Functional studies of specific imidazoline-2 receptor ligands.
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Animals↗
Biomedical subjects
H Jackson
Publications and source records attributed to H Jackson.
Incidence of acute symptomatic toxoplasma retinochoroiditis in south London according to country of birth.
OBJECTIVE: To determine the incidence of acute symptomatic toxoplasma retinochoroiditis presenting to ophthalmologists for patients born in Britain and elsewhere. DESIGN: Population based, cross sectional study. SETTING: 11 districts in south Greater London. SUBJECTS: All patients presenting to NHS ophthalmologists with symptoms due to acute toxoplasma retinochoroiditis in 1992-3. MAIN OUTCOME MEASURE: Intraocular inflammation in association with a retinochoroidal scar, active adjoining retinitis, and IgG serum antibodies to toxoplasma. RESULTS: The estimated incidence of acute symptomatic retinochoroiditis for all people born in Britain was 0.4/100,000/year. If a mean of two symptomatic episodes per lifetime is assumed, 100 people born in Britain may be affected each year, about a fifth of the estimated 500-600 congenitally infected people born each year. CONCLUSIONS: A substantial proportion of people with acute symptomatic toxoplasma retinochoroiditis were born outside the country, and the number born in Britain was smaller than the number previously estimated to develop retinochoroidal lesions due to congenital toxoplasmosis. These findings suggest that prenatal screening for toxoplasmosis in Britain may be of limited benefit.
Acute Disease↗
Orphan prevalence and extended family care in a peri-urban community in Zimbabwe.
An orphan enumeration survey was conducted in 570 households in and around Mutare, Zimbabwe in 1992; 18.3% (95% CI 15.1-21.5%) of households included orphans. 12.8% (95% CI 11.2-14.3%) of children under 15 years old had a father or mother who had died; 5% of orphans had lost both parents. Orphan prevalence was highest in a peri-urban rural area (17.2%) and lowest in a middle income medium density urban suburb (4.3%). Recent increases in parental deaths were noted; 50% of parental deaths since 1987 could be ascribed to AIDS. Orphan household heads were likely to be older and less well-educated than non-orphan household heads. The majority of orphaned children were being cared for satisfactorily within extended families, often under difficult circumstances. Caregiving by maternal relatives represents a departure from the traditional practice of caring for orphans within the paternal extended family and an adaptation of community-coping mechanisms. There was little evidence of discrimination or exploitation of orphaned children by extended family caregivers. The fact that community coping mechanisms are changing does not imply that extended family methods of caring are about to break down. However, the emergence of orphan households headed by siblings is an indication that the extended family is under stress. Emphasis needs to be placed upon supporting extended families by utilizing existing community-based organizations. Orphan support programmes may need to be established initially in high risk communities such as low-income urban areas and peri-urban rural areas.
Acquired Immunodeficiency Syndrome↗
A turnover study in the male rat of plasma-bound 59Fe, 114Inm and 109Cd with particular reference to the gonad.
After intravenous doses of the plasma-bound radionuclides 59Fe, 114Inm and 109Cd, only a minute percentage localizes in the rat testis and remains largely unchanged with time. Intratesticular injection of appropriately reduced volumes led to much higher proportionate percentage retention of 14, 65 and 11 for 59Fe, 114Inm and 109Cd, respectively. By this route, significant feedback of the elements escaping initial binding was prevented. Distinct but different testicular turnovers were now discernible. As a receptor of fluid and spermatozoa from the testicular tubules, the epididymis provides an indication of entry into and interaction of the metals with spermatogenic cells. For 59Fe no measurable changes were detected, whereas a progressive increase in epididymal 114Inm occurred, which had not reached a plateau by 70 days. 109Cd, now demonstrated within the testicular tubules by autoradiography, remained at constant organ level for upwards of 16 days but had declined by 25% by 57 days. At this point, the epididymis showed a five-fold increase in the radionuclide, declining to one-half this value by 126 days. Since 109Cd is carrier free, the data reflect a body turnover of dietary cadmium. These results, overall, are compatible with the entry of a proportion of each radionuclide into the seminiferous tubules and reaction with spermatogenic cells. Possible interpretations of the observed differences are presented.
Animals↗
Differential effects of transforming growth factor-beta 1 on distinct developmental stages of murine megakaryocytopoiesis.
