function. These findings may provide insight into the neurochemical consequences of hyperdopaminergia.
3,4-Dihydroxyphenylacetic Acid↗
Dopamine neuronal transport kinetics and effects of amphetamine.
The dopamine (DA) transporter (DAT) regulates DA neurotransmission by recycling DA back into neurons. Drugs that interfere with DAT function, e.g., cocaine and amphetamine, can have profound behavioral effects. The kinetics of DA transport by DAT in isolated synaptosomal or single cell preparations have been previously studied. To investigate how DA transport is regulated in intact tissue and to examine how amphetamine affects the DAT, the kinetics of DA uptake by the DAT were examined in tissue slices of the mouse caudate-putamen with fast-scan cyclic voltammetry. The data demonstrate that inward DA transport is saturable and sodium-dependent. Elevated levels of cytoplasmic DA resulting from disruption of vesicular storage by incubation with 10 microM Ro 4-1284 did not generate DA efflux or decrease its uptake rate. However, incubation with 10 microM amphetamine reduced the net DA uptake rate and increased extracellular DA levels due to DA efflux through the DAT. In addition, a new, elevated steady-state level of extracellular DA was established after electrically stimulated DA release in the presence of amphetamine, norepinephrine, and exogenous DA. These results from intact tissue are consistent with a kinetic model of the DAT established in more purified preparations in which amphetamine and other transported substances make the inwardly facing DAT available for outward transport of intracellular DA.
Amphetamines↗
Visual perception of motion, luminance and colour in a human hemianope.
Human patients rendered cortically blind by lesions to V1 can nevertheless discriminate between visual stimuli presented to their blind fields. Experimental evidence suggests that two response modes are involved. Patients are either unaware or aware of the visual stimuli, which they are able to discriminate. However, under both conditions patients insist that they do not see. We investigate the fundamental difference between percepts derived for the normal and affected hemifield in a human hemianope with visual stimuli of which he was aware. The psychophysical experiments we employed required the patient, GY, to make comparisons between stimuli presented in his affected and normal hemifields. The subject discriminated between, and was allowed to match, the stimuli. Our study reveals that the stimulus parameters of colour and motion can be discriminated and matched between the normal and blind hemifields, whereas brightness cannot. We provide evidence for associations between the percepts of colour and motion, but a dissociation between the percepts of brightness, derived from the normal and hemianopic fields. Our results are consistent with the proposal that the perception of different stimulus attributes is expressed in activity of functionally segregated visual areas of the brain. We also believe our results explain the patient's insistence that he does not see stimuli, but can discriminate between them with awareness.
Adult↗
Virulence and antigenic characteristics of a cultured Rickettsiales-like organism isolated from farmed Atlantic salmon Salmo salar in eastern Canada.
The present study describes culture, virulence and antigenic characteristics of a Rickettsiales-like organism (RLO) associated with mortality in farmed Atlantic salmon in eastern Canada. Clinical disease was reproduced in naive Atlantic salmon parr by intraperitoneal i.p. inoculation with kidney homogenate from naturally infected fish. Pure cultures of RLO were isolated into chinook salmon embryo (CHSE) cells from kidney of experimentally infected fish. The RLO caused cytopathic effect in cultured CHSE-214 typified by coalescing areas of swollen cells that eventually detached from the substrate. Bacteria in infected culture supernatants reacted with Piscirickettsia salmonis-specific polyclonal sera or monoclonal antibody (MAb) in an indirect fluorescent antibody test. IP inoculation with cultured RLO resulted in mortalities of 100, 62, 22.5 and 0% in Atlantic salmon, coho salmon, rainbow trout and common carp, respectively. Cultured RLO were sensitive to chloramphenicol, flumequine, oxytetracycline and oxolinic acid and insensitive to gentamicin and amphotericin B. RLO antigens were compared with those of 3 strains of P. salmonis from Chilean salmon by SDS-PAGE and immunoblotting. A silver-staining band of about 12 kDa was detected in proteinase K (PK) digests of all RLO strains, and a diffuse band of about 15 kDa was observed in 2 Chilean strains only. No other silver-stained bands were visible in PK digests of any strain examined. The polyclonal serum recognized 9 protein bands and multiple non-protein bands extending from less than 20 kDa to greater than 95 kDa in all isolates. The MAb reacted with an epitope in PK digests that occurred in all 4 strains on structures of widely ranging molecular masses, resulting in a ladder pattern similar to that obtained with polyclonal serum. Treatment of PK digests with periodic acid abolished reactivity with MAb and polyclonal serum. Co-elution of 2-keto-3-deoxyoctonate and MAb reactivity following size exclusion chromatography of solubilized P. salmonis suggested that the MAb recognized a lipopolysaccharide-associated epitope in all 4 RLO isolates. Cultural, virulence and antigenic similarities among the strains examined in the present study indicate that the eastern Canadian salmonid RLO should be considered a strain of P. salmonis.