The effect of transforming growth factor-beta 1 (TGF beta 1) on three developmental stages of megakaryocytopoiesis was investigated. Using a murine bone marrow agar culture system, titrated doses of TGF beta 1 were added to cultures assaying primitive high proliferative megakaryocyte progenitors, committed megakaryocyte precursors, and nondividing, endoreduplicating megakaryocytes. The growth of high proliferative megakaryocyte colony-forming cells (HPP-CFU-Mk) that require the growth factors interleukins-1, 3 and 6 (IL-1 + IL-3 + IL-6) for colony detection was abrogated by the addition of 1 ng TGF beta 1/ml. The sensitivity of committed megakaryocyte progenitors (colony-forming unit-megakaryocyte, CFU-Mk) to TGF beta 1 depended on the growth factor combination. TGF beta 1 (1 ng/ml) completely inhibited megakaryocyte colony formation from CFU-Mk only in cultures stimulated by low doses of IL-3. TGF beta 1 (> 10 ng/ml) could only marginally inhibit megakaryocyte colony formation generated in the presence of either high doses of IL-3 or the combination of low dose IL-3 + IL-6. TGF beta 1 inhibited both IL-3-dependent and IL-6-dependent megakaryocyte growth but tenfold higher doses of TGF beta 1 were required to inhibit growth generated by the combination of IL-3 + IL-6. The data showed that the capacity of TGF beta 1 to inhibit distinct differentiation stages of the megakaryocytopoietic lineage depended on the concentration and combination of growth factors involved.
Animals↗
Outpatient management of small traumatic hyphaemas.
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Adolescent↗
Does topical flurbiprofen affect the pupillary response to acetylcholine?
Pre-operative topical non-steroidal anti-inflammatory drugs (NSAIDs) are known to be effective in maintaining pupillary dilation during cataract surgery. However, previous studies have suggested that pre-treatment with these agents interferes with the miosis produced by intraoperative acetylcholine injection. This study was designed to determine whether the pupillary response to acetylcholine injection is reduced following pre-operative topical flurbiprofen 0.03%. Pupil diameters were measured with a millimetre rule, and the measurements verified using computerised image analysis of digitised video images. Eyes treated with flurbiprofen were compared with controls. There was no significant difference in pupillary diameter before corneal incision, but following aspiration of soft lens matter and insertion of intraocular lens the pupil was significantly larger in the flurbiprofen group (p = 0.002). At 1.0, 2.5 and 5.0 minutes following injection of acetylcholine no significant difference in the degree of miosis was detected. This study confirms that topical flurbiprofen maintains dilation during cataract surgery, and does not find any evidence to suggest that intra-operative response to acetylcholine is reduced.
Acetylcholine↗
The curriculum revolution: what do all those buzz words really mean?
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Curriculum↗
The role of interleukin 6 in megakaryocyte formation, megakaryocyte development and platelet production.
Megakaryocytopoiesis is the cellular amplification and differentiation of precursors into immature megakaryocytes, and the cytoplasmic maturation of these megakaryocytes, a process terminating in the release of platelets into the circulation. Interleukin 6 (IL-6) stimulates megakaryocytopoiesis in the bone marrow, increasing platelet numbers in the circulation. IL-6 alone is poorly active on the growth of stem cell populations, but acts in synergy with stem cell factor (c-kit ligand) to expand the committed myeloid progenitor compartments but not the megakaryocyte progenitors. IL-6 has a direct action on megakaryocyte progenitors but only in synergy with low doses of interleukin 3 (IL-3), increasing the number of immature megakaryocytes and enhancing the processes of development into mature megakaryocytes. IL-6 is about 10 times more active on megakaryocytes than on megakaryocyte progenitors in cell culture. It is active alone and will stimulate increases in cell size and DNA content. IL-6 does not appear to stimulate the process of platelet release. IL-6 is found in bone marrow, in both macrophage subsets and megakaryocytes, indicating that it may be an important physiological regulator of both paracrinal (microenvironmental) and autocrinal mechanisms controlling megakaryocyte development in bone marrow.
Animals↗
A comparative binding of platinum anti-tumour compounds to plasma proteins in the rat (in vivo) and mouse (in vitro).
Plasma protein binding of 195mPt-labelled cisplatin, carboplatin and iproplatin has been studied in vivo in rat and in vitro in mouse, using both electrophoresis and trichloroacetic acid precipitation. After intravenous injection plasma clearance rates were biphasic for all 3 compounds, (t1/2 alpha, 13-17 min) but cisplatin was retained thereafter longer than the others. By 5 min, gel electrophoresis showed protein labelling with all 3 drugs but none involved low mol.wt. proteins (< 16 kDa). At 2 h a notable proportion of the protein bound platinum was associated with the latter components. There was a general resemblance between the distribution patterns of cisplatin and carboplatin whereas iproplatin showed a persistent retention of the label with time to higher mol. wt. proteins. From in vitro incubation with mouse plasma, rates of interaction respectively were cisplatin t1/2 alpha, 35 min, beta 8 h, carboplatin t1/2, 44 h and iproplatin t1/2, 104 h. By electrophoresis the protein bound fraction pattern (1 h) was again similar for cisplatin and carboplatin with virtually no binding to low mol. wt. proteins. After 24 h these were now involved to a high degree (40%). Iproplatin showed relatively marked binding to proteins of higher mol. wt. but no transfer with time to the low mol. wt. protein zone. A possible explanation is the need for in vivo metabolism for this compound as manifest in the rat. It is suggested that the significance of interaction with low mol. wt. proteins merits further investigation in relation to the antitumour and toxicological actions of these drugs.
Animals↗
A highly potent and selective N-methyl-D-aspartate receptor antagonist from the venom of the Agelenopsis aperta spider.
Agatoxin-489, extracted from the venom of the Agelenopsis aperta spider, was studied on acutely isolated perfused hippocampal neurons of rat using the concentration clamp technique. Agatoxin-489 proved to be a selective N-methyl-D-aspartate antagonist; responses to applications of N-methyl-D-aspartate or L-aspartate were blocked by concentrations of agatoxin-489 ranging between 0.1 nM and 1 microM, while responses to kainate were not affected by agatoxin-489 at concentrations up to 10 microM. The actions of agatoxin-489 against responses to N-methyl-D-aspartate or L-aspartate were use- and voltage-dependent, being less pronounced with an increase in the holding potential from -100 to -30 mV. The action of agatoxin-489 could be completely or partially reversed only after washout in the presence of an N-methyl-D-aspartate agonist. The washout was more effective at positive membrane potentials ranging from 0 to +20 mV. These results imply that the spider toxin agatoxin-489, like dizocilpine, is a potent and selective N-methyl-D-aspartate antagonist which preferentially interacts with activated N-methyl-D-aspartate receptors and/or open N-methyl-D-aspartate-activated ionic channels.
Agatoxins↗
Symptomatic response to antipsychotics differs between recent onset and recurrent chronic schizophrenic patients.
The symptomatic response to standard antipsychotic treatment was assessed over the first 4 weeks of hospitalisation in 39 patients with DSM-III schizophrenia, active phase, using the Brief Psychiatric Rating Scale (BPRS). While highly significant improvement was noted overall, 36% of patients either did not improve or worsened. Furthermore there was no diminution in the withdrawal-retardation factor of the BPRS. Patients experiencing their first admission to hospital, all with recent-onset illness, were then compared with patients who presented with a recurrence and had illness of at least 3 years duration. Despite similarities in overall response, withdrawal-retardation scores did not diminish in recent-onset patients, in contrast to multiple admissions who demonstrated significant improvement. These findings suggest greater responsiveness of negative symptoms to treatment in patients with longstanding illness, and possibly a poorer prognosis in first admission patients with deficit manifestations.
Acute Disease↗
Cell-targeted 114Inm and drug (BCNU) combination therapy in a rat acute lymphoblastic leukaemia.
A proportion of syngeneic female rats inoculated intramuscularly with a lethal T-cell lymphoblastic (Roser) leukaemia are cured by a single intraperitoneal injection of bischloroethylnitrosourea (BCNU) (Carmustine) (10 mg kg-1) given towards the end of the preleukaemic phase (day 7). Additional therapy on day 4, using intravenous leukaemia cells lethally labelled with the radionuclide 114Inm, enhanced the overall cure rate by 30%. The spleen is a major site of indium concentration from the targeting cells so that the continuous local radiation field appears to result in a substantial reduction of the body load of leukaemia cells in the enlarged spleen particularly, thus enhancing the curative potential of the drug. The results demonstrate in principle that in patients in remission a single dose of targeted radiotherapy in the spleen combined sequentially with an appropriate drug might provide considerable aid in eliminating a residual population of leukaemia cells.
Animals↗
The nature of an accessory cell in bone marrow stimulating murine megakaryocytopoiesis.
The nature of accessory cells in unstimulated mouse bone marrow that modulates in vitro megakaryocytopoiesis by releasing megakaryocyte potentiator (Mk-potentiator) activity was investigated. An active cell class was identified by the 7/4 and Ia cellular antigens. Bone marrow macrophages were obtained by their defined outgrowth in the presence of growth factors. Bone marrow macrophages grown in the presence of interleukin 3 (IL-3) were more active in producing Mk-potentiator than were macrophages grown in the presence of colony-stimulating factor 1 (CSF-1). The data indicate that the accessory cells producing Mk-potentiator are a select population of bone marrow macrophages that may be responsible for inducing megakaryocyte maturation under steady-state conditions.