Alphaproteobacteria↗
Profound neuronal plasticity in response to inactivation of the dopamine transporter.
The dopamine transporter (DAT) plays an important role in calibrating the duration and intensity of dopamine neurotransmission in the central nervous system. We have used a strain of mice in which the gene for the DAT has been genetically deleted to identify the DAT's homeostatic role. We find that removal of the DAT dramatically prolongs the lifetime (300 times) of extracellular dopamine. Within the time frame of neurotransmission, no other processes besides diffusion can compensate for the lack of the DAT, and the absence of the DAT produces extensive adaptive changes to control dopamine neurotransmission. Despite the absence of a clearance mechanism, dopamine extracellular levels were only 5 times greater than control animals due to a 95% reduction in content and a 75% reduction in release. Paradoxically, dopamine synthesis rates are doubled despite a decrease of 90% in the levels of tyrosine hydroxylase and degradation is markedly enhanced. Thus, the DAT not only controls the duration of extracellular dopamine signals but also plays a critical role in regulating presynaptic dopamine homeostasis. It is interesting to consider that the switch to a dopamine-deficient, but functionally hyperactive, mode of neurotransmission observed in mice lacking the DAT may represent an extreme example of neuronal plasticity resulting from long-term psychostimulant abuse.
Animals↗
Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter.
Amphetamine (AMPH) inhibits uptake and causes release of dopamine (DA) from presynaptic terminals. AMPH can act on both vesicular storage of DA and directly on the dopamine transporter (DAT). To assess the relative importance of these two processes, we have examined the releasing actions of AMPH in mice with a genetic deletion of the DAT. The sequence of actions of AMPH has been determined by following the real time changes of DA in the extracellular fluid of intact tissue with fast scan cyclic voltammetry. In striatal slices from wild-type mice, AMPH causes a gradual (approximately 30 min) increase in extracellular DA, with a concomitant disappearance of the pool of DA available for depolarization-evoked release. Conversely, in slices from mice lacking the DAT, although a similar disappearance of electrically stimulated DA release occurs, extracellular DA does not increase. Similarly, microdialysis measurements of DA after AMPH in freely moving animals show no change in mice lacking the DAT, whereas it increases 10-fold in wild-type mice. In contrast, redistribution of DA from vesicles to the cytoplasm by the use of a reserpine-like compound, Ro4-1284, does not increase extracellular DA in slices from wild-type animals; however, subsequent addition of AMPH induces rapid (<5 min) release of DA. Thus, the DAT is required for the releasing action, but not the vesicle-depleting action, of AMPH on DA neurons, and the latter represents the rate-limiting step in the effects of AMPH. Furthermore, these findings suggest that in the absence of pharmacological manipulation, such as the use of amphetamine, endogenous cytoplasmic DA normally does not reach sufficient concentrations to reverse the DAT.
2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