Animals↗
Interleukin 3 directly stimulates both megakaryocyte progenitor cells and immature megakaryocytes.
A subset of stem cell antigen (sca-1)-positive mouse megakaryocyte progenitors was identified that correlates with other primitive precursors in bone marrow. The responsive bone marrow cells were obtained by depleting the marrow of cells bearing defined lineage markers (neutrophils, macrophages, and lymphoid cells) and enriched for primitive myeloid progenitor cells with high proliferative potential, selecting for cells expressing sca-1. The sca-1-positive megakaryocyte progenitors formed colonies in the presence of interleukin 3 (IL-3) alone. Immature megakaryocytes depleted of mature megakaryocytes and of cells expressing myeloid and lymphoid lineage markers were also responsive to IL-3. These data indicate that in the presence of high doses of IL-3, accessory cells are not obligatory for growth factor stimulation of megakaryocytopoiesis in vitro.
Animals↗
Arylamine toxins from funnel-web spider (Agelenopsis aperta) venom antagonize N-methyl-D-aspartate receptor function in mammalian brain.
The venom of the North American funnel-web spider Agelenopsis aperta contains a variety of arylamine toxins (the alpha-agatoxins) that paralyze insects by blocking glutamatergic neuromuscular transmission. We have tested six synthetic alpha-agatoxins for their ability to antagonize glutamate receptor function in mammalian brain. These compounds produce, at submicromolar concentrations, noncompetitive inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated elevations in the concentration of cytosolic free calcium in cultured rat cerebellar granule neurons. In contrast, the alpha-agatoxins are relatively weak antagonists of elevations in the cytosolic free calcium concentration induced by non-NMDA receptor agonists. The alpha-agatoxins also produce reversible suppression of the NMDA receptor-mediated excitatory postsynaptic potential in rat hippocampal slices at concentrations that have little effect on the non-NMDA receptor-mediated population spike. We conclude that the alpha-agatoxins are selective and reversible noncompetitive antagonists at NMDA receptors in mammalian brain.
Animals↗
Arylamine spider toxins antagonize NMDA receptor-mediated synaptic transmission in rat hippocampal slices.
The effects of arylamine spider toxins on synaptic transmission in rat hippocampal slices were investigated. Two different responses were monitored: the AMPA receptor-mediated population spike recorded in control buffer (selectively antagonized by DNQX) and the NMDA receptor-mediated EPSP recorded in nominally magnesium-free buffer containing 20 microM DNQX (selectively antagonized by AP5, AP7, and dizocilpine (MK-801)). The synthetic arylamine spider toxins JSTX-3, argiotoxin-636, and argiotoxin-659 were 26 to 73 times more potent at antagonizing the NMDA receptor-mediated EPSP (IC50 values ranging from 12 to 24 microM) than the AMPA receptor-mediated population spike (IC50 values ranging from 612 to 878 microM). These results indicate that arylamine spider toxins are selective antagonists of NMDA receptors in the mammalian CNS.
Animals↗
Lymphocyte subpopulations in pyogranulomas of caseous lymphadenitis.
Pyogranulomas of ovine caseous lymphadenitis (CLA) are encapsulated lesions resulting from infections with Corynebacterium pseudotuberculosis, a bacterial pathogen able to grow within macrophages. Immunohistology of CLA lesions showed a band of lymphocytes lining the inside of the collagen capsule in intimate contact with necrotic tissue, the intracapsular lymphocytes being organized into three layers. The innermost layer, immediately adjacent to the central necrotic tissue consisted of a narrow band of MHC class II staining macrophages. Cells staining for CD4, CD8 and gamma delta T cell markers were unevenly distributed throughout the lymphoid layer, tending to be more numerous immediately external to the macrophage layer. The intracapsular lymphoid tissue contained a high proportion of CD8+ lymphocytes (CD4:CD8, 1.5:1) and of gamma delta lymphocytes (CD4:CD8:gamma delta, 1:0.7:0.8). External to the T cell-rich zone and adjacent to the surrounding collagen capsule was a dense band of cells, a proportion of which stained atypically for CD45R and were tentatively identified as B cells. CD8+ and gamma delta+ T cells showed similar distributions and their relative abundance, compared with CD4+ T cells, was a distinguishing feature of the CLA lesion. Staining for factor VIII-related antigen clearly showed endothelial venules throughout the intracapsular lymphoid tissue. The presence of endothelial venules and the organized architecture of the lymphoid tissue teleologically argues that lymphocytes are continually recruited into chronic CLA lesions and play an important role in the ongoing disease process.
Animals↗